Quiz 14
Alcohol Effects on Memory and Learning
Increases activity of dopaminergic neurons of mesolimbic system and increases release of dopamine in NAC Release of dopamine related to positive, alcohol-produced reinforcement NMDA receptors involved in long-term potentiation that plays important role in learning This effect partly accounts for deleterious effects of alcohol on memory and other cognitive functions Alcohol, like other addictive drugs, increases the activity of the dopaminergic neurons of the mesolimbic system and increases the release of dopamine in the NAC as measured by microdialysis (Gessa et al., 1985; Imperato and Di Chiara, 1986) The release of dopamine appears to be related to the positive reinforcement that alcohol can produce As we saw in Chapter 13, NMDA receptors are involved in long-term potentiation, a phenomenon that plays an important role in learning Presumably, this effect at least partly accounts for the deleterious effects of alcohol on memory and other cognitive functions
Commonly Abused Drugs
Look at Slide 10.
Heritability of Substance Abuse and Problem Gambling
Look at slide
Positive and Negative Reinforcement and Punishment
Look at table
Opiate Receptors
Major types of opiate receptors - (mu) - (delta) - (kappa) Research findings - receptors and receptors responsible for reinforcement and analgesia - receptors produces aversive effects As we saw in Chapter 4, there are three major types of opiate receptors: (mu), (delta), and (kappa) Evidence suggests that receptors and receptors are responsible for reinforcement and analgesia and that stimulation of k receptors produces aversive effects
Therapy for Substance Abuse: Opiates
Methadone maintenance Buprenorphine Methadone maintenance . Methadone is a potent opiate, just like morphine or heroin A newer drug, buprenorphine, shows promise of being an even better therapeutic agent for opiate addiction than methadone (Vocci, Acri, and Elkashef, 2005). Buprenorphine is a partial agonist for the opiate receptor.
Therapy for Substance Abuse: Acamprosate
NMDA-receptor antagonis Used in Europe to treat seizure disorders Tested for its ability to stop seizure induced by withdrawal from alcohol Modest therapeutic benefits of acamprosate confirmed As we saw earlier in this chapter, alcohol serves as an indirect agonist at the GABAA receptor and an indirect antagonist at the NMDA receptor Several double-blind studies have confirmed the therapeutic benefits of acamprosate, but the these benefits appear to be modest
Therapy for Substance Abuse: Naltrexone
Opiate antagonists decrease reinforcing value of alcohol in variety of species Reinforcing effect of alcohol produced by secretion of endogenous opioids and activation of opiate receptors in brain Effective as adjunct to programs designed to treat alcohol abuse Currently, many treatment programs using sustained-release form of naltrexone to help treat alcoholism Several studies have shown that opiate antagonists decrease the reinforcing value of alcohol in a variety of species, including our own This finding suggests that the reinforcing effect of alcohol—at least in part—is produced by the secretion of endogenous opioids and the activation of opiate receptors in the brain These results are consistent with reports of the effectiveness of naltrexone as an adjunct to programs designed to treat alcohol abuse Currently, many treatment programs are using a sustained-release form of naltrexone to help treat alcoholism, and results
Alcohol: Endogenous Opiates
Opiate receptors involved in reinforcement mechanism not directly involving dopaminergic neurons Reinforcing effect partly caused by its ability to trigger release of endogenous opioids Endogenous opioids may play role in craving in abstinent alcoholics Opiate receptors appear to be involved in a reinforcement mechanism that does not directly involve dopaminergic neurons The reinforcing effect of alcohol is at least partly caused by its ability to trigger the release of the endogenous opioids In addition, endogenous opioids may play a role in craving in abstinent alcoholics
Alcohol
Primary sites of action Indirect agonist at GABAA receptors Indirect antagonist at NMDA receptors Both actions trigger apoptosis Alcohol actions Enhances action of GABA at GABAA receptors Interferes with transmission of glutamate at NMDA receptors
Effects of Inactivation of the Insula on Reinstatement of Drug-Seeking Behavior in Rats
Rats were trained to work for injections of nicotine, and then the behavior was extinguished. The graph shows that inactivation of the insula substantially reduced drug-seeking behavior elicited by nicotine or cues previously associated with nicotine.
Neuropeptides : MCH (melanin-concentrating hormone)
Synthesized in lateral hypothalamus, and stimulates hunger and reduces metabolic rate Found in several places in brain, including NAC on neurons that also contain DA receptors Blocking MCH receptors decreased effectiveness of cocaine or cocaine-related cues and alcohol intake on animals' behavior The second peptide, MCH (melanin-concentrating hormone), is also synthesized in the lateral hypothalamus, and—as we saw in Chapter 12—stimulates hunger and reduces metabolic rate MCH receptors are found in several places in the brain, including the NAC, where it is found on neurons that also contain DA receptors Chung et al. (2009) found that stimulating both DA receptors and MCH receptors increased firing of NAC neurons, and that administering a drug that blocks MCH receptors decreased the effectiveness of cocaine or cocaine-related cues on the animals' behavior A targeted mutation against the MCH receptor gene had the same effect. Cippitelli et al. (2010) found that MCH played a similar role in alcohol intake
Damage to the Insula and Smoking Cessation
The diagram shows the regions of the brain (shown in red) where damage was most highly correlated with cessation of smoking.
Cravings for Alcohol and μ Opiate Receptor
The drawings of the results of PET scans show the presence of μ opiate receptors in the dorsal striatum of detoxified patients diagnosed with alcohol abuse and healthy control participants. The graph shows the relative alcohol craving score as a function of relative numbers of μ opiate receptors. Heinz et al. (2005) found that one to three weeks of abstinence increased the number of opiate receptors in the NAC The greater the number of receptors, the more intense the craving was Presumably, the increased number of receptors increased the effects of endogenous opiates on the brain and served as a contributing factor to the craving for alcohol
THC and Dopamine Secretion in the Nucleus Accumbens
The graph shows changes in dopamine concentration in the nucleus accumbens, measured by microdialysis, in response to injections of THC or an inert placebo. Chen et al. (1990) injected rats with low doses of THC and measured the release of dopamine in the NAC by means of microdialysis and found that the injections caused the release of dopamine (See Figure 18.18) Chen et al. (1993) found that local injections of small amounts of THC into the ventral tegmental area had no effect on the release of dopamine in the NAC. However, injection of THC into the NAC did cause dopamine release there. Thus, the drug appears to act directly on dopaminergic terminal buttons—presumably on presynaptic heteroreceptors, where it increases the release of dopamine.
Nicotine and Dopamine Release in the Nucleus Accumbens
The graph shows changes in dopamine concentration in the nucleus accumbens, measured by microdialysis, in response to injections of nicotine or saline. The arrows indicate the time of the injections.
Buprenorphine as a Treatment for Opiate Abuse
The graph shows the effects of treatment with buprenorphine, buprenorphine + naloxone, and a placebo on opiate craving in people being treated for opiate abuse. Chen et al. (1990) injected rats with low doses of THC and measured the release of dopamine in the NAC by means of microdialysis and found that the injections caused the release of dopamine (See Figure 18.18) Chen et al. (1993) found that local injections of small amounts of THC into the ventral tegmental area had no effect on the release of dopamine in the NAC. However, injection of THC into the NAC did cause dopamine release there. Thus, the drug appears to act directly on dopaminergic terminal buttons—presumably on presynaptic heteroreceptors, where it increases the release of dopamine.
Varenicline as a Treatment for Smoking
The graph shows the percentage of people who smoked that were treated with varenicline, bupropion, or placebo that abstained from cigarette smoking.
Naltrexone as a Treatment for Alcoholism
The graphs show mean craving score and proportion of patients who abstained from drinking while receiving naltrexone or a placebo.
Early Exposure to Alcohol and Apoptosis
The photomicrographs of sections of rat brain show degenerating neurons (black spots). Exposure to alcohol during the period of rapid brain growth causes cell death by inducing apoptosis. These effects are mediated by the actions of alcohol as an NMDA antagonist and a GABAA agonist. MK-801, an NMDA antagonist, and phenobarbital, a GABAA agonist, also induce apoptosis
Deep Brain Stimulation (DBS)
Therapeutic effects on symptoms of Parkinson's disease, depression, anxiety disorders, and obsessive-compulsive disorder Human subjects studies report NAC appears to be most promising target A review by Luigjes et al. (2011) reported that seven animal studies have investigated the effectiveness of stimulation of the NAC, subthalamic nucleus (STN), dorsal striatum, habenula, medial PFC, and hypothalamus Eleven studies with human subjects have targeted the NAC or the STN. So far, the authors report, the NAC appears to be the most promising target For example, Mantione et al. (2010) stimulated the NAC of a forty-seven-year-old male smoker. The investigators reported that the man effortlessly stopped smoking and lost weight (he was obese)
Alcohol Metabolism
(a) There are two steps in the breakdown of alcohol; inactivity of alcohol dehydrogenase results in the accumulation of a toxic intermediate product that makes people feel ill and avoid alcohol. (b) Each person has two chromosomes with the gene for alcohol-metabolizing enzymes. Two copies (homozygous) of the active form of the gene results in normal metabolism of alcohol. Two copies of the inactive form of the gene results in impaired alcohol metabolism and an aversive reaction. One copy of the inactive gene (heterozygous) results in intermediate alcohol metabolism.
Neural Mechanisms
- Addictive drugs trigger release of dopamine in nucleus accumbens (NAC) - Different drugs stimulate release of dopamine in different ways - Neural changes that begin in VTA and strengthen excitatory synapses on DA neurons - Increased activation of ventral striatum, including NAC - Dorsal striatum in operant conditioning - Addictive drugs—including amphetamine, cocaine, opiates, nicotine, alcohol, PCP, and cannabis—trigger the release of dopamine in the nucleus accumbens (NAC), as measured by microdialysis (Di Chiara, 1995). - Different drugs stimulate the release of dopamine in different ways. - The details of the ways in which particular drugs interact with the mesolimbic dopaminergic system are described later, in sections devoted to particular categories of drugs.
Role of the Prefrontal Cortex
- Adolescence - History of substance abuse and structural abnormalities - Hypofrontality
Stimulant Drugs: Cocaine and Amphetamine
- Amphetamine - Inhibits reuptake of dopamine - Directly stimulates release of dopamine from terminal buttons Methamphetamine - Chemically related to amphetamine, but considerably more potent - Cocaine and amphetamine have similar behavioral effects, because both act as potent dopamine agonists. However, their sites of action are different Cocaine binds with and deactivates the dopamine transporter proteins, thus blocking the reuptake of dopamine after it is released by the terminal buttons - Amphetamine also inhibits the reuptake of dopamine, but its most important effect is to directly stimulate the release of dopamine from terminal buttons - Methamphetamine is chemically related to amphetamine, but is considerably more potent - Freebase cocaine ("crack"), a particularly potent form of the drug, is smoked and thus enters the blood supply of the lungs and reaches the brain very quickly.
Craving and Relapse
- Animal Studies Reinstatement model of drug seeking - Animals trained to make response reinforced by intravenous injections of a drug - Response extinguished - Drug or associated stimulus reinstated - Previously extinguished response returns - Reinstatement model of drug seeking - Animals are first trained to make a response (for example, pressing a lever) that is reinforced by intravenous injections of a drug such as cocaine - Next, the response is extinguished by providing injections of a saline solution rather than the drug - Once the animal has stopped responding, the experimenter administers a "free" injection of the drug (drug reinstatement procedure) or presents a stimulus that has been associated with the drug (cue reinstatement procedure) - In response to these stimuli, the animals begin responding at the lever once more (Kalivas, Peters, and Knackstedt, 2006) - Presumably, this kind of relapse (reinstatement of a previously extinguished response) is a good model for the craving that motivates drug-seeking behavior in a former addict
Stimulant Drugs: Cocaine and Amphetamine
- Cocaine and amphetamine - Similar behavioral effects as potent dopamine agonists - Sites of action different - Cocaine - Binds with and deactivates dopamine transporter proteins - Blocks reuptake of dopamine after it is released by terminal buttons - Cocaine and amphetamine have similar behavioral effects, because both act as potent dopamine agonists. However, their sites of action are different Cocaine binds with and deactivates the dopamine transporter proteins, thus blocking the reuptake of dopamine after it is released by the terminal buttons Amphetamine also inhibits the reuptake of dopamine, but its most important effect is to directly stimulate the release of dopamine from terminal buttons Methamphetamine is chemically related to amphetamine, but is considerably more potent Freebase cocaine ("crack"), a particularly potent form of the drug, is smoked and thus enters the blood supply of the lungs and reaches the brain very quickly
Neural Mechanisms: Volkow
- Cocaine users receive injection of methylphenidate - Smaller release of DA in NAC or dorsal striatum - Cocaine users view video of people smoking cocaine - Increased dopamine in ventral striatum
Repeated use of the substance that results in tolerance to its effects
- Craving for the substance - Intentions to reduce use of the substance - Large amounts of time are spent seeking or using the substance, or recovering from its effects - Continued use of substance despite significant problems in work, school, family or social interactions related to its use - Continued use even in dangerous situations or when substance worsens physical or psychological symptoms
Alcohol
- Differences in alcohol metabolism
Naloxone
- Drug that blocks opiate receptors; antagonizes the reinforcing and sedative effects of opiates
Positive Reinforcement
- Drugs have reinforcing effects - Route of administration and abuse potential - Role of cognition: associating stimulus and reinforcing properties, expectation - Drugs have reinforcing effects - with the exclusion of hallucinogens Snorting, smoking, or injecting a drug automatically increases the abuse potential of the drug compared to using a slower route of administration, such as taking a drug orally, because more of the drug enters the brain more rapidly and activates the reinforcement pathway more strongly
Opiates
- Heroin is illegal drug in most countries and addict become criminal - Substantial percentage of people who inject illicit drugs exposed to hepatitis or AIDS virus - In pregnant addicts, infants become dependent on drug which easily crosses placental barrier - Uncertainty about strength of heroin makes possible adverse or fatal consequences - First, because heroin—the most commonly abused opiate—is an illegal drug in most countries, an addict becomes, by definition, a criminal - Second, because of tolerance, a person must take increasing amounts of the drug to achieve a "high" - Third, an opiate addict often uses unsanitary needles; at present, a substantial percentage of people who inject illicit drugs have been exposed in this way to hepatitis or the AIDS virus - Fourth, if the addict is a pregnant woman, her infant will also become dependent on the drug, which easily crosses the placental barrier - Fifth, the uncertainty about the strength of a given batch of heroin makes it possible for a user to receive an unusually large dose of the drug, with possibly fatal consequences.
Dopamine receptors
- Increases in D1 dopamine receptors - Decreases in D2 dopamine receptors - ACh interneurons - Increases in D1 dopamine receptors: excitation and facilitate behavior - Decreases in D2 dopamine receptors: inhibition and suppress behavior - ACh interneurons: cocaine increased the firing of the interneurons, and that inhibiting the firing of these neurons by optogenetic methods blocked the reinforcing effect of cocaine
Nicotine Facts and Statistics
- International incidence of smokers and death from smoking - Largest single health problem worldwide, with over 6 million deaths per year - Leading cause of preventable death in developed countries - Nicotine might seem rather tame in comparison to opiates, cocaine, and amphetamine. - Approximately one-third of the adult population of the world smokes, and smoking is one of the few causes of death that is rising in developing countries. - The World Health Organization estimates that 50 percent of the people who begin to smoke as adolescents and continue smoking throughout their lives will die from smoking-related diseases. Investigators estimate that in just a few years, tobacco will be the largest single health problem worldwide, with over 6 million deaths per year (Mathers and Loncar, 2006). In fact, tobacco use is the leading cause of preventable death in developed countries
Release of Dopamine in the Nucleus Accumbens
- Many studies have shown that intravenous injections of cocaine and amphetamine increase the concentration of dopamine in the NAC, as measured by microdialysis - For example, Figure 18.9 shows data collected by Di Ciano et al. (1995) in a study with rats that learned to press a lever that delivered intravenous injections of cocaine or amphetamine - The colored bars at the base of the graphs indicate the animals' responses, and the line graphs indicate the level of dopamine in the NAC
Substance abuse instead of addiction
- Medical model - Biological basis - Biopsychosocial approach in treatment
Endogenous Opioids
- Neural Basis of Reinforcing Effects: Release of endogenous opioids play role in reinforcing effects of some addictive drugs Administration of naloxone reduces reinforcing effects of alcohol in humans and laboratory animals
Neural Mechanisms: Belin and Everitt
- Neural changes follow dorsally cascading set of reciprocal connections between striatum and ventral tegmental area - Neurons in ventral NAC project to VTA, which sends dopaminergic projections back to more dorsal region of NAC - Back-and-forth communication continues, connecting increasingly dorsal regions of striatum, all the way up to caudate nucleus and putamen - Belin and Everitt (2008) suggests that the neural changes responsible for addiction follow a dorsally cascading set of reciprocal connections between the striatum and the ventral tegmental area - Anatomical studies show that neurons in the ventral NAC project to the VTA, which sends dopaminergic projections back to a more dorsal region of the NAC, and so on -This back-and-forth communication continues, connecting increasingly dorsal regions of the striatum, all the way up to the caudate nucleus and putamen Belin and Everitt found that bilateral infusions of a dopamine antagonist into the dorsal striatum of rats suppressed responding to a light that had been associated with infusions of cocaine, but that unilateral infusions had no effect They also found that a unilateral lesion of the NAC had no effect on responding. However, they found that a lesion of the NAC on one side of the brain combined with infusion of a dopamine antagonist into the dorsal striatum on the other side of the brain suppressed responding to the light. (See Figure 18.1.)
Nicotine
- Nictonic ACh receptor α5 subunit
Heredity
- Not everyone is equally likely to become addicted to a drug! - Genetic and environmental factors play role - There are both general factors and specific factors - Abusing any category of drug associated with abusing drugs in other categories
Opiate Effects
- Opiate receptors in the nucleus accumbens and ventral tegmental area are involved in reinforcing effects of opiates. Receptors in the preoptic area are involved in hypothermia. Receptors in the periaqueductal gray matter are primarily responsible for analgesia, and receptors in the reticular formation are responsible for sedation.
Opiate Receptor Responsibilities
- Periaqueductal gray matter - analgesia - Preoptic area - hypothermia - Mesencephalic reticular formation - sedation - Ventral tegmental area and NAC -opiate reinforcing effects - Opiate receptors in periaqueductal gray matter are primarily responsible for analgesia, those in preoptic area are responsible for hypothermia, and those in mesencephalic reticular formation are responsible for sedation - As we shall see, opiate receptors in ventral tegmental area and NAC appear to play role in reinforcing effects of opiates
Neuropeptides : Orexin/Hypocretin
- Plays important role in control of sleep stages and food-seeking behavior Administration of addictive drugs or presentation of stimuli associated with them activate orexinergic neurons Infusion of orexin into VTA reinstates drug seeking that was previously extinguished Orexin and MCH play crucial role in reinforcing effects of drugs Synthesized in neurons in lateral hypothalamus and released in many parts of the brain, including those that play a role in addiction, such as the VTA, NAC, and dorsal striatum Administration of addictive drugs or presentation of stimuli associated with them activate orexinergic neurons, and infusion of orexin into the VTA reinstates drug seeking that was previously extinguished
Negative Reinforcement
- Removal or reduction of aversive stimulus that is contingent on particular response - Attendant increase in frequency of that response
Stimulants
- Sirtuins - Avenue for future research
Nicotine: Reinforcement
- Stimulates nicotinic acetylcholine receptors - Increases activity of dopaminergic mesolimbic system Nicotinic agonist into ventral tegmental area reinforces conditioned place preference - Stimulates nicotinic acetylcholine receptors - Increases activity of dopaminergic neurons of mesolimbic system (Mereu et al., 1987) and causes dopamine to be released in NAC (Damsma, Day, and Fibiger, 1989) - Injection of nicotinic agonist directly into ventral tegmental area will reinforce conditioned place preference (Museo and Wise, 1994) - Conversely, injection of nicotinic antagonist into VTA will block ability of nicotine to cause release of dopamine in nucleus accumbens and reduce reinforcing effect of intravenous injections of nicotine (Corrigall, Coen, and Adamson, 1994; Gotti et al., 2010) - Reinforcing effect of nicotine appears to be caused by activation of nicotinic receptors in ventral tegmental area
Genetic Contributions to Abuse
- The genetic basis of addiction to alcohol has received more attention than addiction to other drugs - Alcohol consumption is not distributed equally across the population; in the United States; 10 percent of the people drink 50 percent of the alcohol (Heckler, 1983) - Many twin studies and adoption studies confirm that the primary reason for this disparity is genetic - A susceptibility to alcoholism could conceivably be caused by differences in the ability to digest or metabolize alcohol or by differences in the structure or biochemistry of the brain.
The Reinstatement Procedure: A Model of Relapse
- The graph shows the acquisition of lever pressing for injections of a reinforcing drug during the self-administration phase and the extinction of lever pressing when the drug was no longer administered. A "free" shot of the drug or presentation of a cue associated with the drug during acquisition will reinstate responding.
Social Stress and Cocaine Intake
- The graph shows the cocaine intake of control rats and rats subjected to isolation stress early in life. - administration of CRH can reinstate drug-taking behavior, and administration of a drug that blocks CRH receptors can reduce the likelihood of relapse from drugs or drug cues. CRH receptors in the VTA appear to be particularly important
Establishment of Neural Changes in the Dorsal Striatum
- The graph shows the effects of infusing various amounts of a drug that blocks dopamine receptors into the dorsal striatum contralateral to a lesion of the nucleus accumbens.
Dopamine Release Stimulated by Methylphenidate
- The scatter plot shows that increases in the release of dopamine in the putamen (part of the dorsal striatum) are associated with increased craving in people who abuse cocaine.
Common Features of Substance Abuse
- True or False? - Most people who are exposed to drugs do not become addicted to them.
Alcoholism, Schizophrenia, and Prefrontal Gray Matter
- negative and cognitive symptoms of schizophrenia appear to be a result of hypofrontality—decreased activity of the prefrontal cortex High level of comorbidity of schizophrenia and substance abuse
Neural Mechanisms
Addictive drugs trigger release of dopamine in nucleus accumbens (NAC) Different drugs stimulate release of dopamine in different ways Neural changes that begin in VTA and strengthen excitatory synapses on DA neurons Increased activation of ventral striatum, including NAC Dorsal striatum in operant conditioning Addictive drugs—including amphetamine, cocaine, opiates, nicotine, alcohol, PCP, and cannabis—trigger the release of dopamine in the nucleus accumbens (NAC), as measured by microdialysis (Di Chiara, 1995). Different drugs stimulate the release of dopamine in different ways. The details of the ways in which particular drugs interact with the mesolimbic dopaminergic system are described later, in sections devoted to particular categories of drugs.
Cannabis and It's Effects
Affects human memory Impairs ability to keep track of particular topic Effects of cannabinoids on spatial memory task were similar to those produced by hippocampal lesions Excessive activation of CB1 receptors in field CA1 appears to interfere with normal functioning of hippocampal formation Impairs ability to keep track of particular topic; they frequently lose the thread of a conversation if they are momentarily distracted Evidence indicates that the drug does so by disrupting the normal functions of the hippocampus, which plays such an important role in memory. Pyramidal cells in the CA1 region of the hippocampus release endogenous cannabinoids, which provide a retrograde signal that inhibits GABAergic neurons that normally inhibit them. In this way, the release of endogenous cannabinoids facilitates the activity of CA1 pyramidal cells and facilitates long-term potentiation
Alcohol Dose and Reinforcement
Alcohol Dose Low doses produce mild euphoria and anxiolytic effect and reduces discomfort of anxiety Higher doses produces incoordination and sedation Reinforcement Positive reinforcement as mild euphoria Negative reinforcement is through termination of aversive stimulus
Therapy for Substance Abuse: Varenicline
Approved for therapeutic use to treat nicotine addiction Developed especially as treatment for nicotine addiction Serves partial agonist for nicotinic receptor Maintains moderate level of activation of nicotinic receptors but prevents high levels of nicotine from providing excessive levels of stimulation Serves partial agonist for nicotinic receptor, just as buprenorphine serves as a partial agonist for the opiate receptor. As a partial nicotinic agonist, varenicline maintains a moderate level of activation of nicotinic receptors but prevents high levels of nicotine from providing excessive levels of stimulation.
Neural Mechanisms: Belin and Everitt
Bilateral infusions of dopamine antagonist showed repression, but unilateral infusions had no effect Control of compulsive addictive behavior Interactions between ventral and dorsal striatum Mediated by dopaminergic connections between these regions and VTA Belin and Everitt (2008) suggests that the neural changes responsible for addiction follow a dorsally cascading set of reciprocal connections between the striatum and the ventral tegmental area Anatomical studies show that neurons in the ventral NAC project to the VTA, which sends dopaminergic projections back to a more dorsal region of the NAC, and so on This back-and-forth communication continues, connecting increasingly dorsal regions of the striatum, all the way up to the caudate nucleus and putamen Belin and Everitt found that bilateral infusions of a dopamine antagonist into the dorsal striatum of rats suppressed responding to a light that had been associated with infusions of cocaine, but that unilateral infusions had no effect They also found that a unilateral lesion of the NAC had no effect on responding. However, they found that a lesion of the NAC on one side of the brain combined with infusion of a dopamine antagonist into the dorsal striatum on the other side of the brain suppressed responding to the light. (See Figure 18.1.)
Therapy for Substance Abuse: Rimonabant
Blocks CB1 receptors Effective in helping smokers to quit Decrease in weight gain that typically accompanies cessation of smoking not seen Helps counteract effects of withdrawal from nicotine on these neurons Can cause anxiety and depression that provoked withdrawal of its approval as antiobesity medication But the problem with rimonabant is that some clinical trials have found that the drug can cause anxiety and depression, which provoked the withdrawal of its approval as an antiobesity medication At the present time, approval of rimonabant to treat nicotine addiction seems unlikely
Cannabis
CB1 receptor Site of action of endogenous cannabinoids in brain Lipids Endogenous ligands for the CB1 receptor, anandamide and 2-AG THC Abuse potential Stimulating effect on dopaminergic neurons Administration of a drug that blocks CB1 receptors abolishes the "high" produced by smoking marijuana
Therapy for Substance Abuse: Cocaine and Amphetamine
Dopamine receptors block reinforcing effects of cocaine and amphetamine, but produce dysphoria and anhedonia These drugs just as addictive as drugs they replace and have same deleterious effects on health As we saw earlier, the reinforcing effects of cocaine and amphetamine are primarily a result of the sharply increased levels of dopamine that these drugs produce in the NAC Drugs that block dopamine receptors certainly block the reinforcing effects of cocaine and amphetamine, but they also produce dysphoria and anhedonia People will not tolerate the unpleasant feelings these drugs produce, so they are not useful treatments for cocaine and amphetamine abuse Drugs that stimulate dopamine receptors can reduce a person's dependence on cocaine or amphetamine, but these drugs are just as addictive as the drugs they replace and have the same deleterious effects on health
Effects of Nicotine
Effects of drug in humans and laboratory animals suggest that craving for nicotine, like craving for food, is enhanced by release of endocannabinoids in brain Insular damage (e.g. via stroke) quit smoking more easily Insula larger in smokers
Nicotine
Endogenous cannabinoids play role in reinforcing effects of nicotine Rimonabant blocks cannabinoid CB1 receptors and reduces nicotine self-administration and nicotine-seeking behavior in rats by reducing release of dopamine in NAC Rimonabant helps prevent relapse in people who are trying to quit smoking, but it is not approved for this purpose Studies have found that endogenous cannabinoids play a role in reinforcing effects of nicotine Rimonabant, a drug that blocks cannabinoid CB1 receptors, reduces nicotine self-administration and nicotine-seeking behavior in rats (Cohen, Kodas, and Griebel, 2005), apparently by reducing release of dopamine in NAC (De Vries and Schoffelmeer, 2005) Clinical trials have found that rimonabant appears to help prevent relapse in people who are trying to quit smoking, but it is not approved for this purpose Effects of drug in humans and laboratory animals suggest that craving for nicotine, like craving for food, is enhanced by release of endocannabinoids in brain
Alcohol: Sedative Effect
Exerted at GABAA receptor Ro15-4513 reverses alcohol intoxication by blocking alcohol binding site on this receptor Suzdak et al. (1986) discovered a drug (Ro15-4513) that reverses alcohol intoxication by blocking the alcohol binding site on this receptor