Baclofen decreases compulsive alcohol drinking in rats characterized by reduced levels of GAT-3 in the central amygdala.

While most individuals with access to alcohol drink it recreationally, some vulnerable individuals eventually lose control over their intake and progressively develop compulsive alcohol drinking and decreased interest in alternative sources of reinforcement, two key features of addiction. The neural and molecular mechanisms underlying this vulnerability to switch from controlled to compulsive alcohol intake have not been fully elucidated. It has been shown that rats having reduced levels of expression of the gamma-aminobutyric acid (GABA) transporter, GAT-3, in the amygdala tend to persist in seeking and drinking alcohol even when adulterated with quinine, suggesting that pharmacological interventions aimed at restoring GABA homeostasis in these individuals may provide a targeted treatment to limit compulsive alcohol drinking. Here, we tested the hypothesis that the GABAB receptor agonist baclofen, which decreases GABA release, specifically reduces compulsive alcohol drinking in vulnerable individuals. In a large cohort of Sprague-Dawley rats allowed to drink alcohol under an intermittent two-bottle choice procedure, a cluster of individuals was identified that persisted in drinking alcohol despite adulteration with quinine or when an alternative ingestive reinforcer, saccharin, was available. In these rats, which were characterized by decreased GAT-3 mRNA levels in the central amygdala, acute baclofen administration (1.5 mg/kg, intraperitoneal) resulted in a decrease in compulsive drinking. These results indicate that low GAT-3 mRNA levels in the central amygdala may represent an endophenotype of vulnerability to develop a compulsive drinking of alcohol that is shown here to be mitigated by baclofen.

Decreased motor impulsivity following chronic lithium treatment in male rats is associated with reduced levels of pro-inflammatory cytokines in the orbitofrontal cortex.

Lithium's efficacy in reducing both symptom severity in bipolar disorder (BD) and suicide risk across clinical populations may reflect its ability to reduce impulsivity. Changes in immune markers are associated with BD and suicidality yet their exact role in symptom expression remains unknown. Evidence also suggests that lithium may decrease levels of pro-inflammatory cytokines in the periphery and central nervous system, and that such changes are related to its therapeutic efficacy. However, issues of cause and effect are hard to infer from clinical data alone. Here, we investigated the effects of chronic dietary lithium treatment on rats' performance of the 5-Choice Serial Reaction Time Task (5CSRTT), a well-validated operant behavioural task measuring aspects of impulsivity, attention and motivation. Male Long-Evans rats received a diet supplemented with 0.3% LiCl (n = 13), or the equivalent control diet (n = 16), during behavioural testing. Blood and brain tissue samples were assayed for a wide range of cytokines once any changes in impulsivity became significant. After 12 weeks, chronic lithium treatment reduced levels of motor impulsivity, as indexed by premature responses in the 5CSRTT; measures of sustained attention and motivation were unaffected. Plasma levels of IL-1ß, IL-10 and RANTES (CCL-5) were reduced in lithium-treated rats at this time point. IL-1ß, IL-6 and RANTES were also reduced selectively within the orbitofrontal cortex of lithium-treated rats, whereas cytokine levels in the medial prefrontal cortex and nucleus accumbens were comparable with control subjects. These results are consistent with the hypothesis that lithium may improve impulse control deficits in clinical populations by minimising the effects of pro-inflammatory signalling on neuronal activity, particularly within the orbitofrontal cortex.

Increased motor impulsivity in a rat gambling task during chronic ropinirole treatment: potentiation by win-paired audiovisual cues.

RATIONALE: Chronic administration of D2/3 receptor agonists ropinirole or pramipexole can increase the choice of uncertain rewards in rats, theoretically approximating iatrogenic gambling disorder (iGD). OBJECTIVES: We aimed to assess the effect of chronic ropinirole in animal models that attempt to capture critical aspects of commercial gambling, including the risk of losing rather than failing to gain, and the use of win-paired sensory stimuli heavily featured in electronic gambling machines (EGMs). METHODS: Male Long-Evans rats learned the rat gambling task (rGT; n = 24), in which animals sample between four options that differ in the magnitude and probability of rewards and time-out punishments. In the cued rGT (n = 40), reward-concurrent audiovisual cues were added that scaled in complexity with win size. Rats were then implanted with an osmotic pump delivering ropinirole (5 mg/kg/day) or saline for 28 days. RESULTS: Chronic ropinirole did not unequivocally increase preference for more uncertain outcomes in either the cued or uncued rGT. Ropinirole transiently increased premature responses, a measure of motor impulsivity, and this change was larger and more long-lasting in the cued task. CONCLUSIONS: These data suggest that explicitly signaling loss prevents the increase in preference for uncertain rewards caused by D2/3 receptor agonists observed previously. The ability of win-paired cues to amplify ropinirole-induced increases in motor impulsivity may explain why compulsive use of EGMs is particularly common in iGD. These data offer valuable insight into the cognitive-behavioral mechanisms through which chronic dopamine agonist treatments may induce iGD and related impulse control disorders.

Deep-Brain Stimulation of the Subthalamic Nucleus Selectively Decreases Risky Choice in Risk-Preferring Rats.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) can improve the motor symptoms of Parkinson's disease (PD) and negate the problematic side effects of dopamine replacement therapy. Although there is concern that STN-DBS may enhance the development of gambling disorder and other impulse control disorders in this patient group, recent data suggest that STN-DBS may actually reduce iatrogenic impulse control disorders, and alleviate obsessive-compulsive disorder (OCD). Here, we sought to determine whether STN-DBS was beneficial or detrimental to performance of the rat gambling task (rGT), a rodent analogue of the Iowa Gambling Task (IGT) used to assess risky decision making clinically. Rats chose between four options associated with different amounts and probabilities of sugar pellet rewards versus timeout punishments. As in the IGT, the optimal approach was to favor options associated with smaller per-trial gains but lower timeout penalties. Once a stable behavioral baseline was established, electrodes were implanted bilaterally into the STN, and the effects of STN-DBS assessed on-task over 10 consecutive sessions using an A-B-A design. STN-DBS did not affect choice in optimal decision makers that correctly favored options associated with smaller per-trial gains but also lower penalties. However, a minority (∼25%) preferred the maladaptive "high-risk, high-reward" options at baseline. STN-DBS significantly and progressively improved choice in these risk-preferring rats. These data support the hypothesis that STN-DBS may be beneficial in ameliorating maladaptive decision making associated with compulsive and addiction disorders.

Bidirectional regulation over the development and expression of loss of control over cocaine intake by the anterior insula.

RATIONALE: Increasing evidence suggests that the anterior insular cortex (AIC) plays a major role in cocaine addiction, being implicated in both impaired insight and associated decision-making and also craving and relapse. However, the nature of the involvement of the insula in the development and maintenance of cocaine addiction remains unknown, thereby limiting our understanding of its causal role in addiction. We therefore investigated whether pre- and post-training bilateral lesions of the AIC differentially influenced the development and the expression of the escalation of cocaine self-administration during extended access to the drug. METHODS: In a series of experiments, Sprague Dawley rats received bilateral excitotoxic lesions of the AIC either prior to, or after 3 weeks of training under 12-h extended self-administration conditions, which are known to promote a robust escalation of intake. We also investigated the influence of AIC lesions on anxiety, as measured in an elevated plus maze and sensitivity to conditioned stimuli (CS)- or drug-induced reinstatement of an extinguished instrumental response. RESULTS: Whereas, post-escalation lesions of the AIC, as anticipated, restored control over cocaine intake and prevented drug-induced reinstatement, pre-training lesions resulted in a facilitation of the development of loss of control with no influence over the acquisition of cocaine self-administration or anxiety. CONCLUSIONS: AIC lesions differentially affect the development and maintenance of the loss of control over cocaine intake, suggesting that the nature of the contribution of cocaine-associated interoceptive mechanisms changes over the course of escalation and may represent an important component of addiction.

Dissociable effects of systemic and orbitofrontal administration of adrenoceptor antagonists on yohimbine-induced motor impulsivity.

The α2-adrenoceptor antagonist, yohimbine, is commonly used as a pharmacological stressor. Its behavioural effects are typically attributed to elevated noradrenaline release via blockade of central, inhibitory autoreceptors. We have previously reported that yohimbine increases motor impulsivity in rats on the five-choice serial reaction time task (5CSRTT), a cognitive behavioural assessment which measures motor impulsivity and visuospatial attention. Furthermore, this effect depended on cyclic adenomonophosphate (cAMP) signalling via cAMP response element binding (CREB) protein in the orbitofrontal cortex (OFC). However, the role of specific adrenoceptors in this effect is not well-characterised. We therefore investigated whether the pro-impulsive effects of systemic yohimbine could be reproduced by direct administration into the OFC, or attenuated by intra-OFC or systemic administration of prazosin and propranolol-antagonists at the α1- and ß-adrenoceptor, respectively. Male Long-Evans rats were trained on the 5CSRTT and implanted with guide cannulae aimed at the OFC. Systemically administered α1- or ß-adrenoceptor antagonists attenuated yohimbine-induced increases in premature responding. In contrast, local infusion of yohimbine into the OFC reduced such impulsive responding, while blockade of α1- or ß-adrenoceptors within the OFC had no effect on either basal or yohimbine-stimulated motor impulsivity. Direct administration of selective antagonists at the α1-, α2- or ß-adrenoceptor into the OFC therefore produce clearly dissociable effects from systemic administration. Collectively, these data suggest that the pro-impulsivity effect of yohimbine can be modulated by adrenergic signalling in brain areas outside of the OFC, in addition to non-adrenergic signalling pathways within the OFC.

Chronic administration of the dopamine D2/3 agonist ropinirole invigorates performance of a rodent slot machine task, potentially indicative of less distractible or compulsive-like gambling behaviour.

RATIONALE: Whilst dopamine agonist therapies can successfully manage the symptoms of diseases such as Parkinson's disease (PD), fibromyalgia and restless leg syndrome, they can also cause impulse control and addiction disorders such as gambling disorder (GD). These compulsive behaviours seriously undermine the utility of such treatments. OBJECTIVES: The objective of the study was to model this phenomenon using a rodent slot machine task (rSMT) in order to investigate the neurobiological basis underlying such behavioural changes. METHODS: Male Long Evans rats were trained to perform the rSMT. The D2-like agonist ropinirole, or saline, was then delivered continuously for 28 days via osmotic mini-pump. The effects of ropinirole on baseline rSMT performance, as well as extinction and reinstatement sessions, were determined during this time. Brain samples from key frontostriatal regions implicated in GD and PD were then harvested immediately or after a 4-week washout period during which behaviour returned to pre-drug baseline. RESULTS: Ropinirole invigorated task performance, in that drug treatment resulted in a robust and sustained increase in the number of trials completed. Ex vivo analyses revealed that chronic ropinirole treatment led to a pattern of changes indicative of upregulation within the ß-arrestin-AKT-GSK3ß intracellular cascade, recently theorised to dominate D2-mediated signalling under hyperdopaminergic conditions, in the dorsal striatum, rather than the canonical PKA-dependent signalling pathway associated with D2 receptor activation. CONCLUSIONS: Such findings provide novel insight into the role of dopamine signalling in mediating compulsive-like gambling behaviour and may inform more directed pharmacotherapies for the treatment of both idiopathic and iatrogenic GD.

Prefrontal Cortical Inactivations Decrease Willingness to Expend Cognitive Effort on a Rodent Cost/Benefit Decision-Making Task.

Personal success often necessitates expending greater effort for greater reward but, equally important, also requires judicious use of our limited cognitive resources (e.g., attention). Previous animal models have shown that the prelimbic (PL) and infralimbic (IL) regions of the prefrontal cortex (PFC) are not involved in (physical) effort-based choice, whereas human studies have demonstrated PFC contributions to (mental) effort. Here, we utilize the rat Cognitive Effort Task (rCET) to probe PFC's role in effort-based decision making. In the rCET, animals can choose either an easy trial, where the attentional demand is low but the reward (sugar) is small or a difficult trial on which both the attentional demand and reward are greater. Temporary inactivation of PL and IL decreased all animals' willingness to expend mental effort and increased animals' distractibility; PL inactivations more substantially affected performance (i.e., attention), whereas IL inactivations increased motor impulsivity. These data imply that the PFC contributes to attentional resources, and when these resources are diminished, animals shift their choice (via other brain regions) accordingly. Thus, one novel therapeutic approach to deficits in effort expenditure may be to focus on the resources that such decision making requires, rather than the decision-making process per se.

Dissociable effects of basolateral amygdala lesions on decision making biases in rats when loss or gain is emphasized.

Individuals switch from risk seeking to risk aversion when mathematically identical options are described in terms of loss versus gains, as exemplified in the reflection and framing effects. Determining the neurobiology underlying such cognitive biases could inform our understanding of decision making in health and disease. Although reports vary, data using human subjects have implicated the amygdala in such biases. Animal models enable more detailed investigation of neurobiological mechanisms. We therefore tested whether basolateral amygdala (BLA) lesions would affect risk preference for gains or losses in rats. Choices in both paradigms were always between options of equal expected value-a guaranteed outcome, or the 50:50 chance of double or nothing. In the loss-chasing task, most rats exhibited strong risk seeking preferences, gambling at the risk of incurring double the penalty, regardless of the size of the guaranteed loss. In the betting task, the majority of animals were equivocal in their choice, irrespective of bet size; however, a wager-sensitive subgroup progressively shifted away from the uncertain option as the bet size increased, which is reminiscent of risk aversion. BLA lesions increased preference for the smaller guaranteed loss in the loss-chasing task, without affecting choice on the betting task, which is indicative of reduced risk seeking for losses, but intact risk aversion for gains. These data support the hypothesis that the amygdala plays a more prominent role in choice biases related to losses. Given the importance of the amygdala in representing negative affect, the aversive emotional reaction to loss, rather than aberrant estimations of probability or loss magnitude, may underlie risk seeking for losses.

Dissociable contributions of anterior cingulate cortex and basolateral amygdala on a rodent cost/benefit decision-making task of cognitive effort.

Personal success often requires the choice to expend greater effort for larger rewards, and deficits in such effortful decision making accompany a number of illnesses including depression, schizophrenia, and attention-deficit/hyperactivity disorder. Animal models have implicated brain regions such as the basolateral amygdala (BLA) and anterior cingulate cortex (ACC) in physical effort-based choice, but disentangling the unique contributions of these two regions has proven difficult, and effort demands in industrialized society are predominantly cognitive in nature. Here we utilize the rodent cognitive effort task (rCET), a modification of the five-choice serial reaction-time task, wherein animals can choose to expend greater visuospatial attention to obtain larger sucrose rewards. Temporary inactivation (via baclofen-muscimol) of BLA and ACC showed dissociable effects: BLA inactivation caused hard-working rats to 'slack off' and 'slacker' rats to work harder, whereas ACC inactivation caused all animals to reduce willingness to expend mental effort. Furthermore, BLA inactivation increased the time needed to make choices, whereas ACC inactivation increased motor impulsivity. These data illuminate unique contributions of BLA and ACC to effort-based decision making, and imply overlapping yet distinct circuitry for cognitive vs physical effort. Our understanding of effortful decision making may therefore require expanding our models beyond purely physical costs.

A selective role for dopamine D4 receptors in modulating reward expectancy in a rodent slot machine task.

BACKGROUND: Cognitive distortions regarding gambling outcomes confer vulnerability to pathological gambling. Using a rat slot machine task (rSMT), we previously demonstrated that the nonspecific D2 agonist quinpirole enhances erroneous expectations of reward on near-miss trials, suggesting a pivotal role for the D2 receptor family in mediating the near-miss effect. Identifying which receptor subtype is involved could facilitate treatment development for compulsive slot machine play. METHODS: Thirty-two male Long Evans rats learned the rSMT. Three flashing lights could be set to on or off. A win was signaled if all three lights were set to on, whereas any other light pattern indicated a loss. Rats then chose between responding on the collect lever, which delivered 10 sugar pellets on win trials but a 10-second time penalty on loss trials, or to start a new trial instead. Performance was assessed following systemic administration of selective D2, D3, and D4 receptor ligands. RESULTS: The selective D2 antagonist L-741,626, the D3 antagonist SB-277011-A, and the D3 agonist PD128,907 had no effect. In contrast, the selective D4 agonist PD168077 partially mimicked quinpirole's effects, increasing erroneous collect responses on nonwin trials, whereas the D4 antagonist L-745,870 improved the error rate. L-745,870 was also the only antagonist that could attenuate the deleterious effects of quinpirole. CONCLUSIONS: The dopamine D4 receptor is critically involved in signaling reward expectancy in the rSMT. The ability of L-745,870 to reduce the classification of losses as wins suggests that D4 antagonists could be effective in treating problematic slot machine play.

Irrational choice under uncertainty correlates with lower striatal D(2/3) receptor binding in rats.

Individual differences in dopamine (DA) signaling, including low striatal D(2/3) receptors, may increase vulnerability to substance abuse, although whether this phenotype confers susceptibility to nonchemical addictions is unclear. The degree to which people use "irrational" cognitive heuristics when choosing under uncertainty can determine whether they find gambling addictive. Given that dopaminergic projections to the striatum signal reward expectancy and modulate decision-making, individual differences in DA signaling could influence the extent of such biases. To test this hypothesis, we used a novel task to model biased, risk-averse decision-making in rats. Animals chose between a "safe" lever, which guaranteed delivery of the wager, or an "uncertain" lever, which delivered either double the wager or nothing with 50:50 odds. The bet size varied from one to three sugar pellets. Although the amount at stake did not alter the options' utility, a subgroup of "wager-sensitive" rats increased their preference for the safe lever as the bet size increased, akin to risk aversion. In contrast, wager-insensitive rats slightly preferred the uncertain option consistently. Amphetamine increased choice of the uncertain option in wager-sensitive, but not in wager-insensitive rats, whereas a D(2/3) receptor antagonist decreased uncertain lever choice in wager-insensitive rats alone. Micro-PET and autoradiography using [(11)C]raclopride confirmed a strong correlation between high wager sensitivity and low striatal D(2/3) receptor density. These data suggest that the propensity for biased decision-making under uncertainty is influenced by striatal D(2/3) receptor expression, and provide novel support for the hypothesis that susceptibility to chemical and behavioral addictions may share a common neurobiological basis.

Sensitivity to cognitive effort mediates psychostimulant effects on a novel rodent cost/benefit decision-making task.

Amotivational states and insufficient recruitment of mental effort have been observed in a variety of clinical populations, including depression, traumatic brain injury, post-traumatic stress disorder, and attention deficit hyperactivity disorder. Previous rodent models of effort-based decision making have utilized physical costs whereas human studies of effort are primarily cognitive in nature, and it is unclear whether the two types of effortful decision making are underpinned by the same neurobiological processes. We therefore designed a novel rat cognitive effort task (rCET) based on the 5-choice serial reaction time task, a well-validated measure of attention and impulsivity. Within each trial of the rCET, rats are given the choice between an easy or hard visuospatial discrimination, and successful hard trials are rewarded with double the number of sugar pellets. Similar to previous human studies, stable individual variation in choice behavior was observed, with 'workers' choosing hard trials significantly more than their 'slacker' counterparts. Whereas workers 'slacked off' in response to administration of amphetamine and caffeine, slackers 'worked harder' under amphetamine, but not caffeine. Conversely, these stimulants increased motor impulsivity in all animals. Ethanol did not affect animals' choice but invigorated behavior. In sum, we have shown for the first time that rats are differentially sensitive to cognitive effort when making decisions, independent of other processes such as impulsivity, and these baseline differences can influence the cognitive response to psychostimulants. Such findings could inform our understanding of impairments in effort-based decision making and contribute to treatment development.

Chronic atomoxetine treatment during adolescence decreases impulsive choice, but not impulsive action, in adult rats and alters markers of synaptic plasticity in the orbitofrontal cortex.

RATIONALE: Impulsivity is a key symptom of attention-deficit hyperactivity disorder (ADHD). The use of the norepinephrine reuptake inhibitor, atomoxetine, to treat ADHD suggests that the activity of the norepinephrine transporter (NET) may be important in regulating impulsive behavior. Many ADHD patients receive chronic drug treatment during adolescence, a time when frontal brain regions important for impulse control are undergoing extensive development. OBJECTIVES: The current study aimed to determine the effects of chronic atomoxetine treatment during adolescence in rats on two distinct forms of impulsivity in adulthood and whether any behavioral changes were accompanied by alterations in mRNA or protein levels within the frontal cortices. METHODS: Rats received daily injections of saline or atomoxetine (1 mg/kg) during adolescence (postnatal days 40-54). Two weeks later, animals were trained to perform either the delay-discounting test or the five-choice serial reaction time task (5CSRT). RESULTS: Adolescent atomoxetine treatment caused a stable decrease in selection of small immediate rewards over larger delayed rewards (impulsive choice) in adulthood, but did not affect premature responding (impulsive action) in the 5CSRT. Chronic atomoxetine treatment also altered the ability of acute atomoxetine to modulate aspects of impulsivity, but did not change the response to d-amphetamine. Ex vivo analysis of brain tissue indicated that chronic atomoxetine decreased phosphorylation of CREB and ERK in the orbitofrontal cortex and decreased mRNA for BDNF and cdk5. CONCLUSIONS: These data suggest that repeated administration of atomoxetine in adolescence can lead to stable decreases in impulsive choice during adulthood, potentially via modulating development of the orbitofrontal cortex.

Dopamine modulates reward expectancy during performance of a slot machine task in rats: evidence for a 'near-miss' effect.

Cognitive accounts of gambling suggest that the experience of almost winning-so-called 'near-misses'-encourage continued play and accelerate the development of pathological gambling (PG) in vulnerable individuals. One explanation for this effect is that near-misses signal imminent winning outcomes and heighten reward expectancy, galvanizing further play. Determining the neurochemical processes underlying the drive to gamble could facilitate the development of more effective treatments for PG. With this aim in mind, we evaluated rats' performance on a novel model of slot machine play, a form of gambling in which near-miss events are particularly salient. Subjects responded to a series of three flashing lights, loosely analogous to the wheels of a slot machine, causing the lights to set to 'on' or 'off'. A winning outcome was signaled if all three lights were illuminated. At the end of each trial, rats chose between responding on the 'collect' lever, resulting in reward on win trials, but a time penalty on loss trials, or starting a new trial. Rats showed a marked preference for the collect lever when both two and three lights were illuminated, indicating heightened reward expectancy following near-misses similar to wins. Erroneous collect responses were increased by amphetamine and the D(2) receptor agonist quinpirole, but not by the D(1) receptor agonist SKF 81297 or receptor subtype selective antagonists. These data suggest that dopamine modulates reward expectancy following the experience of almost winning during slot machine play, via activity at D(2) receptors, and this may result in an enhancement of the near-miss effect and facilitate further gambling.