Involvement of dopamine D3 receptor in impulsive choice decision-making in male rats.

Impulsive decision-making has been linked to impulse control disorders and substance use disorders. However, the neural mechanisms underlying impulsive choice are not fully understood. While previous PET imaging and autoradiography studies have shown involvement of dopamine and D2/3 receptors in impulsive behavior, the roles of distinct D1, D2, and D3 receptors in impulsive decision-making remain unclear. In this study, we used a food reward delay-discounting task (DDT) to identify low- and high-impulsive rats, in which low-impulsive rats exhibited preference for large delayed reward over small immediate rewards, while high-impulsive rats showed the opposite preference. We then examined D1, D2, and D3 receptor gene expression using RNAscope in situ hybridization assays. We found that high-impulsive male rats exhibited lower levels of D2 and D3, and particularly D3, receptor expression in the nucleus accumbens (NAc), with no significant changes in the insular, prelimbic, and infralimbic cortices. Based on these findings, we further explored the role of the D3 receptor in impulsive decision-making. Systemic administration of a selective D3 receptor agonist (FOB02-04) significantly reduced impulsive choices in high-impulsive rats but had no effects in low-impulsive rats. Conversely, a selective D3 receptor antagonist (VK4-116) produced increased both impulsive and omission choices in both groups of rats. These findings suggest that impulsive decision-making is associated with a reduction in D3 receptor expression in the NAc. Selective D3 receptor agonists, but not antagonists, may hold therapeutic potentials for mitigating impulsivity in high-impulsive subjects.

A molecularly defined orbitofrontal cortical neuron population controls compulsive-like behavior, but not inflexible choice or habit.

Habits are familiar behaviors triggered by cues, not outcome predictability, and are insensitive to changes in the environment. They are adaptive under many circumstances but can be considered antecedent to compulsions and intrusive thoughts that drive persistent, potentially maladaptive behavior. Whether compulsive-like and habit-like behaviors share neural substrates is still being determined. Here, we investigated mice bred to display inflexible reward-seeking behaviors that are insensitive to action consequences. We found that these mice demonstrate habitual response biases and compulsive-like grooming behavior that was reversible by fluoxetine and ketamine. They also suffer dendritic spine attrition on excitatory neurons in the orbitofrontal cortex (OFC). Nevertheless, synaptic melanocortin 4 receptor (MC4R), a factor implicated in compulsive behavior, is preserved, leading to the hypothesis that Mc4r+ OFC neurons may drive aberrant behaviors. Repeated chemogenetic stimulation of Mc4r+ OFC neurons triggered compulsive and not inflexible or habitual response biases in otherwise typical mice. Thus, Mc4r+ neurons within the OFC appear to drive compulsive-like behavior that is dissociable from habitual behavior. Understanding which neuron populations trigger distinct behaviors may advance efforts to mitigate harmful compulsions.

Prior cocaine self-administration does not impair the ability to delay gratification in rats during diminishing returns.

Previous exposure to drugs of abuse produces impairments in studies of reversal learning, delay discounting and response inhibition tasks. While these studies contribute to the understanding of normal decision-making and how it is impaired by drugs of abuse, they do not fully capture how decision-making impacts the ability to delay gratification for greater long-term benefit. To address this issue, we used a diminishing returns task to study decision-making in rats that had previously self-administered cocaine. This task was designed to test the ability of the rat to choose to delay gratification in the short-term to obtain more reward over the course of the entire behavioral session. Rats were presented with two choices. One choice had a fixed amount of time delay needed to obtain reward [i.e. fixed delay (FD)], while the other choice had a progressive delay (PD) that started at 0 s and progressively increased by 1 s each time the PD option was selected. During the 'reset' variation of the task, rats could choose the FD option to reset the time delay associated with the PD option. Consistent with previous results, we found that prior cocaine exposure reduced rats' overall preference for the PD option in post-task reversal testing during 'no-reset' sessions, suggesting that cocaine exposure made rats more sensitive to the increasing delay of the PD option. Surprisingly, however, we found that rats that had self-administered cocaine 1-month prior, adapted behavior during 'reset' sessions by delaying gratification to obtain more reward in the long run similar to control rats.

Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors.

People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort-based choice tasks can be used, in which rats can select between obtaining a preferred reinforcer by high exertion of effort vs. a low effort/less preferred option. Preclinical data indicate that dopamine transport (DAT) inhibitors can reverse pharmacologically-induced low-effort biases and increase selection of high-effort options in effort-based choice tasks. Although classical DAT blockers like cocaine can produce undesirable effects such as liability for misuse and psychotic reactions, not all DAT inhibitors have the same neurochemical profile. The current study characterized the effort-related effects of novel DAT inhibitors that are modafinil analogs and have a range of binding profiles and neurochemical actions (JJC8-088, JJC8-089, RDS3-094, and JJC8-091) by using two different effort-related choice behavior tasks in male Sprague-Dawley rats. JJC8-088, JJC8-089, and RDS3-094 significantly reversed the low-effort bias induced by the VMAT-2 inhibitor tetrabenazine, increasing selection of high-effort fixed ratio 5 lever pressing vs. chow intake. In addition, JJC8-089 reversed the effects of tetrabenazine in female rats. JJC8-088 and JJC8-089 also increased selection of high-effort progressive ratio responding in a choice task. However, JJC8-091 failed to produce these outcomes, potentially due to its unique pharmacological profile (i.e., binding to an occluded conformation of DAT). Assessment of a broad range of DAT inhibitors with different neurochemical characteristics may lead to the identification of compounds that are useful for treating motivational dysfunction in humans.

Knowledge by omission: the significance of omissions in the 5-choice serial reaction time task.

RATIONALE: The 5-choice serial reaction time task (5-CSRTT) is commonly used to assess attention in rodents. Manipulation of this task by decreasing the light stimulus duration is often used to probe attentional capacity and causes a decrease in accuracy and an increase in omissions. However, although a decrease in response accuracy is commonly interpreted as a decrease in attention, it is more difficult to interpret an increase in omissions in terms of attentional performance. METHODS: Here we present a series of experiments in rats that seeks to investigate the origins of these key behavioral measures of attention in the 5-CSRTT. After an initial training in the 5-CSRTT, rats were tested in a variable stimulus duration procedure to increase task difficulty and probe visual attentional capacity under several specific controlled conditions. CONCLUSIONS: We found that response accuracy reflects visuospatial sustained attentional processing, as commonly interpreted, while response omission reflects rats' ignorance about the stimulus location, presumably due to failure to pay attention to the curved wall during its presentation. Moreover, when rats lack of relevant information, they choose not to respond instead of responding randomly. Finally, pretreatment with nicotine selectively decreased response omissions, without affecting response accuracy, particularly when the attentional demand was high. Overall, our results indicate that response accuracy and response omission thus correspond to two distinct attentional states.

Methamphetamine increases risky choice in rats, but only when magnitude and probability of reinforcement are manipulated within a session.

Risky choice is associated with maladaptive behaviors, particularly substance use disorders. Current animal models of risky choice are often confounded by other constructs like behavioral flexibility and suboptimal choice. The purpose of the current experiment was to determine if the psychostimulant methamphetamine, a drug whose popularity has increased in recent years, increases risky choice in an equivalent expected value (EEV) task. In the EEV task, rats are given a choice between two reinforcer alternatives that differ in magnitude and probability of delivery, but have equivalent expected value. Forty-eight Sprague Dawley rats were tested in three versions of the EEV task. In the first version of the EEV task, both reinforcer magnitude and probability were adjusted across blocks of trials for both alternatives. In the second and the third versions of the EEV task, reinforcer magnitude was held constant across each block of trials (either 1 vs. 2 pellets or 4 vs. 5 pellets). We found that male rats preferred the "riskier" option, except when reinforcer magnitudes were held constant at 4 and 5 pellets across each block of trials. Methamphetamine (0.5 mg/kg) increased preference for the risky option in both males and females, but only when both reinforcer magnitude and probability were manipulated across blocks of trials for each alternative. The current results demonstrate that both magnitude of reinforcement and probability of reinforcement interact to influence risky choice. Overall, this study provides additional support for using reinforcers with expected value to measure risky choice.

Recent Opioid Use Impedes Range Adaptation in Reinforcement Learning in Human Addiction.

BACKGROUND: Drugs like opioids are potent reinforcers thought to co-opt value-based decisions by overshadowing other rewarding outcomes, but how this happens at a neurocomputational level remains elusive. Range adaptation is a canonical process of fine-tuning representations of value based on reward context. Here, we tested whether recent opioid exposure impacts range adaptation in opioid use disorder, potentially explaining why shifting decision making away from drug taking during this vulnerable period is so difficult. METHODS: Participants who had recently (<90 days) used opioids (n = 34) or who had abstained from opioid use for ≥ 90 days (n = 20) and comparison control participants (n = 44) completed a reinforcement learning task designed to induce robust contextual modulation of value. Two models were used to assess the latent process that participants engaged while making their decisions: 1) a Range model that dynamically tracks context and 2) a standard Absolute model that assumes stationary, objective encoding of value. RESULTS: Control participants and ≥90-days-abstinent participants with opioid use disorder exhibited choice patterns consistent with range-adapted valuation. In contrast, participants with recent opioid use were more prone to learn and encode value on an absolute scale. Computational modeling confirmed the behavior of most control participants and ≥90-days-abstinent participants with opioid use disorder (75%), but a minority in the recent use group (38%), was better fit by the Range model than the Absolute model. Furthermore, the degree to which participants relied on range adaptation correlated with duration of continuous abstinence and subjective craving/withdrawal. CONCLUSIONS: Reduced context adaptation to available rewards could explain difficulty deciding about smaller (typically nondrug) rewards in the aftermath of drug exposure.

Increased Risky Choice and Reduced CHRNB2 Expression in Adult Male Rats Exposed to Nicotine Vapor.

While the cognitive enhancing effects of nicotine use have been well documented, it has also been shown to impair decision making. The goal of this study was to determine if exposure to nicotine vapor increases risky decision making. The study also aims to investigate possible long-term effects of nicotine vapor exposure on the expression of genes coding for cholinergic and dopaminergic receptors in brain. Thirty-two adult male Sprague Dawley rats were exposed to 24 mg/mL nicotine vapor or vehicle control, immediately followed by testing in the probability discounting task for 10 consecutive days. Fifty-four days after the 10-day vapor exposure, animals were sacrificed and expression of genes coding for the α4 and ß2 cholinergic receptor subunits, and dopamine D1 and D2 receptors, were analyzed using RT-PCR. Exposure to nicotine vapor caused an immediate and transient increase in risky choice. Analyses of gene expression identified significant reductions in CHRNB2 and DRD1 in the nucleus accumbens core and CHRNB2 and DRD2 in the medial prefrontal cortex of rats previously exposed to nicotine vapor, relative to vehicle controls. Results provide data on the negative cognitive effects of nicotine vapor exposure and identify cholinergic and dopaminergic mechanisms that may affected with repeated use.

The steroidogenic inhibitor finasteride reverses pramipexole-induced alterations in probability discounting.

Pramipexole is a potent agonist of D3 and D2 dopamine receptors, currently approved for clinical use in Parkinson's disease (PD) and restless leg syndrome. Several studies have shown that pramipexole significantly increases the risk of pathological gambling and impulse-control disorders. While these iatrogenic complications can impose a severe social and financial burden, their treatment poses serious clinical challenges. Our group previously reported that the steroidogenic inhibitor finasteride reduced pathological gambling severity in PD patients who developed this complication following pramipexole treatment. To study the mechanisms underlying these effects, here we tested the impact of finasteride in a rat model of pramipexole-induced alterations of probability discounting. We previously showed that, in rats exposed to low doses of the monoamine-depleting agent reserpine (1 mg/kg/day, SC), pramipexole (0.3 mg/kg/day, SC) increased the propensity to engage in disadvantageous choices. This effect was paralleled by a marked D3 receptor upregulation in the nucleus accumbens. First, we tested how finasteride (25-50 mg/kg, IP) intrinsically affects probability discounting. While the highest dose of finasteride produced a marked lack of interest in lever pressing (manifested as a significant increase in omissions), the 25 mg/kg (IP) dose did not intrinsically modify probability discounting. However, this finasteride regimen significantly reduced the adverse effects of reserpine and pramipexole in probability discounting by diminishing rats' propensity to engage in highly disadvantageous probabilistic choices. The same regimen also reversed the upregulation of D3 receptors in the nucleus accumbens induced by reserpine and pramipexole. These findings confirm that finasteride opposes the impulsivity caused by pramipexole and suggest that this effect may be underpinned by a normalizing effect on D3 receptor expression in the nucleus accumbens.

Frustrative nonreward and cannabinoid receptors: Chronic (but not acute) WIN 55,212-2 treatment increased resistance to change in two reward downshift tasks.

Assessing the role of cannabinoid (CB) receptors in behavior is relevant given the trend toward the legalization of medicinal and recreational marijuana. The present research aims at bridging a gap in our understanding of CB-receptor function in animal models of frustrative nonreward. These experiments were designed to (1) determine the effects of chronic administration of the nonselective CB1-receptor agonist WIN 55,212-2 (WIN) on reward downshift in rats and (2) determine whether the effects of chronic WIN were reducible to acute effects. In Experiment 1, chronic WIN (7 daily injections, 10 mg/kg, ip) accelerated the recovery of consummatory behavior after a 32-to-4% sucrose downshift relative to vehicle controls. In addition, chronic WIN eliminated the preference for an unshifted lever when the other lever was subject to a 12-to-2 pellet downshift in free-choice trials, but only in animals with previous experience with a sucrose downshift. In Experiment 2, acute WIN (1 mg/kg, ip) reduced consummatory behavior, but did not affect recovery from a 32-to-4% sucrose downshift. The antagonist SR 141716A (3 mg/kg, ip) also failed to interfere with recovery after the sucrose downshift. In Experiment 3, acute WIN administration (1 mg/kg, ip) did not affect free-choice behavior after a pellet downshift, although it reduced lever pressing and increased magazine entries relative to vehicle controls. The effects of chronic WIN on frustrative nonreward were not reducible to acute effects of the drug. Chronic WIN treatment in rats, like chronic marijuana use in humans, seems to increase resistance to the effects of frustrative nonreward.

Environmental enrichment and intranasal oxytocin administration reverse maternal separation-induced impairments of prosocial choice behavior.

Adverse early life experiences influence behavioral and physiological functions and increase vulnerability to neuropsychiatric disorders. Maternal separation (MS) is an established animal model that reproduces the features of chronic stress or adverse experiences during early life. Previous studies have been shown that MS may lead to impairments of social behaviors. Here, we investigated the effects of MS on mutual reward preferences in a double T-maze prosocial choice task. Since enriched environment (EE) and intranasal oxytocin (OT) administration have beneficial effects on cognition and social behaviors, in the present study we tested whether these treatments, alone or in combination, would affect prosocial behavior of rats which underwent MS during infancy. Rat pups underwent MS paradigm for 180 min/day from postnatal day (PND) 1-21. From PND 22-34, rats were exposed to an EE and/or received intranasal OT (2 µg/µl, 7 days). Hence, the 8 groups consisted of control (CTRL), MS, CTRL+EE, CTRL+OT and the saline groups. Assessment of prosocial choice behavior was started in adolescence. MS impaired prosocial choice behavior and reduced mutual reward preferences. Getting exposed to EE and intranasal OT administration could overcome MS-induced deficits and promoted mutual reward preferences of MS rats. Combination of short-term EE and OT strengthened prosocial behavior. Obtained results showed that EE and OT may be considered as profitable therapeutic approaches for promoting some aspects of social behavior.

Estrogen signaling modulates behavioral selection toward pups and amygdalohippocampal area in the rhomboid nucleus of the bed nucleus of the stria terminalis circuit.

Gonadal steroid hormone influences behavioral choice of adult animals toward pups, parental or aggressive. We previously reported that long-term administration of 17ß-estradiol (E2) to male mice during sexual maturation induces aggressive behavior toward conspecific pups, which is called "infanticide," and significantly enhanced excitatory synaptic transmission in the rhomboid nucleus of bed nucleus of the stria terminalis (BSTrh), which is an important brain region for infanticide. However, it is unclear how estrogen receptor-dependent signaling after sexual maturity regulates neural circuits including the BSTrh. Here we revealed that E2 administration to gonadectomized mice in adulthood elicited infanticidal behavior and enhanced excitatory synaptic transmission in the BSTrh by increasing the probability of glutamate release from the presynaptic terminalis. Next, we performed whole-brain mapping of E2-sensitive brain regions projecting to the BSTrh and found that amygdalohippocampal area (AHi) neurons that project to the BSTrh densely express estrogen receptor 1 (Esr1). Moreover, E2 treatment enhanced synaptic connectivity in the AHi-BSTrh pathway. Together, these results suggest that reinforcement of excitatory inputs from AHi neurons into the BSTrh by estrogen receptor-dependent signaling may contribute to the expression of infanticide.

Maternal sucrose consumption alters behaviour and steroids in adult rat offspring.

Maternal diets can have dramatic effects on the physiology, metabolism, and behaviour of offspring that persist into adulthood. However, the effects of maternal sucrose consumption on offspring remain unclear. Here, female rats were fed either a sucrose diet with a human-relevant level of sucrose (25% of kcal) or a macronutrient-matched, isocaloric control diet before, during, and after pregnancy. After weaning, all offspring were fed a standard low-sucrose rodent chow. We measured indicators of metabolism (weight, adipose, glucose tolerance, and liver lipids) during development and adulthood (16-24 weeks). We also measured food preference and motivation for sugar rewards in adulthood. Finally, in brain regions regulating these behaviours, we measured steroids and transcripts for steroidogenic enzymes, steroid receptors, and dopamine receptors. In male offspring, maternal sucrose intake decreased body mass and visceral adipose tissue, increased preference for high-sucrose and high-fat diets, increased motivation for sugar rewards, and decreased mRNA levels of Cyp17a1 (an androgenic enzyme) in the nucleus accumbens. In female offspring, maternal sucrose intake increased basal corticosterone levels. These data demonstrate the enduring, diverse, and sex-specific effects of maternal sucrose consumption on offspring phenotype.

Characterization of a differential reinforcement of low rates of responding task in non-deprived male and female rats: Role of Sigma-1 receptors.

Impulsive action can be defined as the inability to withhold a response and represents one of the dimensions of the broad construct impulsivity. Here, we characterized a modified differential reinforcement of low rates of responding (DRL) task developed in our laboratory, in which impulsive action is measured in ad libitum fed/watered subjects. Specifically, we first determined the effects of both sex and estrous cycle on impulsive action by systematically comparing male and estrous-synchronized female subjects. In addition, we evaluated the convergent validity of this modified DRL task by testing the effects of the D2R/5HT2AR antagonist, aripiprazole, and the noncompetitive NMDAR antagonist, MK-801. Finally, we tested the effects of the selective antagonist BD-1063 and agonist PRE-084 of Sigma-1 receptor (Sig-1R) on impulsive action using this modified DRL task. We found that female rats showed and increased inability to withhold a response when compared to males, and this effect was driven by the metestrus/diestrus phase of the estrous cycle. In addition, aripiprazole and MK-801 fully retained their capability to reduce and increase impulsive action, respectively. Finally, the selective Sig-1R antagonist, BD-1063 dose-dependently reduced the inability to withhold a response in both sexes, though more potently in female rats. In summary, we show that impulsive action, as measured in a modified DRL task which minimizes energy-homeostatic influences, is a function of both sex and estrous cycle. Furthermore, we validate the convergent validity of the task and provide evidence that Sig-1R antagonism may represent a novel pharmacological strategy to reduce impulsive action.

Effects of Dopamine D1-Like Receptor Ligands on Food-Cocaine Choice in Socially Housed Male Cynomolgus Monkeys.

Although dopamine plays a prominent role in mediating cocaine's abuse-related effects, the specific roles of dopamine receptor subtypes are not fully understood. Whereas the effects of drugs acting at dopamine D2-like receptors (D2Rs) have been characterized, less is known about dopamine D1-like receptors (D1Rs). The present experiments examined the effects of drugs with varying intrinsic efficacy at D1R on the relative reinforcing strength of cocaine in male cynomolgus monkeys. Use of socially housed monkeys permitted the assessment of whether social status influenced the behavioral effects of D1R-acting drugs. The high-efficacy D1R agonist SKF 81297, low-efficacy D1R agonist SKF 38393, and D1R antagonist SCH 23390 were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine-choice dose-effect curve was determined daily. To assess selectivity of behavioral effects on cocaine choice, effects of doses that did not disrupt responding (indicated by a ≥35% decrease in total reinforcers delivered) were analyzed. Neither SKF 81297 nor SCH 23390 affected cocaine choice in dominant or subordinate monkeys. However, the low-efficacy agonist SKF 38393 selectively decreased cocaine choice; this effect was larger and only reached statistical significance in subordinate monkeys. Increasing the time between D1-acting drug administration and the cocaine choice session did not affect these results. The results indicate that, like D2R-acting drugs, the behavioral effects of D1R-acting drugs on cocaine choice can vary according to intrinsic efficacy and social status. Moreover, they demonstrate that D1R-acting drugs affect behavior under a narrower range of conditions than D2R-acting drugs. SIGNIFICANCE STATEMENT: Cocaine use disorder represents an insidious public health concern with no Food and Drug Administration-approved medications. Although dopamine receptors have been strongly implicated in mediating the abuse-related effects of cocaine, the roles of dopamine receptor subtypes are incompletely understood. The present study in nonhuman primates found that cocaine choice was decreased only by a low-efficacy D1R agonist, and that this effect depended on the social status of the monkey.

Exposure to fruit-flavoring during adolescence increases nicotine consumption and promotes dose escalation.

The rise of e-cigarette popularity has sparked interest in the role of palatable flavors on nicotine use. Despite growing evidence that sweet flavorants enhance nicotine reward, their influence on nicotine consumption has not been studied extensively. In addition, the impact that flavored nicotine use in adolescence could have on nicotine reward and dependence in adulthood remains unclear. This study examined the role of flavored nicotine access on nicotine preference and consumption longitudinally, from adolescence to adulthood. Male and female adolescent mice preferred a fruit-flavored nicotine solution over an unflavored nicotine solution. However, only adolescent female mice with access to flavored nicotine consumed higher doses. Furthermore, while adolescent male mice escalated consumption of both flavored and unflavored nicotine, female mice only escalated nicotine consumption when given access to flavored nicotine. As mice matured into adulthood, there was no evidence that a history of flavored-nicotine access altered preference for unflavored nicotine compared to a nicotine-free control in a classic two-bottle choice design. However, when the nicotine concentration was progressively reduced, mice that had consumed strawberry-flavored nicotine in adolescence maintained baseline nicotine consumption levels longer than mice that initiated nicotine use without flavor in adolescence. Finally, addition of fruit-flavorants into the nicotine solution during adulthood led to nicotine preference and increased levels of nicotine consumption, regardless of previous flavored-nicotine access or of familiarity with the selected flavorant. These results indicate that flavorants increase nicotine consumption independent of life stage, possibly posing a disproportionate risk to adolescent females. Our results also point to an effect of adolescent flavored-nicotine use on nicotine dose maintenance in adulthood, which could have implications for the success of future quit attempts.

Contrasting effects of d-amphetamine and atomoxetine on measures of impulsive action and choice.

Amphetamine (AMP) and atomoxetine (ATX) represent two of the most widely studied drug treatments used in the investigation of impulsive behaviour. While both drugs have relatively well defined effects in tests designed to investigate impulsive action (e.g. 5-choice task; 5-CSRTT), the effects of both drugs in tests of impulsive choice (e.g. delay discounting) are less consistent. In the present study both AMP and ATX were tested in a rodent gambling task (rGT) and delay discounting in rats separately trained to either an ascending or descending delay schedule. Effects of both drugs were compared to measures of impulsive action (premature (PREM) responses) and perseverative (PSV) responses measured in the 5-choice and rGT tasks. Consistent with previous studies, AMP (0.1-1 mg/kg) increased both PREM and PSV responses, and ATX (0.5-2 mg/kg) reduced both measures in the 5-choice and rGT tasks. At equivalent doses ATX had no reliable effect on choice behaviour in either the rGT or delay discounting suggesting a null effect of this drug on impulsive choice and risky decision making. The effects of AMP were more complex, with a subtle shift in preference to a low risk (P1) choice in the rGT, and an effect on discounting that was unrelated to reinforcer value, but instead dependent on delay sequence and baseline choice preference. One aspect to these outcomes is to highlight the importance of multiple methodological factors when assessing drug effects on complex behaviours such as impulsive choice, and question what are the most appropriate test conditions under which to examine these drugs on discounting.

High ethanol preference and dissociated memory are co-occurring phenotypes associated with hippocampal GABAAR-δ receptor levels.

Alcohol use disorder (AUD) frequently co-occurs with dissociative disorders and disorders with dissociative symptoms, suggesting a common neurobiological basis. It has been proposed that facilitated information processing under the influence of alcohol, resulting in the formation of dissociated memories, might be an important factor controlling alcohol use. Access to such memories is facilitated under the effect of alcohol, thus further reinforcing alcohol use. To interrogate possible mechanisms associated with these phenotypes, we used a mouse model of dissociative amnesia, combined with a high-alcohol preferring (HAP) model of AUD. Dissociated memory was induced by activation of hippocampal extrasynaptic GABA type A receptor delta subunits (GABAAR-δ), which control tonic inhibition and to which ethanol binds with high affinity. Increased ethanol preference was associated with increased propensity to form dissociated memories dependent on GABAAR-δ in the dorsal hippocampus (DH). Furthermore, the DH level of GABAAR-δ protein, but not mRNA, was increased in HAP mice, and was inversely correlated to the level of miR-365-3p, suggesting an miRNA-mediated post-transcriptional mechanism contributing to elevated GABAAR-δ. The observed changes of DH GABAAR-δ were associated with a severe reduction of excitatory projections stemming from GABAAR-δ-containing pyramidal neurons in the subiculum and terminating in the mammillary body. These results suggest that both molecular and circuit dysfunction involving hippocampal GABAAR-δ receptors might contribute to the co-occurrence of ethanol preference and dissociated information processing.

Lateral habenula cannabinoid CB1 receptor involvement in drug-associated impulsive behavior.

Animal and human studies show that cannabis or its derivatives can increase relapse to cocaine seeking following withdrawal. Moreover, cannabis use in humans is associated with impulse control deficits and animal studies implicate endogenous cannabinoids (eCB) in several impulsivity constructs. However, the brain areas where cannabinoids might control impulsivity or cocaine seeking are largely unknown. Here, we assess Lateral Habenula (LHb) involvement on performance in the 5-choice serial reaction time task (5CSRTT) in rats and investigate whether LHb cannabinoid CB1 receptors (CB1R) are involved in these effects. Systemic cocaine increased premature responding, a measure of impulsivity, at a dose (5 mg/kg) that did not alter other measures of task performance. Intra-LHb infusion of the CB1R antagonist AM251 blocked this effect. Systemic injection of the psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC, 1 mg/kg), also increased 5CSRTT premature responding at a dose that did not otherwise disrupt task performance. This was blocked by intra-LHb infusion of AM251 in a subgroup of rats showing the largest increases in Δ9-THC-evoked premature responses. Systemic Δ9-THC also prompted impulsive cocaine seeking in a Go/NoGo cocaine self-administration task and this was blocked by intra-LHb AM251. These data show that LHb CB1Rs are involved in deficits in impulse control initiated by cocaine and Δ9-THC, as assessed by the 5CSRTT, and play a role in impulsive cocaine seeking during cocaine self-administration. This suggests that the LHb eCB system contributes to the control of impulsive behavior, and thus represents a potential target for therapeutic treatment of substance use disorders (SUDs) in humans.

Chronic SSRI treatment reverses HIV-1 protein-mediated synaptodendritic damage.

HIV-1 infection affects approximately 37 million individuals, and approximately 50% of seropositive individuals will develop symptoms of clinical depression and/or apathy. Dysfunctions of both serotonergic and dopaminergic neurotransmission have been implicated in the pathogenesis of motivational alterations. The present study evaluated the efficacy of a SSRI (escitalopram) in the HIV-1 transgenic (Tg) rat. Behavioral, neurochemical, and neuroanatomical outcomes with respect to HIV-1 and sex were evaluated to determine the efficacy of chronic escitalopram treatment. Escitalopram treatment restored function in each of the behavioral tasks that were sensitive to HIV-1-induced impairments. Further, escitalopram treatment restored HIV-1-mediated synaptodendritic damage in the nucleus accumbens; treatment with escitalopram significantly increased dendritic proliferation in HIV-1 Tg rats. However, restoration did not consistently occur with the neurochemical analysis in the HIV-1 rat. Taken together, these results suggest a role for SSRI therapies in repairing long-term HIV-1 protein-mediated neuronal damage and restoring function.