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Addiction circuitry in human brain
- 1. ADDICTION CIRCUITRY INTHE HUMAN BRAIN
- 2. A study in2010 asked drugharm experts to rank various illegal and legal drugs. These measures include damage to health, drug Wine boy at a Greek symposium dependency, economic costs and crime. Source: Drug harms in the UK: a multicriteria decision analysis, D J Nutt
- 3. DEFINITIONS Addiction: Therepeated and increased use of a substance, the deprivation of which gives rise to symptoms of distress and an irresistible urge to use the agent again and which leads also to physical and mental deterioration. This term is not applied as a diagnostic term. Abuse: Use of any drug, usually by self-administration, in a manner that deviates from approved social or medical patterns. Dependence: The repeated use of a drug or chemical substance, with or without physical dependence. DSM- IV, APA, 1994
- 4. DEFINITIONS (DSM- V) Substance Use Disorders: The essential feature of a substance use disorder is a cluster of cognitive, behavioural, and physiological symptoms indicating that the individual continues using the substance de-spite significant substance-related problems. Substance-induced disorder: It includes intoxication, withdrawal, and other substance/medication-induced mental disorders (e.g., substance-induced psy-chotic disorder, substance-induced depressive disorder). American Psychiatric Association; May 18, 2013
- 5. DSM 5 CRITERIAFOR SUBSTANCE USE DISORDER These symptom criteria must be present within the past 12 months and lead to “clinically significant impairment or distress.” 1. ______ is often taken in larger amounts or over a longer period than was intended. 2. There is a persistent desire or unsuccessful efforts to cut down or control _____ use. 3. A great deal of time is spent in activities necessary to obtain ______, use _____, or recover from its effects. 4. Craving, or a strong desire or urge to use ____. 5. Recurrent _____ use resulting in a failure to fulfil major role obligations at work, school, or home. 6. Continued _____ use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of _____.
- 6. DSM 5 CRITERIAFOR SUBSTANCE USE DISORDER ….CONT. 7. Important social, occupational, or recreational activities are given up or reduced because of _____use. 8. 9. Recurrent _____ use in situations in which it is physically hazardous. Mild Substance Use Disorder 2 – 3 Symptoms ____ use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by _____. 10. Tolerance, as defined by either of the following: Moderate Substance Use 4-5 Symptoms 1. A need forDisorder increased amounts of _____ to achieve markedly intoxication or desired effect. 2. A markedly diminished effect with continued use of the same amount of ____. Severe Substance Use Disorder >6 Symptoms 11. Withdrawal, as manifested by either of the following: I. The characteristic withdrawal syndrome for ____ II. ____ is taken to relieve or avoid withdrawal symptoms.
- 7. IMPORTANT SUBSTANCE FORABUSE (DSM V)
- 8. TOLERANCE AND WITHDRAWAL Tolerance : Phenomenon in which, after repeated administration, a given dose of drug produces a decreased effect or increasingly larger doses must be administered to obtain the effect observed with the original dose. Withdrawal : A syndrome that occurs when blood or tissue concentra-tions of a substance decline in an individual who had maintained prolonged heavy use of the substance.
- 9.
- 10. MECHANISM OF DEPENDENCE& WITHDRAWAL (1) internalization and decreased surface expression of “normal” α1 subunitcontaining GABAA receptors (2) increased surface expression of “low alcohol sensitivity” α4 subunitcontaining GABAA receptors ALCOHOL Dependance (3) increased phosphorylation of NMDA receptors containing “high conductance” NR2B subunits.
- 11. MECHANISM OF DEPENDENCE& WITHDRAWAL (1) Increased µ-opioid receptor internalization and degradation. (2) Decreased efficacy of µ-opioid signal transduction. (3) Hyperactivation of adenylyl cyclase signaling, leading to enhanced GABA release and to increased gene transcription via activation of transcription factors Opioid Dependence
- 12. MECHANISM OF DEPENDENCE& WITHDRAWAL 1. DAT expression increases 2. The number of postsynaptic dopamine receptors decreases 3. Presynaptic dopamine is depleted COCAINE and STIMULANT Dependance
- 13. DISCOVERY OF REWARDCIRCUIT In the 1950s, Olds and Milner implanted electrodes in various regions of the rat brain to systematically determine which neuroanatomic areas could reinforce self-stimulation. The medial forebrain bundle and ventral tegmental area (VTA) in the midbrain were found to be particularly effective sites. These sites have been termed “pleasure centers”
- 14. REWARD CIRCUIT INBRAIN AND ITS FUNCTIONS Parietal lobe Sensory information Frontal lobe Decision-making Problem solving Planning Occipital lobe Vision Temporal lobe Memory Emotion Hearing Language Natural rewards Foodsystem Limbic Water Sex Nurturing Music Art Hippocampus Amygdala Motor coordination Heart rate Breathing Sleeping …and Drugs! Reward circuit
- 15. PSYCHOACTIVE DRUGS “HIJACK”REWARD CIRCUIT
- 16. NEUROADAPTIVE CHANGES INREWARD CIRCUIT DURING DEVELOPMENT OF DEPENDENCE DA and opioid peptide neurons on VTA and the nucleus Accumbens and which are activated during initial alcohol use and early stages of the progression to dependence (i.e.. The binge/intoxication stage) Corticotropin releasing factor (CRF) and norepinephrine (NE)-releasing neurons that converge on GABA interneurons in the central nucleus of the amygdala and which are activated during the development of dependence. SOURCE: Nestler et al. 2005
- 17. PET IMAGES OFD2 AVAILABILITY • Differential adaptation in D1R versus D2R signaling pathways with repeated drug administration is likely to underlie neuroplastic changes in addiction. • Overall in animal studies, the increases in D1R PET: Cocaine markedly reduces dopamine D2 receptor signalling are associated with sensitized availability The striatum to drugs, and the is largely healthy responses of the receptorcontrol (left)while thatred, indicating decreasescocaine in D2R the highest level of availability, of the signaling with compulsive drug intake abuser has little red.
- 18. DRUG MEMORY Amygdala not litup Amygdala activated Front of Brain Back of Brain Nature Video Cocaine Video
- 19. NEUROPLASTIC CHANGES ANDALLOSTASIS Synaptic changes linking environmental stimuli, drug effects, and reward learning in drug dependence Source: Principles of Pharmacology, E. Golan, 3-rd Ed.
- 20. MECHANISM OF RELAPSE Stressinduced relapse Sensory Cue induced relapse Drug re-exposure
- 21. CHOICE BEHAVIOR AND THENOTION OF “SELF-CONTROL” Response Selection food sex Behavio r social drug
- 22. SELF-PERCEIVED “LOSS OFCONTROL” Response Selection food sex Behavio r social drug
- 23. ADDICTION AND HUMANBRAIN … Acb nucleus accumbens BLA basolateral amygdala VTA ventral tegmental area SNc substantia nigra pars compacta VGP ventral globus pallidus DGP dorsal globus pallidus BNST bed nucleus of the stria terminalis Source : Koob et al, 2008
- 24. ADDICTION AND HUMANBRAIN … Binge/intoxication stage: Reinforcing effects of drugs may engage reward neurotransmitters and associative mechanisms in the Nucleus Accumbens shell and core and then engage stimulus–response habits that depend on the dorsal striatum. Two major neurotransmitters mediating the rewarding effects of drugs of abuse are dopamine and opioid peptides.
- 25. ADDICTION AND HUMANBRAIN … The negative emotional state of withdrawal may engage the activation of the extended amygdala. Major neurotransmitters in the extended amygdala hypothesized to have a function in negative reinforcement are corticotropin-releasing factor, norepinephrine, and dynorphin. Major projections of the extended amygdala are to the hypothalamus and brainstem.
- 26. ADDICTION AND HUMANBRAIN … This stage involves the processing of conditioned reinforcement in the BLA and the processing of contextual information by the hippocampus. Executive control depends on the prefrontal cortex and includes subjective states (ie, craving and, presumably, feelings) associated with drugs.
- 27. DOES EVERYBODY BECOMEADDICTED TO DRUGS? VULNERABILTY GENETICS matters …. Genes either increase risk or are protective Biology/Genes Environment Stress Htrlb receptor gene absence greater attraction to cocaine Home and family Genetics and alcohol School/Work Gender Early use Mental disorder Age Repeated DRUG USE Availability Cost Peer influence Curl receptor gene presence makes less responsive to Method morphine of administration ALDH*2 if two copies less likely to develop alcoholism BRAIN changes Persistent drug use leads to gene transcription modification - part of neuroplasticity Addiction
Editor's Notes
- #3 Humans have used drugs of one sort or another for thousands of years. Wine was used at least from the time of the early Egyptians; The world's oldest known winery (dated to 3000 BCE) was discovered in Areni-1 cave in a mountainous area of Armenia. narcotics from 4000 B.C.; and use of marijuana has been dated to 2737 B.C. in China, in the writings of the Chinese emperor ShenNung. Here the picture shows a Wine boy at a Greek symposium.So addictive drugs are old evils of human civilisation and their reign of terror still continues..A study in 2010 asked drug-harm experts to rank various illegal and legal drugs. Alcohol was found to be the most dangerous by far. The researchers claim that the rankings are stable because they are based on so many different measures and would require significant discoveries about these drugs to affect the rankings.Infoplease.com
- #4 Let’s start today’s discussion with definition of addictionThe Diagnostic and Statistical Manual of Mental Disorders (DSM) published by the American Psychiatric Association provides a common language and standard criteria for the classification of mental disorders.Physical dependence indicates an altered physiologic state caused by repeated administration of a drug, the cessation of which results in a specific syndrome.Percent of persons 12 years of age and over with any illicit drug use in the past month: 8.9%, Marijuana – 6.9% (2010, CDC.gov)It is estimated that there are about 6.25 crore alcoholics, 90 lakh Cannabis and 2.5 lakhs opiates and nearly 10 lakh illicit drug users in the country.The drug abuse prevalence is uneven in the country. A high level of alcohol abuse was reported from North East, high cannabis use from North East and Eastern regions and high opiate use in North East, North and Western region.Source: http://ibnlive.in.comNational Family Health Survey (NFHS-3) – Alcohol – M 33%, W 2%... Tobacco – 57% M, W 11%
- #6 Overall, the diagnosis of a substance use disorder is based on a pathological pattern of behaviors related to use of the substance.
- #7 Limitations – 1. It does not have any quantitative measures.
- #8 Tobacco addiction has been addedNo caffeine use Disorder
- #9 Dependence The repeated use of a drug or chemical substance, with or without physical dependence. Physical dependence indicates an altered physiologic state caused by repeated administration of a drug, the cessation of which results in a specific syndrome.Abuse Use of any drug, usually by self-administration, in a manner that deviates from approved social or medical patterns.Misuse Similar to abuse, but usually applies to drugs prescribed by physicians that are not used properly.Addiction The repeated and increased use of a substance, the deprivation of which gives rise to symptoms of distress and an irresistible urge to use the agent again and which leads also to physical and mental deterioration. The term is no longer included in the official nomenclature, having been replaced by the term dependence, but it is a useful term in common usage.Intoxication A reversible syndrome caused by a specific substance (e.g., alcohol) that affects one or more of the following mental functions: memory, orientation, mood, judgment, and behavioral, social, or occupational functioning.Cross-tolerance Refers to the ability of one drug to be substituted for another, each usually producing the same physiologic and psychological effect (e.g., diazepam and barbiturates). Also known as cross-dependence.Neuroadaptation Neurochemical or neurophysiologic changes in the body that result from the repeated administration of a drug. Neuroadaptation accounts for the phenomenon of tolerance. Pharmacokinetic adaptation refers to adaptation of the metabolizing system in the body. Cellular or pharmacodynamic adaptation refers to the ability of the nervous system to function despite high blood levels of the offending substance.Codependence Term used to refer to family members affected by or influencing the behavior of the substance abuser. Related to the term enabler, which is a person who facilitates the abuser's addictive behavior (e.g., providing drugs directly or money to buy drugs). Enabling also includes the unwillingness of a family member to accept addiction as a medical-psychiatric disorder or to deny that person is abusing a substance.
- #10 Innate tolerancerefers to genetically determined lack of sensitivity to a drug that is observed the first time that the drug is administered. Innate tolerance was discussed earlier as a host variable that influences the development of addiction.GABRA1 and GABRA6 gene polymorphism causes reduced alcohol sensitivityPharmacokinetic or dispositional tolerance refers to changes in the distribution or metabolism of a drug after repeated administrations such that a given dose produces a lower blood concentration than the same dose did on initial exposure.Pharmacodynamic tolerancerefers to adaptive changes that have taken place within systems affected by the drug so that response to a given concentration of the drug is reduced. Short term neuroadaptation include drug-induced changes in receptor density or efficiency of receptor coupling to signal-transduction pathways Long term neuroadaptation include alteration in genetic transcription which leads to synaptic rearrangement Learned tolerancerefers to a reduction in the effects of a drug owing to compensatory mechanisms that are acquired by past experiences. Behavioral tolerance. This simply describes the skills that can be developed through repeated experiences with attempting to function despite a state of mild to moderate intoxication. Conditioned Tolerance occurs when environmental cues associated with drug exposure induce reflexive, preemptive compensatory changes. This mechanism of conditioned tolerance production follows classical (pavlovian) principles of learning and results in drug tolerance under circumstances where the drug is "expected." acute tolerancerefers to rapid tolerance developing with repeated use on a single occasion, such as in a "binge." Reverse tolerance This refers to an increase in response with repetition of the same dose of the drug. Sensitization, in contrast to acute tolerance during a binge, requires a longer interval between doses, usually ~1 day.Cross-tolerance occurs when repeated use of a drug in a given category confers tolerance not only to that drug but also to other drugs in the same structural and mechanistic category.
- #11 Alcohol modulates the major inhibitory and excitatory neurotransmitter systems of the brain via effects on GABAA and NMDA receptors, respectively. Alcohol is a positive allosteric modulator of GABAA receptors. Alcohol increases chloride conductance through GABAA receptors, resulting in cellular hyperpolarization. Alcohol also decreases calcium conductance through NMDA receptors, further decreasing cellular excitation. These dual actions on GABAA and NMDA receptors contribute to alcohol’s anxiolytic, sedative, and CNS-depressant effects. During withdrawal (i.e., in the dependent state but in the absence of alcohol), these adaptations result in generalized hyperexcitability of neurons. CNS excitation is expressed as anxiety, insomnia, delirium, and potentially seizures.
- #12 Opioids activate mu-opioid receptors located on synaptic nerve terminals. Acute activation of mu-opioid receptors results in G protein-dependent activation of potassium channels and inhibition of adenylyl cyclase activity. These effects result in cellular hyperpolarization and decreased GABA release from the nerve terminal; the decreased GABA release results in disinhibition of ventral tegmental area (VTA) dopamine neurons. Molecular adaptations to chronic opioid receptor stimulation include: (1) Increased µ-opioid receptor phosphorylation, resulting in receptor internalization and degradation.(2) Decreased efficacy of µ-opioid signal transduction.(3) Hyperactivation of adenylyl cyclasesignaling, leading to enhanced GABA release and to increased gene transcription via activation of transcription factors including cyclic AMP response element binding protein (CREB). (Thus, neuroadaptation results in tolerance to the euphoric effects of opioids. During withdrawal (i.e., in the dependent state but in the absence of opioid), the enhanced GABA release from inhibitory interneurons results in inhibition of VTA dopamine neurons, dysphoria, and anhedonia.
- #13 Acute cocaine exposure inhibits dopamine reuptake transporters (DAT), resulting in increased synaptic dopamine levels and increased postsynaptic dopamine receptor activation at synapses in the nucleus accumbens; in turn, these effects cause feelings of euphoria and increased energy. Increased extrasynaptic dopamine also results in D2 autoreceptor activation, which decreases dopamine synthesis.Amphetamine both releases vesicular transmitter stores into the cytoplasm and inhibits neurotransmitter reuptake into vesicles; these combined actions cause neurotransmitter concentrations to increase in the synaptic cleft. During chronic psychostimulant exposure, DAT expression increases, the number of postsynaptic dopamine receptors decreases, and presynaptic dopamine is depleted. Thus, neuroadaptation results in tolerance to the euphoric effects of psychostimulants. During withdrawal (i.e., in the dependent state but in the absence of psychostimulant), the decreased synaptic levels of dopamine that result from reduced dopamine synthesis and increased clearance through DAT cause decreased activation of postsynaptic dopamine receptors and feelings of dysphoria, fatigue, and anhedonia.
- #16 The mesolimbic dopamine pathway: a final common substrate for the rewarding actions of drugs. All drugs of abuse activate the mesolimbic dopamine pathway, Different interneurons interact with VTA neurons and NAc neurons to modulate mesolimbic neurotransmission. Nicotine interacts with excitatory nicotinic cholinergic receptors located on VTA dopamine neuron cell bodies to enhance dopamine release in the nucleus accumbens (NAc). Cocaine acts predominantly at the dopamine nerve terminal to inhibit reuptake of dopamine via the dopamine transporter (DAT), thus increasing synaptic levels of dopamine that can impinge on NAc. Amphetamine also acts at the dopamine nerve terminal to facilitate release of dopamine-containing vesicles, Both cannabinoids and opioids decrease GABA release from local inhibitory interneurons in the VTA, resulting in disinhibition of dopamine neuron activity and increased dopaminergic neurotransmission. Cannabinoids and opioids can also act within the NAc. Alcohol and other CNS depressants act on NMDA receptors (NMDA-R) to reduce glutamatergic neurotransmission in the NAc. The effects of alcohol on dopaminergic neurons in the VTA appear to be both excitatory and inhibitory, and are the subject of active investigation (not shown).
- #17 Positive reinforcement is the process by which certain consequences of a response increase the probability that the response will recur.Negative reinforcement is a process by which a response that leads to the removal of an aversive event is increased.Corticotropin-releasing hormone is secreted by the paraventricular nucleus (PVN) of the hypothalamus in response to stress. CRH can suppress appetite, increase subjective feelings of anxiety, and perform other functions like boosting attention.
- #20 Natural rewards such as food or sex increase dopamine release in the nucleus accumbens(NAc) and give rise to reward learning that links relevant environmental stimuli (sensory cues) with concurrent rewarding elements by altering neural circuitry in associative areas of the brain. Spiny neurons within the NAc receive glutamatergic inputs from the cortex that relay sensory cue information and dopaminergic inputs from the ventral tegmental area (VTA). The glutamatergic inputs act via NMDA receptors (permeable to calcium) and non-NMDA receptors (permeable to sodium). Coincident release of dopamine and glutamate results in potentiation of NMDA signaling, activation of calcium-calmodulin dependent kinase (CaMKII), and ultimately alterations in transcription of structural protein genes and glutamate receptor genes. These synaptic changes are thought to underlie reward learning. (B) Drugs of abuse induce amplified dopamine release and activate the same synaptic adaptations as natural reinforcers. Thus, drugs of abuse are thought to “hijack” evolutionary brain reward learning systems in a manner that leads to out-of-control drug use. (C) After chronic drug use, synaptic adaptations result in “potentiated synapses.” This potentiation is mediated viaincreased dendritic spine size, increased structural protein expression, and increased glutamate receptor surface expression; all of these adaptations occur in response to long-term transcriptional changes.
- #21 (D) After a period of abstinence from drug use, multiple mechanisms can induce relapse to drug-taking behavior. (1) Stress can trigger relapse by increased dopamine release. In this potentiated state, dopamine can trigger cellular excitation and trigger relapse behaviors. (2) Exposure to drug-related sensory cues can trigger relapse via increased glutamate release, and the increased surface expression of glutamate receptors can lead to cellular excitation and relapse. (3) Exposure to small amounts of drug can reactivate relapse to drug self-administration in this potentiated state, since the amplified dopamine release can trigger cellular excitation.
- #22 This is a illustration showing effects of psychoactive drug in behavioural pattern among drug addicts. Initial stages he can control drug exposure by choosing own response himself.
- #23 But later, when neuroadaptation and dependence took place, he can no longer the ‘BOSS’ of his own decision. This is perceived as “loss of control”
- #24 Neural circuitry associated with the three stages of the addiction cycle. (a) Binge/intoxication stage. Reinforcing effects of drugs may engage rewardneurotransmitters and associative mechanisms in the nucleus accumbens shell and core and then engage stimulus–response habits that depend on the dorsalstriatum. Two major neurotransmitters mediating the rewarding effects of drugs of abuse are dopamine and opioid peptides. (b) Withdrawal/negative affect stage.The negative emotional state of withdrawal may engage the activation of the extended amygdala. The extended amygdala is composed of several basal forebrainstructures, including the bed nucleus of the striaterminalis, central nucleus of the amygdala, and possibly a transition zone in the medial portion (or shell) of thenucleus accumbens. Major neurotransmitters in the extended amygdala hypothesized to have a function in negative reinforcement are corticotropin-releasingfactor, norepinephrine, and dynorphin. Major projections of the extended amygdala are to the hypothalamus and brainstem. (c) Preoccupation/anticipation(craving) stage. This stage involves the processing of conditioned reinforcement in the BLA and the processing of contextual information by the hippocampus.Executive control depends on the prefrontal cortex and includes representation of contingencies, representation of outcomes, and their value and subjectivestates (ie, craving and, presumably, feelings) associated with drugs. The subjective effects termed drug craving in humans involve activation in functional imagingstudies of the orbital and anterior cingulate cortices and temporal lobe, including the amygdala. A major neurotransmitter involved in the craving stage is glutamatelocalized in pathways from frontal regions and the BLA that project to the ventral striatum. Green/blue arrows, glutamatergic projections; orange arrows,dopaminergic projections; pink arrows, GABAergic projections; Acb, nucleus accumbens; BLA, basolateral amygdala; VTA, ventral tegmental area; SNc,substantianigra pars compacta; VGP, ventral globuspallidus; DGP, dorsal globuspallidus; BNST, bed nucleus of the striaterminalis; CeA, central nucleus of theamygdala; NE, norepinephrine; CRF, corticotropin-releasing factor; PIT, Pavlovian instrumental transfer (modified with permission from Koob et al, 2008a).The extended amygdala is composed of several basal forebrain structures, including the bed nucleus of thestriaterminalis, central nucleus of the amygdala, and possibly a transition zone in the medial portion (or shell) of the nucleus accumbens.
- #25 Neural circuitry associated with the three stages of the addiction cycle. (a) Binge/intoxication stage. Reinforcing effects of drugs may engage rewardneurotransmitters and associative mechanisms in the nucleus accumbens shell and core and then engage stimulus–response habits that depend on the dorsalstriatum. Two major neurotransmitters mediating the rewarding effects of drugs of abuse are dopamine and opioid peptides. (b) Withdrawal/negative affect stage.The negative emotional state of withdrawal may engage the activation of the extended amygdala. The extended amygdala is composed of several basal forebrainstructures, including the bed nucleus of the striaterminalis, central nucleus of the amygdala, and possibly a transition zone in the medial portion (or shell) of thenucleus accumbens. Major neurotransmitters in the extended amygdala hypothesized to have a function in negative reinforcement are corticotropin-releasingfactor, norepinephrine, and dynorphin. Major projections of the extended amygdala are to the hypothalamus and brainstem. (c) Preoccupation/anticipation(craving) stage. This stage involves the processing of conditioned reinforcement in the BLA and the processing of contextual information by the hippocampus.Executive control depends on the prefrontal cortex and includes representation of contingencies, representation of outcomes, and their value and subjectivestates (ie, craving and, presumably, feelings) associated with drugs. The subjective effects termed drug craving in humans involve activation in functional imagingstudies of the orbital and anterior cingulate cortices and temporal lobe, including the amygdala. A major neurotransmitter involved in the craving stage is glutamatelocalized in pathways from frontal regions and the BLA that project to the ventral striatum. Green/blue arrows, glutamatergic projections; orange arrows,dopaminergic projections; pink arrows, GABAergic projections; Acb, nucleus accumbens; BLA, basolateral amygdala; VTA, ventral tegmental area; SNc,substantianigra pars compacta; VGP, ventral globuspallidus; DGP, dorsal globuspallidus; BNST, bed nucleus of the striaterminalis; CeA, central nucleus of theamygdala; NE, norepinephrine; CRF, corticotropin-releasing factor; PIT, Pavlovian instrumental transfer (modified with permission from Koob et al, 2008a).
- #26 The extended amygdala is composed of several basal forebrain structures, including the bed nucleus of thestriaterminalis, central nucleus of the amygdala, and possibly a transition zone in the medial portion (or shell) of the nucleus accumbens.
- #27 Preoccupation/anticipation (craving) stage. This stage involves the processing of conditioned reinforcement in the BLA and the processing of contextual information by the hippocampus.Executive control depends on the prefrontal cortex and includes representation of contingencies, representation of outcomes, and their value and subjectivestates (ie, craving and, presumably, feelings) associated with drugs. The subjective effects termed drug craving in humans involve activation in functional imagingstudies of the orbital and anterior cingulate cortices and temporal lobe, including the amygdala. A major neurotransmitter involved in the craving stage is glutamatelocalized in pathways from frontal regions and the BLA that project to the ventral striatum