This document discusses the neurobiological basis of alcohol dependence. It covers topics like alcohol pharmacokinetics and pharmacodynamics, how alcohol affects neurotransmitter systems like GABA, glutamate, dopamine, serotonin, endogenous opioids, and more. It explains how the reinforcing effects of alcohol are mediated by these systems and the brain's reward circuitry. The document also discusses tolerance, withdrawal, and how chronic alcohol exposure leads to neuroadaptations in these systems.
This document discusses the role of glutamate in psychiatry. It notes that glutamate is the major excitatory neurotransmitter in the brain and is involved in memory, emotions, cognition, and various psychiatric conditions like depression, anxiety, schizophrenia, and drug addiction. It then discusses the specific implications of glutamate for anxiety disorders, mood disorders, addiction disorders, and schizophrenia. Finally, it outlines the future implications of targeting glutamate systems for the treatment of these conditions, noting potential drug candidates and the promise of drugs like ketamine for rapidly treating depression.
EEG is a non-invasive method to measure electrical activity in the brain. It can help in psychiatry by ruling out physical causes for psychiatric symptoms, aiding in differential diagnosis and treatment selection, and predicting prognosis. EEG findings can provide clues to underlying conditions in disorders like schizophrenia, mood disorders, OCD, panic attacks, dementia, delirium, and substance abuse. However, EEG findings in psychiatry are often nonspecific and EEG has limitations due to only recording cortical activity from the scalp. It currently has no definitive role in diagnosing Axis I or II psychiatric disorders.
This document summarizes various neurological effects of alcoholism. It discusses acute alcoholic intoxication, alcohol withdrawal including seizures, hallucinations, and delirium tremens. It also covers nutritional deficiencies that can occur like Wernicke-Korsakoff syndrome and neurological complications of uncertain etiology. Specific conditions related to alcoholism are explained such as encephalopathy, trauma, strokes and others. The effects of alcohol on neurotransmitter systems are outlined. Features of alcohol withdrawal syndrome and delirium tremens are defined. Management of withdrawal and complications are addressed.
This document discusses the neurobiology of addiction. It provides an overview of neurotransmission, including action potentials, the neurotransmitter lifecycle, and receptor types. Specific neurotransmitters are examined, such as dopamine, GABA, glutamate, and opioids. The roles of these neurotransmitters in addiction and how various drugs affect neurotransmitter systems are described. Genetic and environmental factors that can contribute to addiction are also reviewed.
This document discusses the anatomy and functional areas of the frontal lobe and their relation to psychiatry. It begins with the anatomical structures of the frontal lobe including the lateral, medial and orbital surfaces. It then covers the primary functional areas - primary motor cortex, premotor cortex, supplementary motor cortex, frontal eye fields, Broca's area, and the prefrontal cortex including dorsolateral, dorsomedial and orbital regions. Neuropsychiatric disorders are discussed like frontal lobe syndrome, traumatic brain injury, frontotemporal dementia, and the relationships between the frontal lobe and conditions like schizophrenia, depression, ADHD, OCD, and alcohol use. Assessment techniques are also covered.
Neurotransmittter and role of dopamine in psychiatryurvashi kumar
Dopamine is a neurotransmitter that plays important roles in many psychiatric and neurological disorders. It acts in several pathways in the brain. The mesolimbic and mesocortical pathways are involved in schizophrenia, mood disorders, and addiction. The nigrostriatal pathway controls motor movements and deficiencies can cause disorders like Parkinson's disease. Dopamine also acts in the tuberoinfundibular pathway in the hypothalamus and pituitary gland.
This document summarizes information about the neurotransmitters glutamate and GABA. It discusses their roles, receptors, and involvement in various neurological conditions and disorders. Glutamate is the primary excitatory neurotransmitter in the brain, while GABA is the primary inhibitory neurotransmitter. The document outlines their synthesis, metabolism, receptor types, and relationships. It also explores how imbalances in glutamate and GABA are implicated in conditions like anxiety, depression, addiction, and neurodegenerative diseases.
This document discusses the role of glutamate in psychiatry. It notes that glutamate is the major excitatory neurotransmitter in the brain and is involved in memory, emotions, cognition, and various psychiatric conditions like depression, anxiety, schizophrenia, and drug addiction. It then discusses the specific implications of glutamate for anxiety disorders, mood disorders, addiction disorders, and schizophrenia. Finally, it outlines the future implications of targeting glutamate systems for the treatment of these conditions, noting potential drug candidates and the promise of drugs like ketamine for rapidly treating depression.
EEG is a non-invasive method to measure electrical activity in the brain. It can help in psychiatry by ruling out physical causes for psychiatric symptoms, aiding in differential diagnosis and treatment selection, and predicting prognosis. EEG findings can provide clues to underlying conditions in disorders like schizophrenia, mood disorders, OCD, panic attacks, dementia, delirium, and substance abuse. However, EEG findings in psychiatry are often nonspecific and EEG has limitations due to only recording cortical activity from the scalp. It currently has no definitive role in diagnosing Axis I or II psychiatric disorders.
This document summarizes various neurological effects of alcoholism. It discusses acute alcoholic intoxication, alcohol withdrawal including seizures, hallucinations, and delirium tremens. It also covers nutritional deficiencies that can occur like Wernicke-Korsakoff syndrome and neurological complications of uncertain etiology. Specific conditions related to alcoholism are explained such as encephalopathy, trauma, strokes and others. The effects of alcohol on neurotransmitter systems are outlined. Features of alcohol withdrawal syndrome and delirium tremens are defined. Management of withdrawal and complications are addressed.
This document discusses the neurobiology of addiction. It provides an overview of neurotransmission, including action potentials, the neurotransmitter lifecycle, and receptor types. Specific neurotransmitters are examined, such as dopamine, GABA, glutamate, and opioids. The roles of these neurotransmitters in addiction and how various drugs affect neurotransmitter systems are described. Genetic and environmental factors that can contribute to addiction are also reviewed.
This document discusses the anatomy and functional areas of the frontal lobe and their relation to psychiatry. It begins with the anatomical structures of the frontal lobe including the lateral, medial and orbital surfaces. It then covers the primary functional areas - primary motor cortex, premotor cortex, supplementary motor cortex, frontal eye fields, Broca's area, and the prefrontal cortex including dorsolateral, dorsomedial and orbital regions. Neuropsychiatric disorders are discussed like frontal lobe syndrome, traumatic brain injury, frontotemporal dementia, and the relationships between the frontal lobe and conditions like schizophrenia, depression, ADHD, OCD, and alcohol use. Assessment techniques are also covered.
Neurotransmittter and role of dopamine in psychiatryurvashi kumar
Dopamine is a neurotransmitter that plays important roles in many psychiatric and neurological disorders. It acts in several pathways in the brain. The mesolimbic and mesocortical pathways are involved in schizophrenia, mood disorders, and addiction. The nigrostriatal pathway controls motor movements and deficiencies can cause disorders like Parkinson's disease. Dopamine also acts in the tuberoinfundibular pathway in the hypothalamus and pituitary gland.
This document summarizes information about the neurotransmitters glutamate and GABA. It discusses their roles, receptors, and involvement in various neurological conditions and disorders. Glutamate is the primary excitatory neurotransmitter in the brain, while GABA is the primary inhibitory neurotransmitter. The document outlines their synthesis, metabolism, receptor types, and relationships. It also explores how imbalances in glutamate and GABA are implicated in conditions like anxiety, depression, addiction, and neurodegenerative diseases.
The document provides information about the frontal lobe:
1. It introduces the frontal lobe as the emotional control center and personality center that is prone to injury.
2. It describes the anatomy of the frontal lobe including lobes, gyri, sulci and blood supply on different surfaces.
3. It outlines some of the major functional areas of the frontal lobe including motor control, language, decision making, memory, and social behavior.
This document discusses the anatomy and functions of the frontal lobe. It begins with the neuroanatomy of the frontal lobe, describing its sulci, fissures and gyri. It then covers the prefrontal cortex in more detail, describing its functional areas including the dorsolateral, orbital and medial prefrontal cortex. The document also discusses the motor cortex, its primary, premotor and supplementary areas. It covers tests used to assess frontal lobe functions and describes frontal lobe syndromes and its involvement in psychiatric illnesses and epilepsy.
This document provides an overview of dopamine, including its history, synthesis, receptors, functions, pathways, and relevance to various psychiatric and neurological conditions. Some key points:
- Dopamine is a catecholamine neurotransmitter synthesized from the amino acid tyrosine. It acts through D1-D5 G protein-coupled receptors.
- Major dopaminergic pathways include the mesocortical, mesolimbic, nigrostriatal, and tuberoinfundibular pathways which are involved in cognition, reward, movement, and prolactin regulation respectively.
- Dopamine plays a role in schizophrenia, mood disorders, attention deficit disorders, substance abuse, and movement disorders like Parkinson's disease
Vortioxetine is a novel antidepressant approved by the FDA in 2013 for the treatment of major depressive disorder. It is manufactured by Takeda Pharmaceuticals and works as a serotonin modulator. It has multiple mechanisms of action including inhibiting the serotonin transporter, acting as an agonist on 5HT1A/B receptors, antagonizing 5HT3 and 5HT7 receptors. Clinical studies showed it was effective in reducing depressive symptoms and had a lower risk of side effects like insomnia compared to SSRIs and SNRIs. Common side effects included nausea, diarrhea and sexual dysfunction. It has a favorable safety and tolerability profile. More long term studies are still needed but it shows promise as a treatment for MDD
This document provides an overview of treatment resistant schizophrenia, including definitions, prevalence, factors leading to treatment resistance, and management approaches. It notes that approximately 30% of schizophrenia patients do not adequately respond to initial treatment. Clozapine is identified as the gold standard treatment for resistant cases, though some patients remain resistant even to clozapine. The document discusses criteria for defining treatment resistance and response, as well as strategies for managing patients who are clozapine-resistant, including augmentation with other pharmacological or psychosocial approaches.
Alcohol related disorders- by Swapnil AgrawalSwapnil Agrawal
The document discusses the history and effects of alcohol use. It notes that alcohol has existed for over 10,000 years and was one of the earliest intentionally fermented substances consumed by humans. It then summarizes some of the key health effects of alcohol, including its impacts on the brain, body, and potential for dependence. Overall, the document provides a broad overview of the long history of alcohol consumption and some of the social and medical issues related to its use.
The document discusses the basal ganglia and their role in various psychiatric disorders. It begins with an overview of the basal ganglia's neuroanatomy and physiology, describing their connections and pathways. It then examines the basal ganglia's involvement in several disorders like OCD, autism, ADHD, schizophrenia, and depression. Imaging studies have found abnormalities in basal ganglia structures in these conditions. Dysfunctions in cortico-basal ganglia loops are believed to underlie repetitive behaviors and thoughts in OCD and autism. Dopamine anomalies in the basal ganglia are also implicated in schizophrenia pathology.
1) Long-acting injectable (LAI) antipsychotics can help improve medication adherence and reduce relapse and re-hospitalization rates in schizophrenia patients by maintaining drug levels between injections.
2) First generation LAIs included fluphenazine, haloperidol, flupentixol, and zuclopenthixol esters dissolved in oil. Risperidone was the first second generation LAI using microsphere technology.
3) Second generation LAIs like paliperidone palmitate offer advantages over first generation LAIs like fewer extrapyramidal side effects, no need for oral supplementation, and availability in 3-month formulations.
The temporal lobe is involved in processing sensory input, memory formation, language comprehension, and emotional processing. It contains structures like the hippocampus and amygdala that are important for memory and emotional associations. Disorders of the temporal lobe can cause problems like epilepsy, memory deficits, language issues like aphasia, and behavioral changes. Temporal lobe epilepsy is a common type of seizure originating in structures of the anteromedial temporal lobe. Bilateral damage to the amygdala and inferior temporal cortex can cause Klüver-Bucy syndrome characterized by changes in behavior and cognition. The temporal lobe also plays a key role in conditions like Alzheimer's disease, frontotemporal dementia, and traumatic brain injury.
Narcolepsy is a condition characterized by excessive daytime sleepiness and symptoms that represent intrusion of REM sleep into waking hours. It is caused by a deficiency of the neurotransmitter hypocretin and is associated with HLA DQB1*0602. Symptoms include irresistible sleep attacks, cataplexy, sleep paralysis, and hypnagogic hallucinations. Diagnosis involves evaluating symptoms, sleep latency on polysomnography and multiple sleep latency tests, and hypocretin levels in cerebrospinal fluid. Treatment focuses on managing symptoms with stimulants like modafinil and antidepressants or SSRIs to reduce cataplexy.
Treatment resistant schizophrenia & Treatment resistant depressionEnoch R G
This document discusses treatment resistant schizophrenia and provides guidelines for its management. It defines treatment resistance and outlines criteria from Kane and others. Factors associated with poor outcomes are biological, symptomatic, environmental, illness-related and pharmacological. The neurobiology of treatment resistant schizophrenia involves dopamine, glutamate, genetics and neuroanatomy. Management guidelines are provided from NICE and involve trials of clozapine as the gold standard treatment. Clozapine details include pharmacology, dosage, side effects, monitoring and predictors of response. Studies demonstrate clozapine's superior efficacy over other antipsychotics for treatment resistant schizophrenia.
This document provides an overview of the basal ganglia, including its history, anatomy, structures, pathways, and functions. It discusses several key points:
- The basal ganglia consists of several structures including the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra.
- It receives input from the cortex, thalamus, and substantia nigra via the corticostriatal, thalamostriatal, and nigrostriatal pathways respectively.
- The basal ganglia is involved in movement through direct and indirect pathways that influence the thalamus and motor cortex. Disorders like Parkinson's disease and Huntington's
a presentation on GABA including its synthesis, storage and degradation, types of receptors, and implications in various neuropsychiatric disorder, and finally a small chart on the drugs acting on GABA system.
Neuromodulation therapies like TMS and ECT allow targeted delivery of electrical or magnetic signals to specific areas of the nervous system to improve neural function. TMS uses magnetic pulses to induce currents in the brain non-invasively, while ECT induces seizures via electrodes. Both can have antidepressant effects by modifying neurotransmitter systems and inducing neuroplasticity. Ongoing research aims to better understand mechanisms of action, optimize dosing parameters, and expand indications to other psychiatric conditions.
The document discusses the anatomy and functions of different areas of the frontal lobe. It describes the primary motor cortex (area 4), premotor cortex (area 6), supplementary motor area (medial area 6), frontal eye fields (area 8), Broca's speech area (areas 44 and 45), orbital prefrontal cortex (areas 10 and 11), dorsomedial prefrontal cortex, and dorsolateral prefrontal cortex (areas 9, 10, 46). It provides details on the connections, functions, and effects of lesions for each area. Bedside tests are also described to assess functions localized to different frontal lobe regions.
Genetic terms used in psychiatry include:
- Concordance and heritability which measure the genetic influences on traits and diseases
- Mendelian and complex diseases which can be caused by single genes or interactions between genes and environment
- Alleles, haplotypes, loci, genetic maps, and linkage disequilibrium which describe genetic variations and inheritance patterns
Genome-wide association studies typically assay common genetic variants like single nucleotide polymorphisms to identify associations with traits and diseases.
This document summarizes research on the course and outcome of schizophrenia. It discusses several landmark studies including the International Pilot Study of Schizophrenia, Determinants of Outcome of Severe Mental Disorder study, and International Study of Schizophrenia. Overall, the studies found that outcomes tended to be better in developing countries compared to developed countries. Within developing countries, outcomes were particularly good in India, with studies in Agra and Chandigarh finding high rates of remission. Acute onset, good premorbid adjustment, younger age, and shorter duration of initial psychotic episode predicted better long-term prognosis.
This document discusses the neuroanatomical circuits and neurochemicals involved in anxiety disorders. It describes the amygdala and its connections to other brain regions like the prefrontal cortex, hippocampus, and brainstem nuclei that are implicated in fear processing and anxiety. Different neurotransmitter systems are also involved like GABA, serotonin, norepinephrine, and glutamate. The roles of these neurocircuits and chemicals help explain symptoms of anxiety disorders and how medications can treat them.
Treatment resistant schizophrenia is defined as lack of satisfactory improvement despite trials of two antipsychotics for adequate duration and dose. Around 20-30% of schizophrenia patients are considered treatment resistant. Clozapine is currently the treatment of choice for such patients, though combination and augmentation strategies with other agents have limited evidence. Definitive treatment guidelines recommend establishing treatment resistance before trials of clozapine or other strategies for treatment resistant schizophrenia.
Neurohumoral Transmission in central nervous systemSONALPANDE5
Neurohumoral transmission in the central nervous system involves four main processes:
1) Neurotransmitters transmit signals across synapses. 2) Neuromodulators produce slower pre- or post-synaptic responses. 3) Neuromediators play a role in eliciting post-synaptic responses. 4) Neurotropic factors regulate neuronal growth and morphology.
Dopamine is a key neurotransmitter in the central nervous system. It is synthesized from tyrosine and functions in motor control, reward, and other behaviors. Dopamine receptors are G-protein coupled and include D1-like and D2-like families. Dopamine pathways project from midbrain regions to other areas and are involved in motor control and reward
Local anesthetics explained in detail while keeping Anaesthesia point of view. it covers introduction,history mechanism of action,classification,individual drugs and systemic toxicity and more points presented by Dr Gaurav Joshi Resident doctor in dept of Anaesthesia (1st year).
The document provides information about the frontal lobe:
1. It introduces the frontal lobe as the emotional control center and personality center that is prone to injury.
2. It describes the anatomy of the frontal lobe including lobes, gyri, sulci and blood supply on different surfaces.
3. It outlines some of the major functional areas of the frontal lobe including motor control, language, decision making, memory, and social behavior.
This document discusses the anatomy and functions of the frontal lobe. It begins with the neuroanatomy of the frontal lobe, describing its sulci, fissures and gyri. It then covers the prefrontal cortex in more detail, describing its functional areas including the dorsolateral, orbital and medial prefrontal cortex. The document also discusses the motor cortex, its primary, premotor and supplementary areas. It covers tests used to assess frontal lobe functions and describes frontal lobe syndromes and its involvement in psychiatric illnesses and epilepsy.
This document provides an overview of dopamine, including its history, synthesis, receptors, functions, pathways, and relevance to various psychiatric and neurological conditions. Some key points:
- Dopamine is a catecholamine neurotransmitter synthesized from the amino acid tyrosine. It acts through D1-D5 G protein-coupled receptors.
- Major dopaminergic pathways include the mesocortical, mesolimbic, nigrostriatal, and tuberoinfundibular pathways which are involved in cognition, reward, movement, and prolactin regulation respectively.
- Dopamine plays a role in schizophrenia, mood disorders, attention deficit disorders, substance abuse, and movement disorders like Parkinson's disease
Vortioxetine is a novel antidepressant approved by the FDA in 2013 for the treatment of major depressive disorder. It is manufactured by Takeda Pharmaceuticals and works as a serotonin modulator. It has multiple mechanisms of action including inhibiting the serotonin transporter, acting as an agonist on 5HT1A/B receptors, antagonizing 5HT3 and 5HT7 receptors. Clinical studies showed it was effective in reducing depressive symptoms and had a lower risk of side effects like insomnia compared to SSRIs and SNRIs. Common side effects included nausea, diarrhea and sexual dysfunction. It has a favorable safety and tolerability profile. More long term studies are still needed but it shows promise as a treatment for MDD
This document provides an overview of treatment resistant schizophrenia, including definitions, prevalence, factors leading to treatment resistance, and management approaches. It notes that approximately 30% of schizophrenia patients do not adequately respond to initial treatment. Clozapine is identified as the gold standard treatment for resistant cases, though some patients remain resistant even to clozapine. The document discusses criteria for defining treatment resistance and response, as well as strategies for managing patients who are clozapine-resistant, including augmentation with other pharmacological or psychosocial approaches.
Alcohol related disorders- by Swapnil AgrawalSwapnil Agrawal
The document discusses the history and effects of alcohol use. It notes that alcohol has existed for over 10,000 years and was one of the earliest intentionally fermented substances consumed by humans. It then summarizes some of the key health effects of alcohol, including its impacts on the brain, body, and potential for dependence. Overall, the document provides a broad overview of the long history of alcohol consumption and some of the social and medical issues related to its use.
The document discusses the basal ganglia and their role in various psychiatric disorders. It begins with an overview of the basal ganglia's neuroanatomy and physiology, describing their connections and pathways. It then examines the basal ganglia's involvement in several disorders like OCD, autism, ADHD, schizophrenia, and depression. Imaging studies have found abnormalities in basal ganglia structures in these conditions. Dysfunctions in cortico-basal ganglia loops are believed to underlie repetitive behaviors and thoughts in OCD and autism. Dopamine anomalies in the basal ganglia are also implicated in schizophrenia pathology.
1) Long-acting injectable (LAI) antipsychotics can help improve medication adherence and reduce relapse and re-hospitalization rates in schizophrenia patients by maintaining drug levels between injections.
2) First generation LAIs included fluphenazine, haloperidol, flupentixol, and zuclopenthixol esters dissolved in oil. Risperidone was the first second generation LAI using microsphere technology.
3) Second generation LAIs like paliperidone palmitate offer advantages over first generation LAIs like fewer extrapyramidal side effects, no need for oral supplementation, and availability in 3-month formulations.
The temporal lobe is involved in processing sensory input, memory formation, language comprehension, and emotional processing. It contains structures like the hippocampus and amygdala that are important for memory and emotional associations. Disorders of the temporal lobe can cause problems like epilepsy, memory deficits, language issues like aphasia, and behavioral changes. Temporal lobe epilepsy is a common type of seizure originating in structures of the anteromedial temporal lobe. Bilateral damage to the amygdala and inferior temporal cortex can cause Klüver-Bucy syndrome characterized by changes in behavior and cognition. The temporal lobe also plays a key role in conditions like Alzheimer's disease, frontotemporal dementia, and traumatic brain injury.
Narcolepsy is a condition characterized by excessive daytime sleepiness and symptoms that represent intrusion of REM sleep into waking hours. It is caused by a deficiency of the neurotransmitter hypocretin and is associated with HLA DQB1*0602. Symptoms include irresistible sleep attacks, cataplexy, sleep paralysis, and hypnagogic hallucinations. Diagnosis involves evaluating symptoms, sleep latency on polysomnography and multiple sleep latency tests, and hypocretin levels in cerebrospinal fluid. Treatment focuses on managing symptoms with stimulants like modafinil and antidepressants or SSRIs to reduce cataplexy.
Treatment resistant schizophrenia & Treatment resistant depressionEnoch R G
This document discusses treatment resistant schizophrenia and provides guidelines for its management. It defines treatment resistance and outlines criteria from Kane and others. Factors associated with poor outcomes are biological, symptomatic, environmental, illness-related and pharmacological. The neurobiology of treatment resistant schizophrenia involves dopamine, glutamate, genetics and neuroanatomy. Management guidelines are provided from NICE and involve trials of clozapine as the gold standard treatment. Clozapine details include pharmacology, dosage, side effects, monitoring and predictors of response. Studies demonstrate clozapine's superior efficacy over other antipsychotics for treatment resistant schizophrenia.
This document provides an overview of the basal ganglia, including its history, anatomy, structures, pathways, and functions. It discusses several key points:
- The basal ganglia consists of several structures including the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra.
- It receives input from the cortex, thalamus, and substantia nigra via the corticostriatal, thalamostriatal, and nigrostriatal pathways respectively.
- The basal ganglia is involved in movement through direct and indirect pathways that influence the thalamus and motor cortex. Disorders like Parkinson's disease and Huntington's
a presentation on GABA including its synthesis, storage and degradation, types of receptors, and implications in various neuropsychiatric disorder, and finally a small chart on the drugs acting on GABA system.
Neuromodulation therapies like TMS and ECT allow targeted delivery of electrical or magnetic signals to specific areas of the nervous system to improve neural function. TMS uses magnetic pulses to induce currents in the brain non-invasively, while ECT induces seizures via electrodes. Both can have antidepressant effects by modifying neurotransmitter systems and inducing neuroplasticity. Ongoing research aims to better understand mechanisms of action, optimize dosing parameters, and expand indications to other psychiatric conditions.
The document discusses the anatomy and functions of different areas of the frontal lobe. It describes the primary motor cortex (area 4), premotor cortex (area 6), supplementary motor area (medial area 6), frontal eye fields (area 8), Broca's speech area (areas 44 and 45), orbital prefrontal cortex (areas 10 and 11), dorsomedial prefrontal cortex, and dorsolateral prefrontal cortex (areas 9, 10, 46). It provides details on the connections, functions, and effects of lesions for each area. Bedside tests are also described to assess functions localized to different frontal lobe regions.
Genetic terms used in psychiatry include:
- Concordance and heritability which measure the genetic influences on traits and diseases
- Mendelian and complex diseases which can be caused by single genes or interactions between genes and environment
- Alleles, haplotypes, loci, genetic maps, and linkage disequilibrium which describe genetic variations and inheritance patterns
Genome-wide association studies typically assay common genetic variants like single nucleotide polymorphisms to identify associations with traits and diseases.
This document summarizes research on the course and outcome of schizophrenia. It discusses several landmark studies including the International Pilot Study of Schizophrenia, Determinants of Outcome of Severe Mental Disorder study, and International Study of Schizophrenia. Overall, the studies found that outcomes tended to be better in developing countries compared to developed countries. Within developing countries, outcomes were particularly good in India, with studies in Agra and Chandigarh finding high rates of remission. Acute onset, good premorbid adjustment, younger age, and shorter duration of initial psychotic episode predicted better long-term prognosis.
This document discusses the neuroanatomical circuits and neurochemicals involved in anxiety disorders. It describes the amygdala and its connections to other brain regions like the prefrontal cortex, hippocampus, and brainstem nuclei that are implicated in fear processing and anxiety. Different neurotransmitter systems are also involved like GABA, serotonin, norepinephrine, and glutamate. The roles of these neurocircuits and chemicals help explain symptoms of anxiety disorders and how medications can treat them.
Treatment resistant schizophrenia is defined as lack of satisfactory improvement despite trials of two antipsychotics for adequate duration and dose. Around 20-30% of schizophrenia patients are considered treatment resistant. Clozapine is currently the treatment of choice for such patients, though combination and augmentation strategies with other agents have limited evidence. Definitive treatment guidelines recommend establishing treatment resistance before trials of clozapine or other strategies for treatment resistant schizophrenia.
Neurohumoral Transmission in central nervous systemSONALPANDE5
Neurohumoral transmission in the central nervous system involves four main processes:
1) Neurotransmitters transmit signals across synapses. 2) Neuromodulators produce slower pre- or post-synaptic responses. 3) Neuromediators play a role in eliciting post-synaptic responses. 4) Neurotropic factors regulate neuronal growth and morphology.
Dopamine is a key neurotransmitter in the central nervous system. It is synthesized from tyrosine and functions in motor control, reward, and other behaviors. Dopamine receptors are G-protein coupled and include D1-like and D2-like families. Dopamine pathways project from midbrain regions to other areas and are involved in motor control and reward
Local anesthetics explained in detail while keeping Anaesthesia point of view. it covers introduction,history mechanism of action,classification,individual drugs and systemic toxicity and more points presented by Dr Gaurav Joshi Resident doctor in dept of Anaesthesia (1st year).
Nicotine acts on nicotinic acetylcholine receptors (nAchRs) throughout the brain and body. In the brain, it activates nAchRs located on dopamine neurons, increasing dopamine release in reward pathways. This causes feelings of pleasure and reinforcement of smoking behavior. Long-term exposure leads to upregulation of high-affinity nAchRs and altered glutamate and GABA signaling. Nicotine withdrawal involves hyperexcitability of these sensitized nAchRs. Nicotine also impacts other neurotransmitter systems and has widespread effects outside the brain, increasing health risks. It can interact with many medications by affecting their metabolism and clearance from the body.
This document discusses antiparkinsonian drugs, focusing on levodopa. It provides background on Parkinson's disease and Parkinsonism, describing the pathophysiology as a dopamine deficiency in the striatum due to degeneration of neurons in the substantia nigra. Levodopa is identified as the most effective treatment for Parkinson's disease symptoms. While levodopa effectively treats many symptoms, prolonged use can lead to motor fluctuations and dyskinesia. Carbidopa and benserazide are described as peripheral decarboxylase inhibitors that increase levodopa bioavailability by inhibiting its conversion to dopamine peripherally while allowing conversion in the brain.
The adrenal glands consist of an outer cortex and inner medulla. The cortex produces mineralocorticoids like aldosterone and glucocorticoids like cortisol. Cortisol regulates metabolism and immune function. Aldosterone regulates sodium and potassium levels. Their release is controlled by the HPA axis and renin-angiotensin system. The medulla produces catecholamines like epinephrine and norepinephrine which increase heart rate and blood pressure through adrenergic receptors. Together these hormones help regulate vital processes and the stress response.
There are three main categories of cellular receptors discussed in the document:
1) Ionotropic receptors which are ligand-gated ion channels that produce fast responses. Examples include glutamate and GABA receptors.
2) G protein-coupled receptors which signal through secondary messengers and produce slower responses. Examples include neuromodulators.
3) Intracellular receptors which act as transcription factors and influence gene expression.
The document also discusses signaling pathways downstream of receptors including protein kinases, transcription factors, and long-term changes in neuronal function mediated by phosphorylation of proteins like CREB.
This document discusses NMDA receptors and drugs that act on them. It begins by introducing glutamate as the principal excitatory neurotransmitter in the central nervous system. It then describes the different types of glutamate receptors, focusing on NMDA receptors. Key points about NMDA receptors are that they are pentamers with high calcium permeability and play important roles in processes like memory acquisition and synaptic plasticity. The document outlines mechanisms of long-term potentiation and excitotoxicity that involve glutamate receptors. Finally, it provides details on several drugs that act as agonists or antagonists of NMDA receptors, including their mechanisms and uses.
마더리스크라운드 - Dopamine transporter in ADHD & Alcohol intakemothersafe
Dopamine transporter (DAT) plays a key role in regulating dopamine levels in the brain. DAT is implicated in attention deficit hyperactivity disorder (ADHD) and the mechanisms of ADHD medications in several ways: 1) ADHD medications target DAT to indirectly activate dopamine receptors, 2) DAT gene is associated with ADHD, and 3) abnormal DAT levels have been found in ADHD patients' brains. Understanding the role of DAT may provide insights into the pathophysiology of ADHD and how medications work.
Addiction is a complex illness caused by changes in the brain due to repeated drug use. Drugs of abuse trigger the brain's reward system by increasing the neurotransmitter dopamine, especially in the nucleus accumbens. Over time, this causes long-lasting changes in other brain systems and behaviors. Current pharmacological treatments aim to manage withdrawal, achieve and maintain abstinence, and reduce harms. Methadone maintenance is effective by occupying opioid receptors and blocking the effects of other opioids. New treatments target other neurotransmitter systems and pathways involved in addiction and relapse.
Propofol, thiopentone, ketamine, dexmedetomidine, and etomidate are common induction agents used in anesthesia. Propofol acts through GABA receptors and has a rapid onset and short duration. Thiopentone is a barbiturate that also acts through GABA, has a very rapid onset due to high lipid solubility, and a longer duration. Ketamine is a dissociative anesthetic that acts through NMDA receptors and has analgesic properties with a rapid onset but longer duration than other agents. Dexmedetomidine is a sedative that acts through alpha-2 receptors. Etomidate is a nonbarbiturate hypnotic that acts through modulation
Pharmacodynamics is the study of how drugs act on the body. Drugs can alter the normal function of tissues but cannot confer new functions. Their effects are quantitative, not qualitative. Drugs act through receptor-mediated or non-receptor mediated mechanisms. Receptors are proteins that recognize chemical signals and induce cell changes when drugs bind to them. The drug-receptor interaction leads to a series of events through effector molecules that ultimately produce a biological response. Major receptor families include intracellular receptors, plasma membrane receptors like ligand-gated ion channels and G-protein coupled receptors.
Role of Neurotransmitters with their detailed descriptionAwanish Mishra
Neurotransmitters are chemical messengers that transmit signals between neurons. The document discusses the major categories of neurotransmitters including amino acids, biogenic amines, neuropeptides, and others. It describes the processes involved in neurotransmission such as biosynthesis, storage, transport, and receptor binding. The summary focuses on some of the key neurotransmitters and includes:
1. Glutamate and GABA are the major excitatory and inhibitory amino acid neurotransmitters respectively. They act through ionotropic and metabotropic receptors.
2. Dopamine, norepinephrine, and serotonin are examples of biogenic amines that have modulatory functions. Dopamine is involved in reward and motivation while norepinephrine influences
Neurotransmitters are chemical messengers that transmit signals between neurons. There are several categories of neurotransmitters including amino acids, biogenic amines, neuropeptides, and others. Neurotransmission involves the biosynthesis, storage, release, binding to receptors, reuptake or degradation of neurotransmitters. Neurotransmitters act through ionotropic or metabotropic receptors. Drugs can act as agonists or antagonists at these receptor sites to alter neurotransmission. The evolutionary role of neurotransmitters like dopamine and opioids was to increase Darwinian fitness by motivating behaviors important for survival and reproduction, but these same systems can be hijacked by drugs of abuse in modern environments.
Neurotransmitters are chemical messengers that transmit signals between neurons. There are several categories of neurotransmitters including amino acids, biogenic amines, neuropeptides, and others. Neurotransmission involves the biosynthesis, storage, release, binding to receptors, reuptake or degradation of neurotransmitters. Receptors can be ionotropic, allowing ion flow, or metabotropic initiating intracellular signaling cascades. Common neurotransmitters involved in reward and addiction pathways include dopamine, serotonin, endorphins, GABA, and glutamate. External drugs can hijack the brain's natural incentive mechanisms involved in motivation and reward, disrupting neuroadaptation and contributing to addiction.
This document discusses alcohols including their history, forms, pharmacokinetics, pharmacodynamics, treatment of alcoholism, and methyl alcohol poisoning. It covers how alcohols are absorbed and metabolized in the liver, their central nervous system depressant effects, and reinforcing mechanisms related to dopamine and opioid systems. Tolerance and withdrawal symptoms are also summarized. Treatment of alcoholism includes disulfiram to induce nausea when drinking, naltrexone to reduce reward, and acamprosate for anti-craving effects. Methyl alcohol poisoning is discussed along with supportive treatments and use of ethanol or fomepizole to preferentially block methyl alcohol metabolism.
Adrenergic Agonist & Sympathomimetic Drugs.
It includes:
Sympathetic Nervous System
Structures of the major catecholamines
Drugs acting at adrenergic neurons
Structure-Activity Relationship of sympathomimetic Amines
Structure & main clinical use of important sympathomimetic drugs
Adrenergic Receptors: Types, Nomenclature
Sympathomimetic drugs (with Recent Advances)
Beta-adrenergic blockers as a potential treatment for COVID-19 patients
Summary
This document provides an overview of alcohol abuse and treatment. It discusses the types of alcoholic beverages and their alcohol concentrations. Moderate drinking is defined as up to 2 drinks per day for men and 1 for women, while binge drinking is 5 or more drinks in 2 hours for men and 4 for women. It then covers the pharmacokinetics of alcohol absorption, distribution and elimination in the body. Medical complications of alcohol abuse are outlined affecting the nervous system, GI tract, liver, nutrition, endocrine system and increasing cancer risk. Treatments discussed include medications like disulfiram, naltrexone, acamprosate, topiramate and psychological therapies. Adaptations for treating alcoholics in the workplace
The document discusses the anatomy and function of the adrenal medulla. It notes that the adrenal medulla is composed of chromaffin cells that are derived from neural crest cells and act as a sympathetic ganglion. The adrenal medulla secretes the catecholamines epinephrine, norepinephrine, and dopamine in response to sympathetic nervous system stimulation. It summarizes the biosynthesis pathway of catecholamines from tyrosine and discusses how the hormones signal through alpha and beta adrenergic receptors to produce various effects in different tissues.
Nitric oxide (NO) is a highly reactive free radical that functions as a vasodilator and neurotransmitter. It is synthesized from arginine by nitric oxide synthase (NOS) and diffuses to nearby cells to activate guanylate cyclase, increasing cyclic GMP and causing smooth muscle relaxation. There are three isoforms of NOS: neuronal NOS regulates neurotransmitter release, inducible NOS is involved in immune response, and endothelial NOS maintains blood pressure. Glutamate is the major excitatory neurotransmitter, acting on ionotropic AMPA, kainate and NMDA receptors or metabotropic receptors. GABA is the primary inhibitory neurotransmitter, inducing neuronal hyperpolarization through
Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
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TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kol...rightmanforbloodline
TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kolb, Ian Q. Whishaw, Verified Chapters 1 - 16, Complete Newest Versio
TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kolb, Ian Q. Whishaw, Verified Chapters 1 - 16, Complete Newest Version
TEST BANK For An Introduction to Brain and Behavior, 7th Edition by Bryan Kolb, Ian Q. Whishaw, Verified Chapters 1 - 16, Complete Newest Version
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The UK is currently facing a Adhd Medication Shortage Uk, which has left many patients and their families grappling with uncertainty and frustration. ADHD, or Attention Deficit Hyperactivity Disorder, is a chronic condition that requires consistent medication to manage effectively. This shortage has highlighted the critical role these medications play in the daily lives of those affected by ADHD. Contact : +1 (747) 209 – 3649 E-mail : sales@trinexpharmacy.com
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
2. Introduction
• Alcohol
– the king of liquids
– excites the taste to the highest degree
– various preparation have opened up to mankind
new sources of enjoyment
– a well known social lubricant
– excessive use produce the most harm to society
of all drugs of abuse (NIAA 2005)
3. Alcohol – the molecule
• Alcohol represents a wide series of compounds
• The alcohol suitable for drinking is ethanol
• Ethanol is a small molecule
– With low binding energy
& compared to other drugs
– A high Hill coefficient,
– require much higher concentrations for intoxication
4. Alcohol - Pharmacokinetics
• Universal solvent
• Readily miscible in water &
• Low lipid solubility
• Readily crosses the cell membrane
• Absorption
– 20% in stomach
– 80% in small intestine
• Elimination
– 5~10% excreted unchanged in urine & from lung
– Rest : metabolized in liver
6. Pharmacokinetics & Dependence
Genetic variation in alcohol metabolizing enzymes
Allelic variation in ADH/ALDH system is responsible for
differential alcohol elimination
Inactivation of ALDH2: protective factor against alcohol
dependence
Mutant ALDH2 gene:
Mongoloids: 40~50%
Native Americans: 2~5%
Europeans: 0%
(Goedde 1992)
7. Pharmacokinetics & Dependence
• Metabolic tolerance
– Increased MEOS activity
– P4502E1 is increased 4 times in liver biopsies
of alcoholics
(Tsutsumi 1989)
– increased alcohol dehydrogenase activity
8. Alcohol-Pharmacodynamics
• Old theory:
Alcohol increases membrane fluidity leading to altered
function of macromolecules in the cell membrane
• Recent Evidence :
Alcohol binds to hydrophobic pockets of proteins,
changing their three-dimensional structure and their
function
– Ion channels
– Neurotransmitter receptors
– Enzymes involved in signal transduction
9. Alcohol : CNS Effects
• Alcohol is a CNS depressant
• Apparent stimulatory effects result from
depression of inhibitory control mechanisms in the
brain
• Characteristic response:
– euphoria,
– Anxiolytic like effect,
– impaired thought processes,
– decreased mechanical efficiency
10. Alcohol & CNS
Neurotransmitter systems
• GABAergic system
• Glutaminergic system
• Serotonergic system
• Dopaminergic system
• Nicotinic acetylcholine system
• Glycine neurotransmitter
system
• Nor epinephrine systems
• Endogenous opioid system
• Endocannabinoid system
• Neurosteroids
• neuropeptides
Voltage gated ion channels
• Calcium channel
• Sodium channel
• Potassium channel
Second messenger systems
• Adenosine
Protein kinases
Neurotrophic factors
11. GABA acts on two receptor subtypes GABAa & GABAb
GABAa receptors are pentameric protein connected to a chloride
channel
GABAa receptors have a magnitude of subunits : α β γ δ
GABA
system
12. GABA system
• Renders acute central effects
– Anxiolytic, sedative, anticonvulsant, motor
incoordination
• Enhances GABAergic neurotransmission
– Presynaptic : increase GABA release
– Postsynaptic : agonist to GABAa receptor
• > direct action
• > facilitate GABA binding
(Roberto 2003)
Net effect: increased Cl influx > hyperpolarisation
13. GABA system
• Alcohol potentates GABAa mediated inhibition
– Selective
– depend on the heterogeneity of GABAa receptor
subunit composition (Criswell 2005)
– No single composition implicated
– Presence of α2 subunit increases sensitivity to alcohol
• Also act on GABAb receptor
– Counter the action of GABAa ( Weiner 2004)
14. GABA system
• Alcohol does not increase GABAa mediated inhibition in
all brain regions, all cell types in the same region, nor at all
GABAa receptors on the same neuron
• Molecular basis for the selectivity of the action of alcohol
on the GABAa receptor has been proposed to depend on
the heterogeneity of GABAa receptor subunit composition
(Criswell 2005)
• Various composition have been proposed by different
researchers
• Controversery still present in this regard
15. GABA system
• Effect of chronic alcohol exposure
– Down regulation of GABAa receptor
• Reduced no of GABA-benzodiazepine receptor complex,
especially in frontal lobes
• Reduction of receptors is related to amount of alcohol &
severity of addiction
• Decrease in GABA agonist induced Cl flux
• Reduced gene expression ( mRNA & protein) for alpha1
subunit of GABAa receptor (Malcom 2003)
16. Glutamate system
• Main excitatory neurotransmitter in brain
• 2 categories of receptors
– Ionotropic: NMDA, AMPA, kainate
– Metabotropic: G-protein coupled
• Alcohol : inhibitory effect on NMDA recptors
EPSP
blocks Ca influx inhibits
LTP
• Also inhibits other receptors (Carta 2002)
17. Glutamate system
• Play important role in memory & learning
• Play important role in
– Reinforcing effect in alcohol intake
– Repeating alcohol through learning of environmental
cues
• Glutamate antagonists claimed to suppress conditioning
behavior caused by alcohol
(Shaham 2002)
• Clinical study: reduced cue-induced relapse
(Backstrom 2004)
18. Glutamate system
• Adaptation to chronic alcohol exposure
– Up-regulation of NMDA system
• Increase in receptor subunits
• Increase interaction of NMDA with intracellular messengers :
increase NO synthesis
– Up-regulation of non NMDA pathways
– Increase synaptic glutamate release
• Net result: increased glutamate activity
– In locus ceruleus: withdrawal symptoms
– In neocortex: amnesia
19. Glutamate system
• Protracted withdrawal
– Increased NMDA receptors in VTA
– Hyperexciation in mesolimbic DA pathway
– Depolarization blockade
– Decrease in dopamine release (Rossetti 1998)
• Time course for dissipation of the change in NMDA receptor
properties paralleled the time course for disappearance of protracted
withdrawal symptoms (Snell 1996)
• NMDA antagonists effective in protracted withdrawal
20. Dopaminergic system
• Alcohol increases synthesis & release of dopamine
• Positive reinforcing property of alcohol because of activatation of
mesolimbic dopaminergic pathway
– Dopamine neuron with cell bodies in VTA
– Projections to the NA, amygdala, frontal cortex & other limbic areas
• Proved in animal studies & electrophysiological studies
• Greater increase in alcohol preferring rats
• Administration of dopamine agonists decreased alcohol intake in P
rats (Weiss 1993)
21. Dopaminergic system
• How alcohol increases dopaminergic activity?
– Direct excitatory cellular activation (Brodie 2000)
– Inhibit NMDA receptors (glutamatergic system exerts tonic
inhibitory control on mesolimbic dopaminergic neurons)
(Hoffman 1995)
– Promote binding of opioid agonists to μ receptors present on cell
bodies of dopamine neuron in VTA (Di Chiara 1988)
– Glycine recept in NA also act as a target for alcohol in its
mesolimbic DA activating effect (Molander 2005)
22. Dopaminergic system
• Result of chronic alcohol intake
– Decrease mesostriatal dopamine activity in animal
– Decrease level of dopamine & its metabolites in alcoholic patients
(Diana 1996)
– Adaptive change (increased density) of dopamine receptors
(Rommelspacher 1992)
• Consequences: gradual increase in reward threshold
23. Serotonergic system
• Alcohol stimulate serotonin release in NA
(Yoshimoto 1991)
• 5-HT3 receptor system is implicated in mediating alcohol
sensitivity
– Microinjection of serotonin in VTA enhance dopamine release in
nucleus accumbens
– This dopamine release can be blocked by 5-HT3 antagonist
(Campbell 1995)
24. Serotonergic system
• Some of the pleasurable effects of alcohol are mediated by binding to
5-HT3 receptors
– Shown by co-administration of alcohol & 5-HT3 antagonist
(Johnson 1993)
• Majority of the studies support the hypothesis that increase in
Serotonergic function leads to decrease in alcohol consumption
• Conversely majority of the studies don’t support that decrease in
Serotonergic function leads to increase in alcohol consumption
(LeMarquand 1994)
• Serotonin transporter density was lower in cortex of alcoholic subjects
(Manterew 2002)
25. Endogenous Opioids
• Endogenous opioid systems modulates reinforcing & other
actions of alcohol.
• Reduced alcohol consumption & reduced alcohol-
reinforced operant responding in μ receptor null mutant
mice (Gianoulakis 2001)
• Exact mechanism still not clear
• Increases exrta-cellular β-endorphin levels in nucleus
accumbens (Olive 2001)
26. Endocannabinoid system
• Endocannabinoid & CB1 receptor involved in brain reward
mechanism
• CB1 receptor activation associated with increased DA release in NA
(Gessa 1998)
• CB1 antagonist shown to decrease voluntary alcohol intake in
Sardinian alcohol- preferring rat
(Colombo 1998)
• In mice lacking CB1 receptor gene
– Reduced voluntary intake of alcohol
– Completely lacked alcohol induced DA release as compared to wild mice
(Basalingappa et al 2003)
27. Endocannabinoid system
• Chronic alcohol intake
– increases synthesis of endogenous cannabinoids
– down regulation of CB1 receptors & its signal transduction
(Basavarajappa 2002)
• Above findings
– Provides a novel basis for development of drug targeting CB1
receptor function as a potential treatment for alcohol dependence.
28. Nicotinic acetylcholine receptor system
• Ethanol potentiates central n-Ach receptor function
• Ethanol induced activation of mesolimbic dopamine
system is mediated by stimulation of n-Ach receptor in
ventral tagmentum area
• Imply a role in modulation of ethanol’s
reinforcing/motivational effect
(Soderpalm 2000)
29. Neurosteroids
• Ethanol increases de novo synthesis of neurosteroids in
brain by local action independent of HPA axis
– Increase allopregnanolone content in brain without any increase in
plasma corticosteroids
– Modulate GABAa receptor function : increase amplitude of
GABA mediated IPSP
– May contribute to disturbances in reproductive functions &
associated psychiatric disorder Chronic alcohol exposure
decreases the sensitivity of GABA recptors to neurosteroids
(Paolo 2005)
30. Neuropeptides
• Two neuropeptides appear to be involved in
alcohol related stress
– Corticotropin releasing factor : increased stress
response & negative affect
– Neuropeptide Y : anxiolytic properties
31. Neuropeptides
• Corticotropin releasing factor (CRF)
– Behavioral response to stress mediated by CRF occurs
independently of the HPA axis
– Two receptors : CRF1 & CRF 2
– Anti anxiety property of alcohol involve a suppression of brain
CRF system
– Chronic ethanol exposure
• up regulation of CRF receptors
• hypersensitivity to stress
– Abstinence
• Heightened CRF activity
• A key mediator of the anxious state
• Increased susceptibility to relapse (Valdez 2004)
32. Neuropeptides
• Neuropeptide-Y (NPY)
– Alcohol potentiate the activity of NPY
– mediate anti anxiety & sedative action of alcohol
– Chronic alcohol exposure : blunted NPY activity
(Badia 2003)
– Negative reinforcing effects of alcohol
• Alcohol self administration to alleviate anxiety during
withdrawal (Glenn 2004)
33. Norepinephrine
• During initial stage of alcohol withdrawal
– Excess norepinephrine activity in the region of LC (kovacs 2002)
– Increased level norepinephrine in plasma & CSF (Patkar 2003)
• These findings are indirect indicators of alcohol’s
suppressive action on norepinephrine system
(Ertugrul 2006)
34. Calcium channel
• Effect not only NMDA-dependent Ca channel, but also voltage-gated
calcium channel
• Acute alcohol intake inhibit passage through voltage-gated CA
channel
• chronic alcohol intake causes up-regulation of these channel
(Morad 2003)
• Hyper excitation in alcohol withdrawal is partly due to hyperactivity of
these channel
• CA channel inhibitors is considered useful in treatment of alcohol
withdrawal & in prevention of withdrawal sensitization
(Uzbay 2004)
35. Second Messenger system
• Alcohol inhibits adenosine reuptake
increases extra cellular adenosine
promotes activation of adenosine A2 receptor
activation of cAMP-PKA second messenger system
stimulation of cAMP response-element binding protein (CREB)
gene expression changes via stimulation of CREB transcription
• Changes in gene expression is an important reason of down-regulation
or sensitization of different neurotransmitter system
36. Neurotrophic Factors
• Growth factors important for the development &
maintenance of nervous system
• Ethanol increases NGF (nerve-derived growth factor) &
FGF( fibroblast growth factor) induced signal conduction
to nucleus (Roivainen 1996)
– Produce modulatory effects on neuronal signaling & synaptic
plasticity
– Protect neuronal cells against alcohol’s neurotoxic effects
– Helps to maintain tolerance to alcohol’s effects (Valenzuela 1996)
37. Why do Some Become Addicted?
Occasional /controlled/social use
Chronic/compulsive/uncontrollable use
Genetic variables
Environmental factors
Psychosocial factors
Drug related factors
All
?
41. Reinforcing effect of alcohol
• Through wide, but selective action on neurotransmitter
systems in the brain reward system
• GABA system
– Systemic injection of GABAa antagonists decrease operant
alcohol self- administration (Rassnick 1993)
– Selective GABA-b receptor agonist baclofen also decrease alcohol
self administration (Janak 2003)
• Endogenous opioid peptide system (Herz 1997)
– Naltrexone decreases alcohol drinking & self administration in a
variety of animal models (O’Malley 1992)
– clinical use of naltrexone in preventing relapse
42. Reinforcing effect of alcohol
• Mesolimbic dopamine system
– Alcohol self administration increase extra cellular levels of dopamine in
nucleus accumbens in non dependent rats
(Weiss 1993)
– Micro- injections of dopamine receptors antagonists in basal fore-brain
decrease responding for alcohol (Koob 1995)
– Lesion in the mesolimbic dopamine system fail to block operant self
administration of alcohol (Lyness 1992)
• Serotonergic transmission
– increases in the synaptic availability of serotonin with precursor loading
& blockade of serotonin reuptake , decrease alcohol intake
(Sellers 1992)
– Microinjection of 5-HT3 antagonists into amygdala of rats significantly
attenuated alcohol drinking (Kostowski 1995)
43. Reinforcing effect of alcohol
• Other systems attributing to positive
reinforcement
– NMDA glutamate system
– Endocannabinoid system
44. Tolerance
• Progressive shift to right in the concentration-
response function
• gradual decrease in positive reinforcing effects of
alcohol
– Depositional
– Functional : Neuro-adaptive responses to chronic
alcohol exposure
– Down-regulation of GABA, dopamine, endocannabinoids,
neurosteroids, NPY
– Up- regulation of glutamate, calcium channel, CRF
45. Withdrawal & dependence
• A latent state of hyper excitability, representing a
rebound phenomenon from the previously
chronically depressed CNS
• The classic neurotransmitters associated with
regulating the positive reinforcing properties of
alcohol, are compromised during alcohol
withdrawal
46. Withdrawal & dependence
• Negative emotional aspects of withdrawal appear to be more involved
in continued alcohol craving (Glenn 2004)
• Physical withdrawal symptoms are not highly correlated with relapse
in alcoholics
• <25% of the alcoholics attributed physical withdrawal symptoms for
continued drinking whereas >80% of these same patients reported
drinking due to feeling of anxiety, irritability or depressed mood
(Hershon 1997)
• Follow-up study: human alcoholics showed strong correlation between
negative affective symptoms & relapse up to 2 years following
withdrawal (De Soto 1999)
• Rats self-administer alcohol up to 8 weeks post withdrawal in absence
of any physical withdrawal signs (Roberts 2002)
47. Withdrawal & dependence
• protracted withdrawals underscore the chronic nature of
alcohol dependence
• negative affective states are a diving factor in relapse
following long term abstention from alcohol
• The learned association between alcohol & alleviation of
negative affect appears to be critical to excessive drinking
during dependence
48. Withdrawal & dependence
Kindling
• Repeated withdrawals from chronic alcohol intake lead to a
progressive intensification of the withdrawal syndrome
• Increases the severity of physical signs of withdrawals
• Influence the affective & motivational component of withdrawal
• Proved in multiple animal models (Rimodini 2003)
• Results from progressive sensitization of ongoing neuroadaptive
changes with each withdrawal episode
• Stress is capable of facilitating the neuroadaptive processes related to
withdrawal (George 2004)
49. Withdrawal & dependence
Neurochemical basis of physical withdrawal
• Decreased GABA receptor function
• Increased glutamate receptor function
• Increased norepinephrine activity
• Hyperactivity of voltage gated calcium channel
50. Withdrawal & dependence
• Neurobiological basis of the motivational effect of alcohol
withdrawal
– counteradaptive neurochemical events within the brain emotional
system, normally used to maintain emotional homeostasis
(Koob 2001)
– compromised brain reward system as reflected in increase in brain
reward threshold (Schulteis 1996)
• Neurotransmitters involved
– CRF, NPY, dopamine, serotonin, GABA, glutamate
51. Withdrawal & dependence
• Corticotropin-releasing factor
– Increase in extra cellular level of CRF in amygdala during alcohol
withdrawal (Olive 2002)
– Anxiogenic like responses during acute & protracted withdrawal
reversed by intra-cerebral & systemic administration of CRF
antagonist (Breese 2005)
– CRF antagonists that have no effect on alcohol self administration
in non-dependent rats effectively eliminates excessive drinking in
dependent rats
(Valdez 2002)
52. Withdrawal & dependence
• Neuropeptide Y
– Acute withdrawal : decrease in the level of NPY in amygdala & piriform
cortex (Roy 2002)
– NPY administered intra-cerebroventricularly decreases alcohol intake
(Thorsell 2002)
• Dopamine
– Mesolimbic dopamine function is also compromised during alcohol
withdrawal
– Animals self-administered just enough alcohol to return the dopamine
level in the nucleus accumbens back to pre-dependence baseline level
(Weiss 1996
– Reduced dopaminergic neurotransmission is prolonged, outlasting the
physical signs of withdrawal (Bailey 2000)
53. Withdrawal & dependence
• Glutamate receptor system
– Competitive glutamate NMDA antagonists partially
reversed the anxiogenic-like effects of alcohol
withdrawal (Gatch 1999)
• Other systems potentially involved in the
anxiogenic-like effects of alcohol withdrawal
include serotonergic & GABA systems
54. Allostasis
• Allostasis is a concept that was first used to described fluctuation in
blood pressure & immune system function that were inexplicable in
terms of homeostasis.
• Whereas homeostasis refers to the consistency of internal parameters
within a normal range, allostasis describes maintaining a state of
stability outside the normal range in which body varies the parameters
of its physiological systems to match environmental demands
• Allostasis takes into account the concept of tolerance & sensitization
& involves two separate systems : brain reward system & brain stress
regulating system
55. Allostasis
• When alcohol is taken, a positive mood state is experienced followed
by an equally powerful negative affective state.
• Following the negative affect the mood of the alcoholic would return
to a normal homeostatic baseline level
• On repeated administration of alcohol, the positive mood state
diminishes due to tolerance, whereas the subsequent negative affective
state becomes greater due to sensitization
• With progression of time, alcohol use shifts from an state of positive
reinforcement to negative reinforcement state
56. Allostasis
• Chronic elevation in reward threshold
– decrease in the function of GABA, dopamine, serotonin & opioid peptides
in brain reward pathway due to tolerance
• Dysregulation of brain stress system
– involves central nucleus of amygdala, locus ceruleus, & the
hypothalamus
– maintains a balance between CRF & NPY & this balance is crucial in the
regulation of stress, anxiety & depression
– Chronic ethanol intake alter the long term function of CRF & NPY system
• NPY system becomes blunted
• CRF system gets sensitized
57. Allostasis
• Enduring changes in these 2 systems leads to the
development of allostatic state that is represented by
– Chronic deviation of reward set point
– A new set point for mood regulation
• Allostatic state is clinically manifested as loss of control &
compulsive drinking in a failed attempt to regulate their
mood in a homeostatic range
• The neurocircuitry pathology persists into protracted
abstinence, thereby providing a strong motivational basis
for relapse
60. Neurochemical markers Joelle et al 2002
• Whether vulnerability to alcoholism is associated with pre-
existing abnormality within neurotransmitter system?
• Indices of activity of 5 neurotransmitter systems assessed
in Alcoholics & their children
– GABA, 5-HT, DA, NE, B-endorphine
• 3 criteria to be met for identification of a trait marker
– Heritability
– State independent
– Associated with alcoholism in general population
61. Biological markers Joelle et al 2002
• Studies included
– Baseline studies
– Challenge test studies
– Bio-chemical & neuroimaging studies
– Postmortem studies
– Studies compared neurochemical activities between alcoholics &
unrelated non-alcoholic controls
– Twin & adoption studies
– Studies compared neurochemical activities between individuals at
high risk for alcoholism & low-risk controls
62. Biological markers Joelle et al 2002
• Outcomes
– Increased baseline activity of serotonin transporter
– Increased responsiveness of the pituitary B-
endorphin system to challenges
– Decreased responsiveness in GABA neurotransmission
& reduced baseline GABA level in plasma
– Decreased dopamine receptor reactivity & low plasma
dopamine level
63. Biological markers
• Limitations
– Not assessed in family co-segregation studies
• COGA: collaborative study of the genetics of alcoholism
– Candidate genes on chromosome 4 & 11 reported for genetic
linkage to alcohol dependence ( Long et al 1998)
– GABA receptor gene on chromosome 4 & dopamine receptor
gene on chromosome 11
65. Conclusion
• Simplest molecule among all substance of abuse
• Wide & complex interaction with neurobiological systems
• No neurotransmitter system spared
• Despite of extensive research & better understanding of
neurobiological basis of its action over last few decades
– only two molecules with limited efficacy for long term pharmacological
intervention
– still to look forward for a better medication
• Warrants more research : large scale-long term clinical trials with
newer molecules which showed efficacy in preclinical studies & small
scale clinical trials