Brain Reward Circuits Research Articles

Affective Analgesia Following Muscarinic Activation of the Ventral Tegmental Area in Rats

Cholinergic stimulation of dopamine neurons in the ventral tegmental area (VTA) underlies activation of the brain reward circuitry. Activation of this circuit is proposed to preferentially suppress the affective reaction to noxious stimulation. Vocalization afterdischarges (VADs) are a validated model of the affective response of rats to noxious tail shock. The antinociceptive action of the acetylcholine agonist carbachol microinjected into the VTA on VAD threshold was compared with its effect on the thresholds of other tail shock-elicited responses (VDS, vocalizations during shock; SMR, spinal motor reflexes). Whereas VADs are organized within the forebrain, VDSs and SMRs are organized at medullary and spinal levels of the neuraxis, respectively. Carbachol (1 microg, 2 microg, and 4 microg) injected into VTA produced dose-dependent increases in VAD and VDS thresholds, although increases in VAD threshold were significantly greater than increases in VDS threshold. Administration of carbachol into VTA failed to elevate SMR threshold. Elevations in vocalization thresholds produced by intra-VTA carbachol were reversed in a dose-dependent manner by local administration of the muscarinic receptor antagonist atropine sulfate (30 microg and 60 microg). These results provide the first demonstration of the involvement of the VTA in muscarinic-induced suppression of pain affect. Cholinergic activation of the brain reward circuit produced a preferential suppression of rats' affective reaction to noxious stimulation. The neurobiology that relates reinforcement to suppression of pain affect may provide insights into new treatments for pain and its associated affective disorders.

Food Reward in the Absence of Taste Receptor Signaling

Food palatability and hedonic value play central roles in nutrient intake. However, postingestive effects can influence food preferences independently of palatability, although the neurobiological bases of such mechanisms remain poorly understood. Of central interest is whether the same brain reward circuitry that is responsive to palatable rewards also encodes metabolic value independently of taste signaling. Here we show that trpm5-/- mice, which lack the cellular machinery required for sweet taste transduction, can develop a robust preference for sucrose solutions based solely on caloric content. Sucrose intake induced dopamine release in the ventral striatum of these sweet-blind mice, a pattern usually associated with receipt of palatable rewards. Furthermore, single neurons in this same ventral striatal region showed increased sensitivity to caloric intake even in the absence of gustatory inputs. Our findings suggest that calorie-rich nutrients can directly influence brain reward circuits that control food intake independently of palatability or functional taste transduction.

Neurobiological mechanisms of cannabinoid addiction

The endocannabinoid system is implicated in the regulation of a variety of physiological processes, among which conditioning, motivation, habit forming, memory, learning, and cognition play pivotal roles in drug reinforcement and reward. In this article we will give a synopsis of last developments in research on cannabinoid actions on brain reward circuits coming from behavioral, neurochemical and electrophysiological studies. Central cannabinoid-induced effects as measured by animal models of addiction, in vivo cerebral microdialysis, in vitro and in vivo electrophysiological recording techniques, will be reviewed. Brain sites that have been implicated in the mediation of addictive cannabinoid properties include primarily the ventral tegmental area, the nucleus accumbens, and the medial prefrontal cortex, although the amygdala, the substantia nigra, the globus pallidus, and the hippocampus have also been shown to be critical structures mediating motivational and reinforcing effects of cannabinoids. Putative neurobiological mechanisms underlying these effects will be delineated.

How Mice Cope with Stressful Social Situations

Individuals differ greatly in their psychological responses to chronic stress. As a step toward understanding the neural basis for these individual differences, Krishnan et al. (2007) reveal molecular changes in the brain's reward circuits that make some mice resistant to the effects of social defeat.

Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions

While stressful life events are an important cause of psychopathology, most individuals exposed to adversity maintain normal psychological functioning. The molecular mechanisms underlying such resilience are poorly understood. Here, we demonstrate that an inbred population of mice subjected to social defeat can be separated into susceptible and unsusceptible subpopulations that differ along several behavioral and physiological domains. By a combination of molecular and electrophysiological techniques, we identify signature adaptations within the mesolimbic dopamine circuit that are uniquely associated with vulnerability or insusceptibility. We show that molecular recapitulations of three prototypical adaptations associated with the unsusceptible phenotype are each sufficient to promote resistant behavior. Our results validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance, and illustrate the importance of plasticity within the brain's reward circuits in actively maintaining an emotional homeostasis.

Altered levels of sex and stress steroid hormones assessed daily over a 28-day cycle in early abstinent cocaine-dependent females

There is growing evidence of alterations in brain stress and reward circuits associated with cocaine dependence. Sex differences are also documented and sex steroid hormones have been linked to cocaine reinforcement. The current study therefore assessed daily fluctuations in stress and sex hormones in cocaine-dependent females compared with healthy females. Daily salivary samples of cortisol, progesterone, and estradiol were collected at waking across 28 days from 12 cocaine-dependent females receiving inpatient treatment and 10 healthy females. Participants also completed mood-rating scales each week corresponding to four phases of the menstrual cycle and cocaine craving was monitored in cocaine patients at each phase. Cocaine-dependent females in their first month of abstinence demonstrated significantly higher levels of both cortisol and progesterone across the menstrual cycle and significantly lower estradiol/progesterone (E2/P) ratios compared to healthy controls. They also showed significantly increased negative mood compared with controls, but no variation in cocaine craving across the menstrual cycle. Findings indicate altered stress and sex hormones suggestive of an overactive stress system during the first month of cocaine abstinence after chronic cocaine abuse. These increased levels of cortisol and progesterone could impact both abstinence-related symptoms such as negative mood and susceptibility to drug-seeking behavior in cocaine-dependent females.

USING NEUROBIOLOGY TO REFRAME THE NEED FOR ALCOHOL POLICY INTERVENTIONS

The tobacco field provides a useful lesson for how alcohol prevention experts could implement Dr Giesbrecht's [1] call for educational programs that increase public support for policy-level interventions. Consumers are remarkably willing to let tobacco and alcohol companies sell them probabilistically dangerous products, so further explication of the health damage of these products may have little impact. In contrast, the public is less willing to be knowingly tricked or cheated in their dealings. Knowledge that tobacco companies purposely enhanced the addictiveness of their product and withheld information about risks to increase sales fostered support for successful tobacco-control interventions. Similarly, explaining how alcohol biologically distorts purchasing decisions to trick consumers into paying more for alcohol may facilitate support for controls on alcohol sales and marketing. New research on the pharmacological effects of alcohol on behavioral decision-making shows that alcohol has a predictable unfair advantage over other products. Models have explicated the neurobiological mechanisms that underlie our ability to make behavioral choices based upon the expected value of potentially available rewards [2, 3]. These studies show that alcohol, like all addictive drugs, specifically disrupts calculations made by the brain's reward circuitry. To determine the value of naturally rewarding products, the brain conducts an in-depth calculation of the impact of consumption of the product on the consumer within his current and historical environment. Alcohol short-circuits this assessment by pharmacologically augmenting a signal indicating the difference between the predicted value of the reward and the observed reward, such that the circuit mistakenly calculates that it underestimated the value of consuming alcohol regardless of whether the drinker was helped or hurt as a result of drinking. As the brain corrects its ‘underestimates’, it increases expectations about the value of alcohol consumption. This leads the drinker to overvalue alcohol and thus favor working harder to obtain alcohol, even if the product provided no objective or subjective benefit to the user. While other products undergo strict evaluations of their worth by the brain's reward circuitry, alcohol ‘cheats’ by reprogramming the circuit to rate it as better than expected regardless of the actual effects on the user or original expectations. These neurobiological results demonstrate that the alcohol industry's profits derive in part from a form of trickery. Their product includes a chemical that directly distorts the brains' decisions about how much work to devote to consuming their product—thus ensuring that people will pay more to get the product than the product is worth. Were an industry to play the same trick outside the brain (e.g. use a computer virus to reprogram purchasing systems to overcharge for their product), the practice would probably be declared illegal and governments would intervene. It seems unlikely that consumers or other producers would allow the alcohol industry this unfair advantage if they understood it. In light of these effects, intervention by alcohol industries to prevent recommendation or implementation of regulation on alcohol marketing is, as Giesbrect notes, unethical. Were alcohol purchasing governed by the same decision-making processes as all other products, then singling out alcohol for tighter regulation than other potentially unhealthful products would be unfair. However, alcohol bypasses brain processes that limit purchasing and consumption to levels commensurate with the consumers' personal benefit from the product. Thus, regulation of alcohol sales only compensates for pharmacological effects of alcohol on purchasing decisions. With this argument, whether alcohol benefits or harms the consumer is irrelevant; alcohol should be regulated to correct for purchasing induced by ‘tricking’ brain reward circuits. Policy-level intervention does not penalize alcohol industries for the harm that results from consumers' misuse of alcohol; it simply levels the playing field so that alcohol industries do not have an unfair market advantage. Punishing one group for another's mistakes is generally not appealing, but ensuring fair competition is a commonly held goal, and may make for a more persuasive argument for policy interventions.

Issues for DSM-V: Should Obesity Be Included as a Brain Disorder?

Issues for DSM-V: Should Obesity Be Included as a Brain Disorder?

Substance Abuse and Schizophrenia: Pharmacological Approaches

ABSTRACT This brief report reviews the common co-occurrence of substance use disorder in patients with schizophrenia, and its negative consequences. We suggest that a neurobiological basis for the co-occurring disorder may be important, and may relate to a dysfunctional brain reward circuit in these patients. The atypical antipsychotic medication clozapine appears to have an unusual ability to limit substance abuse in patients with schizophrenia, and other atypical antipsychotics may share at least some of this effect of clozapine. We have proposed that clozapine's ability to limit substance abuse in patients with schizophrenia may be due to its broad spectrum of pharmacological effects that serve to ameliorate the dysfunctional brain reward circuit. We have also proposed that neuroimaging techniques may be used to identify brain reward circuit dysfunction, and to track the effects of pharmacological agents that may limit substance abuse in these patients. Finally, we note the existence of a number of new agents for the treatment of alcoholism, and indicate that some of these medications may be used adjunctively in patients with schizophrenia to limit alcohol abuse.

Schizophrenia and Co-Occurring Substance Use Disorder

Schizophrenia and Co-Occurring Substance Use Disorder

Pharmacotherapy for schizophrenia and co-occurring substance use disorders

Substance use disorder (SUD) occurs commonly in patients with schizophrenia and is associated with a poor outcome. Despite this common co-morbid occurrence (and its negative impact on the course of schizophrenia), there have been very few studies assessing pharmacological strategies for optimal treatment of these patients. A number of theories have been advanced to help explain the high rate of substance use disorder in patients with schizophrenia. Our group has suggested that the brain reward circuit dysfunction model, which may incorporate aspects of all of these models, may help direct research aimed at developing new pharmacological treatments for patients with schizophrenia and co-occurring SUD. Although typical antipsychotic medications appear to be of limited value in these patients, emerging, but preliminary, data suggest that the atypical antipsychotics, particularly clozapine, may be particularly helpful. The role of adjunctive medications, such as those medications that have recently been shown to be useful for the treatment of alcoholism, may have a role in the treatment of these patients, although only naltrexone has, thusfar, been carefully tested in these comorbid patients. Further studies are indicated to assess the role of novel pharmacologic treatment strategies for these patients. Ultimately, any medication given to these patients will need to be prescribed within psychosocial treatment programs aimed at assisting these patients in limiting and ultimately ceasing substance use.

Emotion-based decision-making in healthy subjects: short-term effects of reducing dopamine levels.

Converging evidences from animal and human studies suggest that addiction is associated with dopaminergic dysfunction in brain reward circuits. So far, it is unclear what aspects of addictive behaviors are related to a dopaminergic dysfunction. We hypothesize that a decrease in dopaminergic activity impairs emotion-based decision-making. To demonstrate this hypothesis, we investigated the effects of a decrease in dopaminergic activity on the performance of an emotion-based decision-making task, the Iowa gambling task (IGT), in 11 healthy human subjects. We used a double-blind, placebo-controlled, within-subject design to examine the effect of a mixture containing the branched-chain amino acids (BCAA) valine, isoleucine and leucine on prolactin, IGT performance, perceptual competency and visual aspects of visuospatial working memory, visual attention and working memory, and verbal memory. The expectancy-valence model was used to determine the relative contributions of distinct IGT components (attention to past outcomes, relative weight of wins and losses, and choice strategies) in the decision-making process. Compared to placebo, the BCAA mixture increased prolactin levels and impaired IGT performance. BCAA administration interfered with a particular component process of decision-making related to attention to more recent events as compared to more distant events. There were no differences between placebo and BCAA conditions for other aspects of cognition. Our results suggest a direct link between a reduced dopaminergic activity and poor emotion-based decision-making characterized by shortsightedness, and thus difficulties resisting short-term reward, despite long-term negative consequences. These findings have implications for behavioral and pharmacological interventions targeting impaired emotion-based decision-making in addictive disorders.

Anhedonia After a Selective Bilateral Lesion of the Globus Pallidus

Anhedonia After a Selective Bilateral Lesion of the Globus Pallidus

Introduction: Current Research on Co-occurring Substance-Use Disorder in Schizophrenia

The 5 excellent articles in this section stand on their own as scientific contributions and together highlight important progress in schizophrenia research. The first 2 articles, by Caton and colleagues and by Mueser and colleagues, clarify unique features of 2 co-occurring disorders subgroups and may help us to understand the development and heterogeneity of co-occurrence in ways that lead to prevention and treatment. Caton documents that many individuals who appear to present with substance-induced psychosis also have some traditional risk factors for schizophrenia and are at high risk for psychosis 1 year later and for converting to a diagnosis of primary psychosis. Like the research of Caspi and colleagues, 1 her article suggests that genetic vulnerability can combine with substance use in important ways to increase the likelihood of primary psychosis. Mueser’s article suggests that childhood conduct disorder may be a key to understanding some of the variance in the cooccurring disorders population. Consistent with earlier research, 2 his article suggests that conduct disorder and antisocial behaviors may be key vulnerability markers for substance-use disorder during the prepsychotic phase of schizophrenic illness. The next 2 articles, by Brunette and colleagues and by Petrakis and colleagues, describe pharmacologic research that may lead to clues regarding both the treatment and the neurobiology of co-occurring disorders. Brunette’s article shows that medications may be critical in the relapse prevention stage of substance-abuse treatment and that clozapine continues to demonstrate unique properties among antipsychotic medications as a treatment for schizophrenia and co-occurring substance-use disorder. Petrakis’ article, which describes one of the few randomized controlled trials to test medications for alcoholism, such as disulfiram and naltrexone, in patients with cooccurring disorders, suggests that these medications are probably effective for those with psychotic disorders. The final article by McHugo and colleagues reviews several methodological implications drawn from intervention research on co-occurrence over the past 20 years. McHugo’s suggestions may help the field begin to standardize research approaches and develop more robust clinical trials, ones that are feasible and applicable to the large population of patients with co-occurring disorders. Considering these articles in relation to the larger field of co-occurring disorders invokes several scientific trends. Because animal and human studies expand, theories of co-occurrence will likely become more refined. It is now clear that patients with schizophrenia have heightened vulnerability to substance abuse before and after they become psychotic. 3 Both the genetic profiles and the neurocognitive features of patients with schizophrenia may lead to enhanced sensitivity to substances of abuse and almost certainly predispose them to high rates of substance-use disorder. This could imply converging neurobiological vulnerabilities (to schizophrenia and to substance abuse), perhaps within the brain reward circuit, consistent with a common mechanism for the dual effects of clozapine. 4,5 Prepsychotic neurocognitive

Δ9-THC administered into the medial prefrontal cortex disrupts the spatial working memory

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC) disrupts working memory. The prefrontal cortex (PFC) is involved in the processing of working memory, and its medial portion (mPFC) is part of a brain reward circuit as constituted by the mesocorticolimbic dopaminergic system. This study examined the involvement of the mPFC in the effects of Delta(9)-THC on spatial working memory. Ten male Wistar rats well-trained in a radial arm maze and with bilateral cannula implanted in the mPFC received Delta(9)-THC intra-cortically (Delta(9)-THC IC) at doses of 0 (VEH), 32, 100 or 180 microg, 5 min before a 5-s or a 1-h delayed task in order to measure a short- or long-term spatial working memory, respectively. By contrast, 11 other animals received Delta(9)-THC intraperitoneally (Delta(9)-THC IP) at doses of 0 (VEH), 0.32, 1 or 1.8 mg/kg, 30 min before a 5-s or a 1-h delayed task. Additionally, after a 15-day washout, the effect of an IP or IC pre-exposure of Delta(9)-THC was examined by repeating both dose-effect curves in a crossover order for the routes of administration. Delta(9)-THC IP produced significantly larger number of errors at doses of 0.32 or 1 mg/kg as compared to VEH in the 1-h post-delay performance. Delta(9)-THC 100 microg IC also produced significantly larger number of errors as compared to VEH and also to the other doses (32 or 180 microg) IC in the 1-h post-delay performance. Previous exposure to Delta(9)-THC IP or IC did not significantly affect the disruptive effect of this cannabinoid. Delta(9)-THC administered directly in the mPFC impaired 1-h delayed task in the radial arm maze in a manner similar to that observed for its systemic administration, suggesting that the mPFC is involved in the disruptive effects of Delta(9)-THC on spatial working memory.

Current evidence supporting a role of cannabinoid CB1 receptor (CB1R) antagonists as potential pharmacotherapies for drug abuse disorders

Since the discovery of the cannabinoid CB1 receptor (CB1R) in 1988, and subsequently of the CB2 receptor (CB2R) in 1993, there has been an exponential growth of research investigating the functions of the endocannabinoid system. The roles of CB1Rs have been of particular interest to behavioral pharmacologists because of their selective presence within the central nervous system (CNS) and because of their association with brain-reward circuits involving mesocorticolimbic dopamine systems. One potential role that has become of considerable recent focus is the ability of CB1Rs to modulate the effects of drugs of abuse. Many drugs of abuse elevate dopamine levels, and the ability of CB1R antagonists or inverse agonists to attenuate these elevations has suggested their potential application as pharmacotherapies for treating drug abuse disorders. With the identification of the selective CB1R antagonist, SR141716, in 1994, and its subsequent widespread availability, there has been a rapid expansion of research investigating its ability to modulate the effects of drugs of abuse. The preliminary clinical reports of its success in retarding relapse in tobacco users have accelerated this expansion. This report critically reviews preclinical and clinical studies involving the ability of CB1R antagonists to attenuate the effects of drugs of abuse, while providing an overview of the neuroanatomical and neurochemical points of contact between the endocannabinoid system and systems mediating abuse-related effects.

Regulation of dopaminergic transmission and cocaine reward by the Clock gene

Although there are clear interactions between circadian rhythms and drug addiction, mechanisms for such interactions remain unknown. Here we establish a role for the Clock gene in regulating the brain's reward circuit. Mice lacking a functional Clock gene display an increase in cocaine reward and in the excitability of dopamine neurons in the midbrain ventral tegmental area, a key brain reward region. These phenotypes are associated with increased expression and phosphorylation of tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis), as well as changes in several genes known to regulate dopamine activity in the ventral tegmental area. These findings demonstrate the involvement of a circadian-associated gene, Clock, in regulating dopamine function and cocaine reward.

Cannabinoid CB1 Receptor Antagonists as Promising New Medications for Drug Dependence

This review examines the development of cannabinoid CB(1) receptor antagonists as a new class of therapeutic agents for drug addiction. Abused drugs [alcohol, opiates, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), and psychostimulants, including nicotine] elicit a variety of chronically relapsing disorders by interacting with endogenous neural pathways in the brain. In particular, they share the common property of activating mesolimbic dopamine brain reward systems, and virtually all abused drugs elevate dopamine levels in the nucleus accumbens. Cannabinoid CB(1) receptors are expressed in this brain reward circuit and modulate the dopamine-releasing effects of Delta(9)-THC and nicotine. Rimonabant (SR141716), a CB(1) receptor antagonist, blocks both the dopamine-releasing and discriminative and rewarding effects of Delta(9)-THC in animals. Blockade of CB(1) receptor activity by genetic invalidation also decreases rewarding effects of opiates and alcohol in animals. Although CB(1) receptor blockade is generally ineffective in reducing the self-administration of cocaine in rodents and primates, it reduces the reinstatement of extinguished cocaine-seeking behavior produced by cocaine-associated conditioned stimuli and cocaine-priming injections. Likewise, CB(1) receptor blockade is effective in reducing nicotine-seeking behavior induced by re-exposure to nicotine-associated stimuli. Some of these findings have been recently validated in humans. In clinical trials, Rimonabant blocks the subjective effects of Delta(9)-THC in humans and prevents relapse to smoking in exsmokers. Findings from both clinical and preclinical studies suggest that ligands blocking CB(1) receptors offer a novel approach for patients suffering from drug dependence that may be efficacious across different classes of abused drugs.

Marijuana and cannabinoid regulation of brain reward circuits.

The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Delta(9)-THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation of these receptors located within the central brain reward circuits that is thought to play an important role in sustaining the self-administration of marijuana in humans, and in mediating the anxiolytic and pleasurable effects of the drug. Here we describe the cellular circuitry of the VTA and the NAc, define the sites within these areas at which cannabinoids alter synaptic processes, and discuss the relevance of these actions to the regulation of reinforcement and reward. In addition, we compare the effects of Delta(9)-THC with those of other commonly abused drugs on these reward circuits, and we discuss the roles that endogenous cannabinoids may play within these brain pathways, and their possible involvement in regulating ongoing brain function, independently of marijuana consumption. We conclude that, whereas Delta(9)-THC alters the activity of these central reward pathways in a manner that is consistent with other abused drugs, the cellular mechanism through which this occurs is likely different, relying upon the combined regulation of several afferent pathways to the VTA.

Adaptations in cholinergic transmission in the ventral tegmental area associated with the affective signs of nicotine withdrawal in rats

Chronic administration of nicotine induces adaptations in the brain reward circuit to counteract the acute drug effects; when nicotine administration ceases, these adaptations remain unopposed and lead to drug withdrawal. The present studies were conducted to assess the effects of chronic nicotine administration on nicotinic acetylcholine receptor (nAChR) activity in the ventral tegmental area (VTA) and the nucleus accumbens (Nacc) shell. A discrete-trial intracranial self-stimulation procedure that provides current-intensity thresholds as measures of brain reward function was used in rats. Previous studies have shown that withdrawal from nicotine-induced elevations in brain reward thresholds that are indicative of a decrease in brain reward function. We show here that injections of the nAChR antagonist dihydro-β-erythroidine (DHβE; 0.6–20 μg total bilateral dose) into the VTA, but not outside the VTA, resulted in significant elevations in brain reward thresholds in nicotine dependent rats (9 mg/kg/day nicotine hydrogen tartrate) while having no effect in saline-treated controls. By contrast, DHβE (0.6–20 μg total bilateral dose) injected into the Nacc shell had no effect on brain reward thresholds of nicotine- or saline-treated rats. The adaptations in cholinergic transmission in the VTA are likely to mediate, at least partly, the affective signs of nicotine withdrawal in humans.