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Drug Addiction
The document discusses drug addiction, defining key concepts such as drug abuse, tolerance, physical and psychological dependence, and withdrawal symptoms. It explains the neurobiological mechanisms underlying addiction, highlighting the role of dopamine release in the brain's reward pathways and the compulsive nature of drug-seeking behavior. Additionally, it touches upon biochemical changes that occur with chronic drug use and the distinct pathways through which different substances exert their addictive effects.
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Drug Addiction
- 1. DRUG ADDICTION Mohsin Aziz 1
- 2. BSc., Pharm.D, RPh. Mohsin Aziz 2
- 3. Definitions: Drug Abuse: • Drug abuse is any recurrent use of drug that is illegal or causes harm to individual. • Using a drug as a habit • Use of a drug to an extent that it produces impairment of social, psychological or physiological functioning. Mohsin Aziz 3
- 4. Definitions: Tolerance: Reduction in pharmacological effects on repeated administration of drug, requiring escalation of dose to maintain same effects. Physical Dependence: The state of response to a drug whereby removal of the drug evokes unpleasant symptoms, usually the opposite of drug effects. Mohsin Aziz 4
- 5. Definitions: Withdrawal Symptoms ( Abstinence Syndrome) : • Signs and symptoms that follows the abrupt discontinuation or reduction in the use of a substance or after blockage of the actions of a substance with antagonists. • Tend to be opposite to original effects of drug. • Evidence of physical or psychological dependence. Mohsin Aziz 5
- 6. Definitions: Psychological Dependence: The state of response to a drug whereby the drug taker feels compelled to use the drug and suffers anxiety if doesn’t take drug. Reinforcement: Refers to the capacity of drugs to produce Hedonic (pleasureable) effects that make user wish to take them again. (Reward of Drug) Mohsin Aziz 6
- 7. Definitions: Drug Addicition : Drug addiction is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behavior persists despite serious negative consequences. The Stages of Addiction • Exposure • Compulsion • Loss of control Mohsin Aziz 7
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- 9. How does abrain become addicted….??? • A person takes a drug of abuse. • Drug activates the same brain circuits as do behaviors linked to survival, such as eating, bonding and sex. • The drug causes a surge in levels of a brain chemical called dopamine, which results in feelings of pleasure. The brain remembers this pleasure and wants it repeated. • Just as food is linked to survival in day-to-day living, drugs begin to take on the same significance for the addict. The need to obtain and take drugs becomes more important than any other need, including truly vital behaviors like eating. The addict no longer seeks the drug for pleasure, but for relieving distress. Mohsin Aziz 9
- 10. How does abrain become addicted….??? Acutely, addictive drugs are both • rewarding (i.e., interpreted by the brain as intrinsically positive) and • reinforcing (i.e.,behaviors associated with drug use tend to be repeated). • With repeated use, however, addictive drugs produce molecular changes that, within a vulnerable brain, promote continued drug-taking behavior in a manner that becomes increasingly difficult to control. The central feature of addiction is compulsive drug use—the loss of control over the apparently voluntary acts of drug seeking and drug taking. Mohsin Aziz 10
- 11. Why do somepeople become addict while others do not………??????????? Mohsin Aziz 11
- 12. Biochemical Mechanism OfDrug Addiction Mohsin Aziz 12
- 13. Where Drugs Act Mohsin Aziz 13
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- 15. Medial Forebrain Bundle • ventral tegmental area (VTA) • (lateral) hypothalamus (LH) • nucleus accumbens (NAc) • frontal cortex (FC) - key portions - prefrontal cortex (pfc) - orbitofrontal cortex (ofc) Mohsin Aziz 15
- 16. Dopaminergic Mesolimbic Pathway A prevailing view is that the primary brain circuits relevant to drug addiction (responsible for activation of neurochemical reward pathways) involve dopaminergic mesolimbic pathways. The mesolimbic dopamine system extends from dopamine (DA)1 -containing cell bodies within the ventral tegmental area (VTA) in brainstem to the nucleus accumbens (NuAcc) (part of the basal ganglia), prefrontal cortex and amygdala. The hypothesis is that many abused substances (except the benzodiazepines) enhance dopamine release in • nucleus accumbens or • pre- frontal cortex or both. (Ó 2000 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 25.) Mohsin Aziz 16
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- 18. Dopaminergic Mesolimbic Pathway Cocaine, for example, The primary mechanism of action believed to be related to its misuse is the inhibition of the dopamine transporter, which is responsible for the reuptake of dopamine into the presynaptic nerve terminal. Inhibition of the dopamine transporter (DAT) increases the synaptic concentrations of dopamine, enabling more activation of DA receptors. Mohsin Aziz 18
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- 22. Effects ofDrugs on Dopamine Release Mohsin Aziz 22
- 23. 1100 1000 900 800 700 600 500 400 300 200 100 0 Accumbens AMPHETAMINE 0 1 2 3 4 5 hr Time After Amphetamine % of Basal Release DA DOPAC HVA 250 200 150 100 0 NICOTINE 0 1 2 3 hr Time After Nicotine % of Basal Release Accumbens Caudate 250 200 150 100 ETHANOL 0 1 2 3 4hr Time After Ethanol % of Basal Release 0.25 0.5 1 2.5 Accumbens 0 Dose (g/kg ip) Mohsin Aziz 23
- 24. Natural RewardsElevate Dopamine Levels Mohsin Aziz 24
- 25. 200 150 100 50 0 FOOD 0 60 120 180 Time (min) % of Basal DA Output NAc shell Empty Box Feeding Source: Di Chiara et al. 200 150 100 DA Concentration (% Baseline) Scr SEX Mounts Intromissions Ejaculations 15 10 5 0 Copulation Frequency Sample Number ScrScr BasFemale 1 Present Scr Female 2 Present 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Source: Fiorino and Phillips Mohsin Aziz 25
- 26. Dopaminergic Mesolimbic Pathway NEUROCHEMICAL REWARD PATHWAY • The mesolimbic dopamine system, including its projections to the nucleus accumbens, and local GABAergic afferents, has been most clearly associated with the habit-forming aspects of drugs of abuse. Mohsin Aziz 26
- 27. Dopaminergic Mesolimbic Pathway ANTI-REWARD SYSTEMS • Negative reinforcement (in the form of dysphoric affective and physical withdrawal symptoms) plays an important. • Hence, cessation of drug-taking results in physical and affective motivation to take drug again and again. Mohsin Aziz 27
- 28. Dopaminergic Mesolimbic Pathway Effets of chronic Drug Use • Studies have showed that chronic administration of drugs of abuse, among many other changes, induces higher levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. • Chronic drug exposure causes: Mohsin Aziz 28
- 29. Dopaminergic Mesolimbic Pathway • decreased levels of neurofilament (NF) proteins (major structural determinants of neurons) • increased glial fibrillary acidic protein (GFAP), which are major structural determinants of glia within the VTA. • Together, these neuroadaptations identified in the VTA are suggestive of a state of neuronal injury • reductions in NF proteins in the VTA might result in reductions in the caliber of the neuronal processes and possibly an overall decrease in their size. Mohsin Aziz 29
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- 31. Biochemical Mechanism of Drug Addiction Mohsin Aziz 31
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- 33. Mechanism Of drug Addiction Since each addictive drug has a specific molecular target to activate mesolimbic system, Three classes can be distinguished: First Group,binds Gio-coupled receptors,eg.,Opioids,Canbinoids,LSD etc. Second group,binds to Ion Channels,eg.,Nicotine,Alcohol,BZD. Third group,binds to transporters of biogenic amines,eg.,Cocaine,amphetamine Mohsin Aziz 33
- 34. Mechanism Of drug Addiction The Common Signaling Pathway of All these drugs is: Mohsin Aziz 34
- 35. Mechanism Of drug Addiction Activation Of Dopamine receptors D1 D5 Activation of G Protien G s Activation of Adenyl Cyclase AC converts ATP into cAMP Causes phosphorylation of cAMP dependent Protein Kinase A,DARPP-32 ( 32kDa-Dopamine and cAMP regulated Phosphoprotein) This phosphorylated DARPP-32 act as an inhibitor of Protein Phosphatase(dec. cAMP) such as protein phosphatase-1 and Calcineurin Mohsin Aziz 35
- 36. Mechanism Of drug Addiction Thus acting parallel to PK and Inc Phosphorylation An amplifying mechanism. On chronc administration these drugs inc, activity of AC in nAcc; Morphine,for example, dec. AC Dec. in AC leads to secondary rise in AC expression Inc. AC exp. Leads to tolerance On cessation of morphine excessive cAMP production occurs (withdrawal Symptoms) Mohsin Aziz 36
- 37. Mechanism Of drug Addiction Chronic treatment inc. amount of not only AC itself but also of other components of signaling pathways i.e. G proteins and various PKs. This inc. in cAMP leads to inc. in cAMP dep. PKs which control the activity of : Ion channels (making cells more excitable) Various Enzymes Transcription factors ( particularly cAMP response element-binding protein CREB is upregulated in nAcc) CREB plays Key role in var. cAMP sig. pathways. Mohsin Aziz 37
- 38. And Afterall these changes what Happens………???????? Mohsin Aziz 38
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- 41. REFERENCES H.P RANG, et al.RANG AND DALE’S Pharmacology.6th edition.Churchill livingstone.2007 Betram G. KATZUNG.Basic and Clinincal Pharmacology.10th edition.Mc Graw Hill.2007 Goodman & Gillman’s Manual of Pharmacology and Therapeautics.Laurence L.Brunton, Keith L.Parker edis.Mc Graw Hill.USA.2008 Jennifer Chao and Eric J. Nestler. MOLECULAR NEUROBIOLOGY OF DRUG ADDICTION. Department of Psychiatry and Center for Basic Neuroscience, The University of Texas,Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas.2004 Robinson TE, Berridge KC. 2003. Addiction.Annu. Rev. Psychol. 54:25–53 Koob GF, Le Moal M. 2001. Drug addiction,dysregulation of reward, and allostasis.Neuropsychopharmacology 24:97–129 Nestler EJ, Aghajanian GK. 1997. Molecular and cellular basis of addiction. Science 278:58–63 Nestler EJ. 2001. Molecular basis of longterm plasticity underlying addiction. Nat. Rev. Neurosci. 2:119–28 Foote SL, Bloom FE, Aston-Jones G.1983. Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol. Rev. 63:844–914 Mohsin Aziz 41
Editor's Notes
- #6 For example: activation of mew receptors by an agonist causes inhibition of release of norepinephrine in Locus Cerelous(in limbic system).to overcome this inhibition Nepi synthesis increases,n during wuthdrawal when agonist is absent there is an excessive secretion of nEpi in LC n causes symptoms…such as Diarhea,nausea,vomiting,insomnia etc.