Prolonged exposure to cocaine self-administration results in a continued progression of alterations in functional activity in a nonhuman primate model.

Background: Studies of nonhuman primates with exposures of up to 100 days of cocaine self-administration (SA) have provided evidence that the central effects of cocaine progress over time. These durations of cocaine exposure, however, may be insufficient to capture the extent of the neurobiological alterations observed in cocaine users, many of whom use the drug for years. The goal of the present study was to determine whether 1.5 years of cocaine SA would result in further progression of alterations in functional brain activity. Methods: Adult male rhesus monkeys were exposed to 300 sessions of high-dose cocaine SA over 1.5 years. Following the final session rates of local cerebral glucose utilization (LCGU) were assessed with the 2-[14C]-deoxyglucose method and compared to rates of LCGU in control monkeys who responded for food reinforcement. In addition, LCGU in these animals was compared to a previously published group of monkeys that had self-administered cocaine or food for 100 sessions over a 4-5 month period. Results: Compared to 100 days of exposure, 300 days of cocaine SA further reduced LCGU in the post-commissural striatum and produced reductions in areas unaffected by the shorter duration of exposure, such as the hypothalamus, all of the amygdala, and large expanses of cortex. Conclusions: These findings demonstrate a clear progression of the impact of cocaine on functional activity with increasing durations of drug experience and have important implications for the development of potential strategies for the treatment of cocaine use disorder.

Residual deficits in functional brain activity after chronic cocaine self-administration in rhesus monkeys.

Previous studies in humans and in animals have shown dramatic effects of cocaine on measures of brain function that persist into abstinence. The purpose of this study was to examine the neurobiological consequences of abstinence from cocaine, using a model that removes the potential confound of cocaine cues. Adult male rhesus monkeys self-administered cocaine (0.3 mg/kg/injection; N = 8) during daily sessions or served as food-reinforcement controls (N = 4). Two times per week, monkeys were placed in a neutral environment and presented with a cartoon video for ~30 min, sometimes pre- and sometimes post-operant session, but no reinforcement was presented during the video. After ~100 sessions and when the cocaine groups had self-administered 900 mg/kg cocaine, the final experimental condition was a terminal 2-[14C]-deoxyglucose procedure, which occurred in the neutral (cartoon video) environment; for half of the monkeys in each group, this occurred after 1 day of abstinence and for the others after 30 days of abstinence. Rates of local cerebral glucose metabolism were measured in 57 brain regions. Global rates of cerebral metabolism were significantly lower in animals 1 day and 30 days post-cocaine self-administration when compared to those of food-reinforced controls. Effects were larger in 30- vs. 1-day cocaine abstinence, especially in prefrontal, parietal and cingulate cortex, as well as dorsal striatum and thalamus. Because these measures were obtained from monkeys while in a neutral environment, the deficits in glucose utilization can be attributed to the consequences of cocaine exposure and not to effects of conditioned stimuli associated with cocaine.

The Effects of the Dopamine Transporter Ligands JJC8-088 and JJC8-091 on Cocaine versus Food Choice in Rhesus Monkeys.

Although there are no Food and Drug Administration-approved treatments for cocaine use disorder, several modafinil analogs have demonstrated promise in reducing cocaine self-administration and reinstatement in rats. Furthermore, the range of dopamine transporter (DAT) compounds provides an opportunity to develop pharmacotherapeutics without abuse liability. This study extended the comparison of JJC8-088 and JJC8-091, the former compound having higher DAT affinity and predicted abuse liability, to rhesus monkeys using a concurrent cocaine versus food schedule of reinforcement. First, binding to striatal DAT was examined in cocaine-naïve monkey tissue. Next, intravenous pharmacokinetics of both JJC compounds were evaluated in cocaine-experienced male monkeys (n = 3/drug). In behavioral studies, acute and chronic administration of both compounds were evaluated in these same monkeys responding under a concurrent food versus cocaine (0 and 0.003-0.1 mg/kg per injection) schedule of reinforcement. In nonhuman primate striatum, JJC8-088 had higher DAT affinity compared with JJC8-091 (14.4 ± 9 versus 2730 ± 1270 nM, respectively). Both JJC compounds had favorable plasma pharmacokinetics for behavioral assessments, with half-lives of 1.1 hours and 3.5 hours for JJC8-088 (0.7 mg/kg, i.v.) and JJC8-091 (1.9 mg/kg, i.v.), respectively. Acute treatment with both compounds shifted the cocaine dose-response curve to the left. Chronic treatment with JJC8-088 decreased cocaine choice in two of the three monkeys, whereas JJC8-091 only modestly reduced cocaine allocation in one monkey. Differences in affinities of JJC8-091 DAT binding in monkeys compared with rats may account for the poor rodent-to-monkey translation. Future studies should evaluate atypical DAT blockers in combination with behavioral interventions that may further decrease cocaine choice. SIGNIFICANCE STATEMENT: Cocaine use disorder (CUD) remains a significant public health problem with no Food and Drug Administration-approved treatments. The ability of drugs that act in the brain in a similar manner to cocaine, but with lower abuse liability, has clinical implications for a treatment of CUD.

Gender parity and homophily in the Drug and Alcohol Dependence editorial process.

BACKGROUND: Despite efforts towards gender parity and some improvement over time, gender bias in peer review remains a pervasive issue. We examined gender representation and homophily in the peer review process for Drug and Alcohol Dependence (DAD). METHODS: We extracted data for papers submitted to DAD between 2004 and 2019, inclusive. Inferred gender was assigned to handling editors and reviewers using the NamSor gender inference Application Programming Interface (API). RESULTS: Men and women handling editors were approximately equally likely to invite women reviewers over time, with only a few exceptions. Over time, 47.1% of editors were women, and 42.6% of review invitations were sent to women. Men were largely consistent over time in their likelihood of accepting a review invitation, while the likelihood of women accepting a review invitation was more variable over time. Gender differences in rates of accepting a review invitation were minimal; however, as women approached half of all invited reviewers in recent years, there has been a greater trend for women, relative to men, to decline review invitations. Evidence of homophily on the part of reviewers accepting invitations was minimal, but in certain years, a tendency to accept review invitations at higher rates from editors of the same gender was observed. DISCUSSION: Given the benefits of diversity in scientific advancement, these results underline the importance of continuing efforts to increase gender diversity among editors and in reviewer pools, and the need for reviewers to be mindful of their own reviewing practices.

Chronic phenmetrazine treatment promotes D2 dopaminergic and α2-adrenergic receptor desensitization and alters phosphorylation of signaling proteins and local cerebral glucose metabolism in the rat brain.

Phenmetrazine (PHEN) is a putative treatment for cocaine and psychostimulant recidivism; however, neurochemical changes underlying its activity have not been fully elucidated. We sought to characterize brain homeostatic adaptations to chronic PHEN, specifically on functional brain activity (local cerebral glucose utilization), G-Protein Coupled Receptor-stimulated G-protein activation, and phosphorylation of ERK1/2Thr202/Tyr204, GSK3ßTyr216, and DARPP-32Thr34. Male Sprague-Dawley rats were implanted with sub-cutaneous minipumps delivering either saline (vehicle), acute (2-day) or chronic (14-day) low dose (25 mg/kg/day) or high dose (50 mg/kg/day) PHEN. Acute administration of high dose PHEN increased local cerebral glucose utilization measured by 2-[14C]-deoxyglucose uptake in basal ganglia and motor-related regions of the rat brain. However, chronically treated animals developed tolerance to these effects. To identify the neurochemical changes associated with PHEN's activity, we performed [35S]GTPγS binding assays on unfixed and immunohistochemistry on fixed coronal brain sections. Chronic PHEN treatment dose-dependently attenuated D2 dopamine and α2-adrenergic, but not 5-HT1A, receptor-mediated G-protein activation. Two distinct patterns of effects on pERK1/2 and pDARPP-32 were observed: 1) chronic low dose PHEN decreased pERK1/2, and also significantly increased pDARPP-32 levels in some regions; 2) acute and chronic PHEN increased pERK1/2, but chronic high dose PHEN treatment tended to decrease pDARPP-32. Chronic low dose, but not high dose, PHEN significantly reduced pGSK3ß levels in several regions. Our study provides definitive evidence that extended length PHEN dosage schedules elicit distinct modes of neuronal acclimatization in cellular signaling. These pharmacodynamic modifications should be considered in drug development for chronic use.

Functional brain activity is globally elevated by dopamine D2 receptor knockdown in the ventral tegmental area.

The mesocorticolimbic system is comprised of dopaminergic neurons in the ventral tegmental area (VTA) and their projection targets in the ventral striatum, amygdala, prefrontal cortex, and hippocampus, among others. Regulation of dopamine transmission within this system is achieved in part through a negative feedback mechanism via dopamine D2 autoreceptors located on somatodendrites and terminals of VTA dopaminergic neurons. Dysregulation of this mechanism has been implicated in addiction and other psychiatric disorders, although the biological bases for these associations are unclear. In order to elucidate the functional consequences of VTA D2 receptor dysregulation, this study investigated alterations in local cerebral glucose utilization throughout the brain following Drd2 knockdown in the VTA. Male Sprague-Dawley rats received bilateral injections of lentivirus encoding shRNAs against the rat dopamine D2 receptor, scrambled shRNA or phosphate buffered saline. The autoradiographic 2-[14C]deoxyglucose metabolic mapping procedure was conducted 22 days post-infection. Brains were sectioned for autoradiography and glucose utilization was measured across distinct regions throughout the brain. Local cerebral glucose utilization was found to be elevated in the Drd2 knockdown group as compared to control groups. These greater levels of metabolic activity following Drd2 knockdown in the VTA were observed not only in the mesocorticolimbic system and associated dopamine pathways, but also in a global pattern that included many areas with far less concentrated VTA dopamine inputs. This suggests that even a partial Drd2 deletion in the VTA can have widespread consequences and impact information flow in diverse networks that process sensory, cognitive, motor and emotional information.

Brain activity associated with social exclusion overlaps with drug-related frontal-striatal circuitry in cocaine users: A pilot study.

BACKGROUND: Exposure to various types of stress can elevate craving for cocaine and hasten relapse among substance dependent individuals. This investigation evaluated the effects of social exclusion on brain activity in cocaine dependent individuals. METHOD: Forty three individuals (18 crack-cocaine users, 25 controls) were recruited from the community to participate in functional neuroimaging study in which they performed a simulated 3 person ball-tossing game (Cyberball). Each participant was told that the other 2 players were in nearby MRI scanners. Task blocks included: Inclusion (likelihood of our participant receiving the ball = 50%), Exclusion (likelihood gradually decreases to 0%), and Rest. Self-worth variables (e.g self-esteem, locus of control) were measured before and after the ball-tossing game. General linear model-based statistics were used to measure the brain response to inclusion and exclusion within and between the groups with respect to rest. RESULTS: Relative to controls, cocaine users had significantly more activity during Exclusion versus Inclusion in 3 areas: the right medial frontal gyrus (Brodmann Area 9,10), left ventral lateral frontal gyrus (Brodmann Area 10,47) and right caudate. This was driven by a higher response to social exclusion in the cocaine users. There was no difference between groups in the brain reactivity to social inclusion. CONCLUSION: Cocaine dependent individuals have an amplified brain response to social exclusion stress in cortical regions associated with emotional regulation, arousal, craving and perception of physical pain. These data suggest that there may be a neurological basis for the well-established relationship between social stress and addiction.

Regional elevations in microglial activation and cerebral glucose utilization in frontal white matter tracts of rhesus monkeys following prolonged cocaine self-administration.

It has been shown that exposure to cocaine can result in neuroinflammatory responses. Microglia, the resident CNS immune cells, undergo a transition to an activated state when challenged. In rodents, and possibly humans, cocaine exposure activates microglia. The goal of this study was to assess the extent and magnitude of microglial activation in rhesus monkeys with an extensive history of cocaine self-administration. Male rhesus monkeys (N = 4/group) were trained to respond on a fixed-interval 3-min schedule of food or 0.3 mg/kg/injection cocaine presentation (30 reinforcers/session) for 300 sessions. At the end of the final session, monkeys were administered 2-[14C]deoxyglucose intravenously and 45 min later euthanized. Brain sections were used for autoradiographic assessments of glucose utilization and for microglia activation with [3H]PK11195, a marker for the microglial 18-kDa translocator protein. There were no group differences in gray matter [3H]PK11195 binding, while binding was significantly greater in cocaine self-administration animals as compared to food controls in 8 of the 11 white matter tracts measured at the striatal level. Binding did not differ from control at other levels. There were also significant increases in white matter local cerebral glucose utilization at the striatal level, which were positively correlated with [3H]PK11195 binding. The present findings demonstrate an elevation in [3H]PK11195 binding in forebrain white matter tracts of nonhuman primates with a prolonged history of cocaine self-administration. These elevations were also associated with greater cerebral metabolic rates. These data suggest that white matter deficits may contribute to behavioral, motivational, and cognitive impairments observed in cocaine abusers.

Neurophysiological capacity in a working memory task differentiates dependent from nondependent heavy drinkers and controls.

BACKGROUND: Determining the neurobehavioral profiles that differentiate heavy drinkers who are and are not alcohol dependent will inform treatment efforts. Working memory is linked to substance use disorders and can serve as a representation of the demand placed on the neurophysiology associated with cognitive control. METHODS: Behavior and brain activity (via fMRI) were recorded during an N-Back working memory task in controls (CTRL), nondependent heavy drinkers (A-ND) and dependent heavy drinkers (A-D). Typical and novel step-wise analyses examined profiles of working memory load and increasing task demand, respectively. RESULTS: Performance was significantly decreased in A-D during high working memory load (2-Back), compared to CTRL and A-ND. Analysis of brain activity during high load (0-Back vs. 2- Back) showed greater responses in the dorsal lateral and medial prefrontal cortices of A-D than CTRL, suggesting increased but failed compensation. The step-wise analysis revealed that the transition to Low Demand (0-Back to 1-Back) was associated with robust increases and decreases in cognitive control and default-mode brain regions, respectively, in A-D and A-ND but not CTRL. The transition to High Demand (1-Back to 2-Back) resulted in additional engagement of these networks in A-ND and CTRL, but not A-D. CONCLUSION: Heavy drinkers engaged working memory neural networks at lower demand than controls. As demand increased, nondependent heavy drinkers maintained control performance but relied on additional neurophysiological resources, and dependent heavy drinkers did not display further resource engagement and had poorer performance. These results support targeting these brain areas for treatment interventions.

Social Status in Monkeys: Effects of Social Confrontation on Brain Function and Cocaine Self-Administration.

Individual differences in response to social stress and environmental enrichment may contribute to variability in response to behavioral and pharmacological treatments for drug addiction. In monkeys, social status influences the reinforcing effects of cocaine and the effects of some drugs on cocaine self-administration. In this study, we used male cynomolgus macaques (n=15) living in established social groups to examine the effects of social confrontation on the reinforcing effects of cocaine using a food-drug choice procedure. On the test day, a dominant or subordinate monkey was removed from his homecage and placed into another social pen; 30 min later he was studied in a cocaine-food choice paradigm. For the group, following social confrontation, sensitivity to cocaine reinforcement was significantly greater in subordinate monkeys compared with dominant animals. Examining individual-subject data revealed that for the majority of monkeys (9/15), serving as an intruder in another social group affected cocaine self-administration and these effects were dependent on the social rank of the monkey. For subordinate monkeys, sensitivity to the reinforcing effects of cocaine increased while sensitivity decreased in dominant monkeys. To investigate potential mechanisms mediating these effects, brain glucose metabolism was studied in a subset of monkeys (n=8) using [18F]fluorodeoxyglucose ([18F]FDG) with positron emission tomography. Dominant and subordinate monkeys displayed distinctly different patterns of brain glucose metabolism in their homecage, including areas associated with vigilance and stress/anxiety, respectively, and during social confrontation. These data demonstrate that, depending on an individual's social status, the same social experience can have divergent effects on brain function and cocaine self-administration. These phenotypic differences in response to social conditions support a personalized treatment approach to cocaine addiction.

Moderate-Heavy Alcohol Consumption Lifestyle in Older Adults Is Associated with Altered Central Executive Network Community Structure during Cognitive Task.

Older adults today consume more alcohol than previous generations, the majority being social drinkers. The effects of heavy alcohol use on brain functioning closely resemble age-related changes, but it is not known if moderate-heavy alcohol consumption intensifies brain aging. Whether a lifestyle of moderate-heavy alcohol use in older adults increased age-related brain changes was examined. Forty-one older adults (65-80 years) that consumed light (< 2 drinks/week and ≥ 1 drink/month, n = 20) or moderate-heavy (7-21 drinks/week, non-bingers, n = 21) amounts of alcohol were enrolled. Twenty-two young adults (24-35 years) were also enrolled (light, n = 11 and moderate-heavy, n = 11). Functional brain networks based on magnetic resonance imaging data were generated for resting state and during a working memory task. Whole-brain, Central Executive Network (CEN), and Default Mode Network (DMN) connectivity were assessed in light and moderate-heavy alcohol consuming older adults with comparisons to young adults. The older adults had significantly lower whole brain connectivity (global efficiency) and lower regional connectivity (community structure) in the CEN during task and in the DMN at rest. Moderate-heavy older drinkers did not exhibit whole brain connectivity differences compared to the low drinkers. However, decreased CEN connectivity was observed during the task. There were no differences in the DMN connectivity between drinking groups. Taken together, a lifestyle including moderate-heavy alcohol consumption may be associated with further decreases in brain network connectivity within task-related networks in older adults. Further research is required to determine if this decrease is compensatory or an early sign of decline.

Neural Correlates of Exposure to Cocaine Cues in Rhesus Monkeys: Modulation by the Dopamine Transporter.

BACKGROUND: A major goal of treatments for cocaine addiction is to reduce relapse-associated cravings, which are typically induced by environmental stimuli associated with cocaine use and related to changes in dopamine neurotransmission. METHODS: The present study used an animal model of cocaine seeking to determine functional consequences of cue exposure using fluorodeoxyglucose positron emission tomography and to relate findings to juvenile levels of dopamine transporter and D2-like receptor availabilities determined before any drug exposure. Adult male rhesus monkeys (N = 11) self-administered cocaine (0.2 mg/kg per injection) under a second-order schedule of reinforcement, in which responding was maintained by conditioned reinforcers. Positron emission tomography scans assessing glucose utilization, a marker of functional activation, were conducted during cocaine-cue responding and food-reinforced responding in a context where cocaine was never available. RESULTS: Compared with the noncocaine condition, we found significant functional activation in the medial prefrontal cortex, anterior cingulate, precuneus region of the parietal cortex, and striatum-findings similar to those reported in humans who abuse cocaine. Furthermore, these functional activations in the prefrontal, cingulate, and parietal cortex measured during cocaine-cue responding were significantly correlated with juvenile measures of dopamine transporter availability, whereas no significant relationship with prior D2-like receptor availability was observed in any brain region. CONCLUSIONS: The similarity between the present findings and findings in humans who use cocaine supports the use of this model for examination of factors that affect the development and intensity of cue-induced drug seeking and provides evidence for potential biomarkers for the evaluation of potential treatments (behavioral and pharmacologic) for cocaine abuse.

Abnormal medial prefrontal cortex activity in heavy cannabis users during conscious emotional evaluation.

RATIONALE: Long-term heavy cannabis users (cannabis users) who are not acutely intoxicated have diminished subconscious neural responsiveness to affective stimuli. OBJECTIVE: This study sought to determine if abnormal processing extends to the conscious evaluation of emotional stimuli. METHODS: Functional magnetic resonance imaging (fMRI) was used to examine brain activity as cannabis users (N = 16) and non-cannabis-using controls (N = 17) evaluated and categorized standardized International Affective Picture System (IAPS) stimuli. Individual judgments were used to isolate activity during the evaluation of emotional (i.e., emotional evaluation) or neutral (i.e., neutral evaluation) stimuli. Within- and between-group analyses were performed. RESULTS: Both groups judged the same stimuli as emotional and had activations in visual, midbrain, and middle cingulate cortices during emotional evaluation, relative to neutral. Within-group analyses also revealed amygdalar and inferior frontal gyrus activations in controls, but not cannabis users, and medial prefrontal cortex (mPFC) deactivations in cannabis users, but not controls, during emotional evaluation, relative to neutral. Between-group comparisons found that mPFC activity during positive and negative evaluation was significantly hypoactive in cannabis users, relative to controls. CONCLUSIONS: Abnormal neural processing of affective content extends to the level of consciousness in cannabis users. The hypoactive mPFC responses observed resembles the attenuated mPFC responses found during increased non-affective cognitive load in prior research. These findings suggest that abnormal mPFC singling in cannabis users during emotional evaluation might be associated with increased non-affective cognitive load.

Functional consequences of cocaine expectation: findings in a non-human primate model of cocaine self-administration.

Exposure to stimuli and environments associated with drug use is considered one of the most important contributors to relapse among substance abusers. Neuroimaging studies have identified neural circuits underlying these responses in cocaine-dependent subjects. But these studies are often difficult to interpret because of the heterogeneity of the participants, substances abused, and differences in drug histories and social variables. Therefore, the goal of this study was to assess the functional effects of exposure to cocaine-associated stimuli in a non-human primate model of cocaine self-administration, providing precise control over these variables, with the 2-[(14) C]deoxyglucose method. Rhesus monkeys self-administered 0.3 mg/kg/injection cocaine (n = 4) under a fixed-interval 3-minute (FI 3-min) schedule of reinforcement (30 injections/session) for 100 sessions. Control animals (n = 4) underwent identical schedules of food reinforcement. Sessions were then discontinued for 30 days, after which time, monkeys were exposed to cocaine- or food-paired cues, and the 2-[(14) C]deoxyglucose experiment was conducted. The presentation of the cocaine-paired cues resulted in significant increases in functional activity within highly restricted circuits that included portions of the pre-commissural striatum, medial prefrontal cortex, rostral temporal cortex and limbic thalamus when compared with control animals presented with the food-paired cues. The presentation of cocaine-associated cues increased brain functional activity in contrast to the decreases observed after cocaine consumption. Furthermore, the topography of brain circuits engaged by the expectation of cocaine is similar to the distribution of effects during the earliest phases of cocaine self-administration, prior to the onset of neuroadaptations that accompany chronic cocaine exposure.

Effects of abstinence from chronic cocaine self-administration on nonhuman primate dorsal and ventral noradrenergic bundle terminal field structures.

Repeated exposure to cocaine is known to dysregulate the norepinephrine system, and norepinephrine has also been implicated as having a role in abstinence and withdrawal. The goal of this study was to determine the effects of exposure to cocaine self-administration and subsequent abstinence on regulatory elements of the norepinephrine system in the nonhuman primate brain. Rhesus monkeys self-administered cocaine (0.3 mg/kg/injection, 30 reinforcers/session) under a fixed-interval 3-min schedule of reinforcement for 100 sessions. Animals in the abstinence group then underwent a 30-day period during which no operant responding was conducted, followed by a final session of operant responding. Control animals underwent identical schedules of food reinforcement and abstinence. This duration of cocaine self-administration has been shown previously to increase levels of norepinephrine transporters (NET) in the ventral noradrenergic bundle terminal fields. In contrast, in the current study, abstinence from chronic cocaine self-administration resulted in elevated levels of [(3)H]nisoxetine binding to the NET primarily in dorsal noradrenergic bundle terminal field structures. As compared to food reinforcement, chronic cocaine self-administration resulted in decreased binding of [(3)H]RX821002 to α2-adrenoceptors primarily in limbic-related structures innervated by both dorsal and ventral bundles, as well as elevated binding in the striatum. However, following abstinence from responding for cocaine binding to α2-adrenoceptors was not different than in control animals. These data demonstrate the dynamic nature of the regulation of norepinephrine during cocaine use and abstinence, and provide further evidence that the norepinephrine system should not be overlooked in the search for effective pharmacotherapies for cocaine dependence.

Chronic methylphenidate treatment during early life is associated with greater ethanol intake in socially isolated rats.

BACKGROUND: Methylphenidate (MPH) is a stimulant prescribed to treat attention-deficit/ hyperactivity disorder. Its primary mechanism of action is in the dopamine system, alterations of which are associated with vulnerability to alcohol abuse. There are concerns that juvenile MPH treatment may influence adult drinking behavior. This study examined the interaction of MPH treatment and environmental rearing conditions, which are known to independently influence ethanol (EtOH) drinking behavior, on anxiety-like behavior and vulnerability to alcohol abuse in a juvenile rodent model. METHODS: Male Sprague-Dawley rats were housed in enriched, standard, or isolated conditions for 4 weeks, starting at postnatal day 21. Rats were concurrently treated with 8 mg/kg/d MPH or saline, delivered via osmotic minipump. Anxiety-like behavior was determined at the end of the treatment session, and 5 weeks later. After MPH treatment, rats were exposed to a 2-bottle choice EtOH drinking procedure that lasted 3 weeks. RESULTS: Early life chronic MPH treatment was associated with greater EtOH intake and greater EtOH preference, but only in socially isolated animals. Isolated animals had greater levels of anxiety-like behavior than standard-housed or enriched animals after 4 weeks of exposure to the housing conditions, a difference that persisted even after all animals had been individually housed for an additional 5 weeks and exposed to EtOH. CONCLUSIONS: These results suggest that early life MPH treatment may increase vulnerability to EtOH drinking in adulthood in a subset of the population. Additionally, this study highlights the importance of early rearing condition for establishing long-lasting behavioral phenotypes. Environmental histories should be considered when prescribing MPH treatment to young children.

Functional consequences of cocaine re-exposure after discontinuation of cocaine availability.

Cocaine users exhibit a wide range of behavioral impairments accompanied by brain structural, neurochemical and functional abnormalities. Metabolic mapping studies in cocaine users and animal models have shown extensive functional alterations throughout the striatum, limbic system, and cortex. Few studies, however, have evaluated the persistence of these effects following cessation of cocaine availability. The purpose of this study, therefore, was to assess the functional effects of re-exposure to cocaine in nonhuman primates after the discontinuation of cocaine self-administration for 30 or 90 days, using the quantitative autoradiographic 2-[14C]deoxyglucose (2DG) method. Rhesus monkeys self-administered cocaine (fixed interval 3-min schedule, 30 infusions per session, 0.3 mg/kg/infusion) for 100 sessions followed by 30 (n=4) or 90 days (n=3) during which experimental sessions were not conducted. Food-reinforced control animals (n=5) underwent identical schedules of reinforcement. Animals were then re-exposed to cocaine or food for one final session and the 2DG method applied immediately after session completion. Compared to controls, re-exposure to cocaine after 30 or 90 day drug-free periods resulted in lower rates of glucose utilization in ventral and dorsal striatum, prefrontal and temporal cortex, limbic system, thalamus, and midbrain. These data demonstrate that vulnerability to the effects of cocaine persists for as long as 90 days after cessation of drug use. While there was some evidence for recovery (fewer brain areas were affected by cocaine re-exposure at 90 days as compared to 30 days), this was not uniform across regions, thus suggesting that recovery occurs at different rates in different brain systems.

Age-related differences in advantageous decision making are associated with distinct differences in functional community structure.

Human decision making is dependent on not only the function of several brain regions but also their synergistic interaction. The specific function of brain areas within the ventromedial prefrontal cortex has long been studied in an effort to understand choice evaluation and decision making. These data specifically focus on whole-brain functional interconnectivity using the principles of network science. The Iowa Gambling Task (IGT) was the first neuropsychological task used to model real-life decisions in a way that factors reward, punishment, and uncertainty. Clinically, it has been used to detect decision-making impairments characteristic of patients with prefrontal cortex lesions. Here, we used performance on repeated blocks of the IGT as a behavioral measure of advantageous and disadvantageous decision making in young and mature adults. Both adult groups performed poorly by predominately making disadvantageous selections in the beginning stages of the task. In later phases of the task, young adults shifted to more advantageous selections and outperformed mature adults. Modularity analysis revealed stark underlying differences in visual, sensorimotor and medial prefrontal cortex community structure. In addition, changes in orbitofrontal cortex connectivity predicted behavioral deficits in IGT performance. Contrasts were driven by a difference in age but may also prove relevant to neuropsychiatric disorders associated with poor decision making, including the vulnerability to alcohol and/or drug addiction.

Regionally-specific alterations in myelin proteins in nonhuman primate white matter following prolonged cocaine self-administration.

BACKGROUND: Neuroimaging studies of cocaine users have demonstrated white matter abnormalities associated with behavioral measures of impulsivity and decision-making deficits. The underlying bases for this dysregulation in white matter structure and function have yet to be determined. The aim of the present studies was to investigate the influence of prolonged cocaine self-administration on the levels of myelin-associated proteins and mRNAs in nonhuman primate white matter. METHODS: Rhesus monkeys (N=4) self-administered cocaine (0.3mg/kg/inj, 30 reinforcers per session) for 300 sessions. Control animals (N=4) responded for food. Following the final session monkeys were euthanized and white matter tissue at three brain levels was processed for immunoblotting analysis of proteolipid protein (PLP) and myelin basic protein (MBP), as well as for in situ hybridization histochemical analysis of PLP and MBP mRNAs. RESULTS: Both MBP and PLP immunoreactivities in white matter at the level of the precommissural striatum were significantly lower in tissue from monkeys self-administering cocaine as compared to controls. No significant differences were seen for either protein at the levels of the prefrontal cortex or postcommissural striatum. In addition, no differences were observed in expression of mRNA for either protein. CONCLUSIONS: These preliminary findings, in a nonhuman model of prolonged cocaine self-administration, provide further evidence that compromised myelin may underlie the deficits in white matter integrity described in studies of human cocaine users.

Long-term moderate alcohol consumption does not exacerbate age-related cognitive decline in healthy, community-dwelling older adults.

Recent census data has found that roughly 40% of adults 65 years and older not only consume alcohol but also drink more of it than previous generations. Older drinkers are more vulnerable than younger counterparts to the psychoactive effects of alcohol due to natural biological changes that occur with aging. This study was specifically designed to measure the effect of long-term moderate alcohol consumption on cognitive health in older adult drinkers. An extensive battery of validated tests commonly used in aging and substance use literature was used to measure performance in specific cognitive domains, including working memory and attention. An age (young, old) (*) alcohol consumption (light, moderate) factorial study design was used to evaluate the main effects of age and alcohol consumption on cognitive performance. The focus of the study was then limited to light and moderate older drinkers, and whether or not long-term moderate alcohol consumption exacerbated age-related cognitive decline. No evidence was found to support the idea that long-term moderate alcohol consumption in older adults exacerbates age-related cognitive decline. Findings were specific to healthy community dwelling social drinkers in older age and they should not be generalized to individuals with other consumption patterns, like heavy drinkers, binge drinkers or ex-drinkers.