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.

Brain multimodal co-alterations related to delay discounting: a multimodal MRI fusion analysis in persons with and without cocaine use disorder.

BACKGROUND: Delay discounting has been proposed as a behavioral marker of substance use disorders. Innovative analytic approaches that integrate information from multiple neuroimaging modalities can provide new insights into the complex effects of drug use on the brain. This study implemented a supervised multimodal fusion approach to reveal neural networks associated with delay discounting that distinguish persons with and without cocaine use disorder (CUD). METHODS: Adults with (n = 35) and without (n = 37) CUD completed a magnetic resonance imaging (MRI) scan to acquire high-resolution anatomical, resting-state functional, and diffusion-weighted images. Pre-computed features from each data modality included whole-brain voxel-wise maps for gray matter volume, fractional anisotropy, and regional homogeneity, respectively. With delay discounting as the reference, multimodal canonical component analysis plus joint independent component analysis was used to identify co-alterations in brain structure and function. RESULTS: The sample was 58% male and 78% African-American. As expected, participants with CUD had higher delay discounting compared to those without CUD. One joint component was identified that correlated with delay discounting across all modalities, involving regions in the thalamus, dorsal striatum, frontopolar cortex, occipital lobe, and corpus callosum. The components were negatively correlated with delay discounting, such that weaker loadings were associated with higher discounting. The component loadings were lower in persons with CUD, meaning the component was expressed less strongly. CONCLUSIONS: Our findings reveal structural and functional co-alterations linked to delay discounting, particularly in brain regions involved in reward salience, executive control, and visual attention and connecting white matter tracts. Importantly, these multimodal networks were weaker in persons with CUD, indicating less cognitive control that may contribute to impulsive behaviors.

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.

Daily, but not occasional, cannabis use is selectively associated with more impulsive delay discounting and hyperactive ADHD symptoms in binge-drinking young adults.

RATIONALE: There is increasing interest in and evidence for the negative impacts of cannabis use in cognitive performance and symptoms of attention-deficit/hyperactivity disorder (ADHD), with age of first cannabis use as a potential amplifier of these associations. However, the existing literature is inconsistent, which may be due to methodological limitations, including small sample sizes. OBJECTIVE: To examine current cannabis use and age of first cannabis use in relation to neurocognitive task performance and ADHD symptoms in a large sample of binge-drinking young adults. METHODS: Participants were young adults (N=730, M age=21.44, 52.6% female) assessed for current cannabis use, neurocognitive task performance, and ADHD symptoms. Three-group ANCOVAs compared individuals reporting frequent (daily/multiple times daily), occasional (weekly/monthly), or no cannabis use. RESULTS: Covarying alcohol use, tobacco use, age, sex, income, and education, daily cannabis users exhibited significantly more impulsive delay discounting and hyperactive-impulsive ADHD symptoms compared to both other groups. However, cannabis use was not associated with inattentive ADHD symptoms, verbal intelligence, working memory, probability discounting, short-term verbal memory, or behavioral inhibition. Age of initiation of cannabis use exhibited neither main effects nor interactions in relation to any domains of cognitive performance or ADHD symptomatology. CONCLUSIONS: The current findings provide support for a link between cannabis use in relation to immediate reward preference and symptoms of hyperactive-impulsive ADHD in young adults, but only among frequent users. No other neurocognitive domains exhibited associations with cannabis and age of first use was neither independently nor interactively associated with cognitive outcomes.

Effects of vapourized THC and voluntary alcohol drinking during adolescence on cognition, reward, and anxiety-like behaviours in rats.

Cannabis and alcohol co-use is prevalent in adolescence, but the long-term behavioural effects of this co-use remain largely unexplored. The aim of this study is to investigate the effects of adolescent alcohol and Δ9-tetrahydracannabinol (THC) vapour co-exposure on cognitive- and reward-related behaviours. Male Sprague-Dawley rats received vapourized THC (10 mg vapourized THC/four adolescent rats) or vehicle every other day (from post-natal day (PND) 28-42) and had continuous voluntary access to ethanol (10% volume/volume) in adolescence. Alcohol intake was measured during the exposure period to assess the acute effects of THC on alcohol consumption. In adulthood (PND 56+), rats underwent behavioural testing. Adolescent rats showed higher alcohol preference, assessed using the two-bottle choice test, on days on which they were not exposed to THC vapour. In adulthood, rats that drank alcohol as adolescents exhibited short-term memory deficits and showed decreased alcohol preference; on the other hand, rats exposed to THC vapour showed learning impairments in the delay-discounting task. Vapourized THC, alcohol or their combination had no effect on anxiety-like behaviours in adulthood. Our results show that although adolescent THC exposure acutely affects alcohol drinking, adolescent alcohol and cannabis co-use may not produce long-term additive effects.

Droxidopa alters dopamine neuron and prefrontal cortex activity and improves attention-deficit/hyperactivity disorder-like behaviors in rats.

Finding alternative treatments for attention-deficit/hyperactivity disorder (ADHD) is crucial given the safety and efficacy problems of current ADHD medications. Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS), is a norepinephrine prodrug that enhances brain norepinephrine and dopamine levels. In this study, we used electrophysiological tests to examine effects of L-DOPS on the prefrontal cortex (PFC) and dopamine neurons in the ventral tegmental area. We also conducted behavioral tests to assess L-DOPS' effects on ADHD-like behaviors in rats. In chloral hydrate-anesthetized rats, PFC local field potentials oscillated between the active, depolarized UP state and the hyperpolarized DOWN state. Mimicking the effect of d-amphetamine, L-DOPS, given after the peripheral amino acid decarboxylase inhibitor, benserazide (BZ), increased the amount of time the PFC spent in the UP state, indicating an excitatory effect of L-DOPS on PFC neurons. Like d-amphetamine, L-DOPS also inhibited dopamine neurons, an effect significantly reversed by the D2-like receptor antagonist raclopride. In the behavioral tests, BZ + L-DOPS improved hyperactivity, inattention and impulsive action of the adolescent spontaneously hypertensive rat (SHR/NCrl), well-validated animal model of the combined type of ADHD. BZ + L-DOPS also reduced impulsive choice and impulsive action of Wistar rats, but did not ameliorate the inattentiveness of Wistar Kyoto rats (WKY/NCrl), proposed model of the ADHD-predominantly inattentive type. In conclusion, L-DOPS produced effects on the PFC and dopamine neurons characteristic of drugs used to treat ADHD. BZ + L-DOPS ameliorated ADHD-like behaviors in rats suggesting its potential as an alternative ADHD treatment.

Dopaminergic modulation of reward discounting in healthy rats: a systematic review and meta-analysis.

RATIONALE: Although numerous studies have suggested that pharmacological alteration of the dopamine (DA) system modulates reward discounting, these studies have produced inconsistent findings. OBJECTIVES: Here, we conducted a systematic review and pre-registered meta-analysis to evaluate DA drug-mediated effects on reward discounting of time, probability, and effort costs in studies of healthy rats. This produced a total of 1343 articles to screen for inclusion/exclusion. From the literature, we identified 117 effects from approximately 1549 individual rats. METHODS: Using random effects with maximum-likelihood estimation, we meta-analyzed placebo-controlled drug effects for (1) DA D1-like receptor agonists and (2) antagonists, (3) D2-like agonists and (4) antagonists, and (5) DA transporter-modulating drugs. RESULTS: Meta-analytic effects showed that DAT-modulating drugs decreased reward discounting. While D1-like and D2-like antagonists both increased discounting, agonist drugs for those receptors had no significant effect on discounting behavior. A number of these effects appear contingent on study design features like cost type, rat strain, and microinfusion location. CONCLUSIONS: These findings suggest a nuanced relationship between DA and discounting behavior and urge caution when drawing generalizations about the effects of pharmacologically manipulating dopamine on reward-based decision-making.

Temporal discounting and smoking cessation: choice consistency predicts nicotine abstinence in treatment-seeking smokers.

INTRODUCTION: Smokers discount delayed rewards steeper than non-smokers or ex-smokers, possibly due to neuropharmacological effects of tobacco on brain circuitry, or lower abstinence rates in smokers with steep discounting. To delineate both theories from each other, we tested if temporal discounting, choice inconsistency, and related brain activity in treatment-seeking smokers (1) are higher compared to non-smokers, (2) decrease after smoking cessation, and (3) predict relapse. METHODS: At T1, 44 dependent smokers, 29 non-smokers, and 30 occasional smokers underwent fMRI while performing an intertemporal choice task. Smokers were measured before and 21 days after cessation if abstinent from nicotine. In total, 27 smokers, 28 non-smokers, and 29 occasional smokers were scanned again at T2. Discounting rate k and inconsistency var(k) were estimated with Bayesian analysis. RESULTS: First, k and var(k) in smokers in treatment were not higher than in non-smokers or occasional smokers. Second, neither k nor var(k) changed after smoking cessation. Third, k did not predict relapse, but high var(k) was associated with relapse during treatment and over 6 months. Brain activity in valuation and decision networks did not significantly differ between groups and conditions. CONCLUSION: Our data from treatment-seeking smokers do not support the pharmacological hypothesis of pronounced reversible changes in discounting behavior and brain activity, possibly due to limited power. Behavioral data rather suggest that differences between current and ex-smokers might be due to selection. The association of choice consistency and treatment outcome possibly links consistent intertemporal decisions to remaining abstinent.

Baseline-dependency: How genotype and signaled delays influence amphetamine's effects on delay discounting.

RATIONALE: Delay discounting, in which an animal chooses between a small, immediate or large, delayed reinforcer, is an experimental model of impulsivity. In previous studies, d-amphetamine has both increased and decreased preference for larger-delayed reinforcers depending on experimental conditions. OBJECTIVE: Identify genotype X environment interactions responsible for these disparate findings in a single study and assess the hypothesis that baseline-dependence unifies d-amphetamine's effects. METHODS: Delay discounting by BALB/c and C57Bl/6 mice was evaluated using a choice procedure in which six delays to a larger reinforcer were presented in a single session. Components were presented both with and without stimuli that uniquely signaled reinforcer delays. d-Amphetamine's (0.1-1.7 mg/kg) effects on delay and magnitude sensitivity were assessed when specific stimuli did or did not uniquely signal the delay to a larger reinforcer. d-Amphetamine's effects were determined using a model-comparison approach. RESULTS: During baseline, magnitude and delay sensitivity were identical across signal conditions for BALB/c mice and generally greater than the C57Bl/6 mice. For C57Bl/6 mice, magnitude and delay sensitivity were higher during the signaled than the unsignaled component. Amphetamine decreased delay sensitivity during both components for BALB/c mice, but this effect was attenuated by delay-specific stimuli. For C57Bl/6 mice, amphetamine decreased their high magnitude and delay sensitivity when delays were signaled and, conversely, increased the low magnitude and delay sensitivity when delays were unsignaled. CONCLUSIONS: BALB/c mice showed high delay and magnitude sensitivity regardless of signal conditions. C57Bl/6's magnitude and delay sensitivity depended on signaling. d-Amphetamine usually decreased high baseline delay- and magnitude sensitivity and increased low sensitivities, a baseline-dependence that occurred regardless of whether delay sensitivity was driven by biological (genotype) or environmental (signaling) variables. The C57Bl/6 mouse may be a good model of environmentally-induced impulsivity while BALB/c mice could model impulsivity with a strong genetic contribution.

Effects of benztropine analogs on delay discounting in rats.

RATIONALE: Methylphenidate and d-amphetamine, medications used for treatment of attention deficit hyperactivity disorder (ADHD), are used recreationally and self-administered by laboratory animals. Benztropine (BZT) analogs, like those medications, increase synaptic dopamine levels but are less effective in maintaining self-administration, suggesting clinical utility with less abuse liability. OBJECTIVES: The current study was designed to evaluate potential therapeutic effects of BZT analogs related to ADHD. METHODS: Rats responded under a delay-discounting procedure in which responses on one lever produced immediate delivery of a single food pellet and alternative responses produced four food pellets either immediately or with various temporal delays, with those delays arranged in ascending or random orders in different groups of rats. Selection of the smaller more immediate reinforcer has been suggested as an aspect of "impulsivity," a trait with suggested involvement in ADHD. Other rats were studied under fixed-interval (FI) 300-s schedules to assess drug effects on behavior under temporal control. RESULTS: d-Amphetamine, methylphenidate, and the BZT analog AHN 1-055, but not AHN 2-005 or JHW 007, increased selection of the large, delayed reinforcer with either arrangement of delays. All drugs changed the temporal distribution of responses within the FI from one with responses concentrated at the end to a more uniform distribution. Changes in the temporal distribution of FI responding occurred with drugs that did not affect discounting suggesting that discounting does not arise directly from the same temporal control processes controlling FI responding. CONCLUSIONS: AHN 1-055 may be of clinical utility in the treatment of ADHD.

Testicular hormones mediate robust sex differences in impulsive choice in rats.

Impairments in choosing optimally between immediate and delayed rewards are associated with numerous psychiatric disorders. Such 'intertemporal' choice is influenced by genetic and experiential factors; however, the contributions of biological sex are understudied and data to date are largely inconclusive. Rats were used to determine how sex and gonadal hormones influence choices between small, immediate and large, delayed rewards. Females showed markedly greater preference than males for small, immediate over large, delayed rewards (greater impulsive choice). This difference was neither due to differences in food motivation or reward magnitude perception, nor was it affected by estrous cycle. Ovariectomies did not affect choice in females, whereas orchiectomies increased impulsive choice in males. These data show that male rats exhibit less impulsive choice than females and that this difference is at least partly maintained by testicular hormones. These differences in impulsive choice could be linked to gender differences across multiple neuropsychiatric conditions.

Dopaminergic Modulation of Human Intertemporal Choice: A Diffusion Model Analysis Using the D2-Receptor Antagonist Haloperidol.

The neurotransmitter dopamine is implicated in diverse functions, including reward processing, reinforcement learning, and cognitive control. The tendency to discount future rewards over time has long been discussed in the context of potential dopaminergic modulation. Here we examined the effect of a single dose of the D2 receptor antagonist haloperidol (2 mg) on temporal discounting in healthy female and male human participants. Our approach extends previous pharmacological studies in two ways. First, we applied combined temporal discounting drift diffusion models to examine choice dynamics. Second, we examined dopaminergic modulation of reward magnitude effects on temporal discounting. Hierarchical Bayesian parameter estimation revealed that the data were best accounted for by a temporal discounting drift diffusion model with nonlinear trialwise drift rate scaling. This model showed good parameter recovery, and posterior predictive checks revealed that it accurately reproduced the relationship between decision conflict and response times in individual participants. We observed reduced temporal discounting and substantially faster nondecision times under haloperidol compared with placebo. Discounting was steeper for low versus high reward magnitudes, but this effect was largely unaffected by haloperidol. Results were corroborated by model-free analyses and modeling via more standard approaches. We previously reported elevated caudate activation under haloperidol in this sample of participants, supporting the idea that haloperidol elevated dopamine neurotransmission (e.g., by blocking inhibitory feedback via presynaptic D2 auto-receptors). The present results reveal that this is associated with an augmentation of both lower-level (nondecision time) and higher-level (temporal discounting) components of the decision process.SIGNIFICANCE STATEMENT Dopamine is implicated in reward processing, reinforcement learning, and cognitive control. Here we examined the effects of a single dose of the D2 receptor antagonist haloperidol on temporal discounting and choice dynamics during the decision process. We extend previous studies by applying computational modeling using the drift diffusion model, which revealed that haloperidol reduced the nondecision time and reduced impulsive choice compared with placebo. These findings are compatible with a haloperidol-induced increase in striatal dopamine (e.g., because of a presynaptic mechanism). Our data provide novel insights into the contributions of dopamine to value-based decision-making and highlight how comprehensive model-based analyses using sequential sampling models can inform the effects of pharmacological modulation on choice processes.

Central but not peripheral oxytocin administration reduces risk-based decision-making in male rats.

The hormone oxytocin has long been associated with social behaviors, but recent evidence suggests that it may also affect reward processing in non-social contexts. Decisions are an integral component of many social and reward-based behavioral paradigms. Thus, a broad role for oxytocin in decision-making may explain the wide variety of effects that have been previously observed and resolve controversies in the literature about its role. To determine if oxytocin can selectively modulate decision-making in male rats, we assessed the dose-dependent effects of central (intracerebroventricular) or peripheral (intraperitoneal) administration of oxytocin on probability and delay discounting, two commonly used decision-making tasks that are free of social contexts. Our results showed that central administration of oxytocin dose-dependently reduced preference for risky outcomes in the probability discounting task, but had no impact on delay discounting or reward sensitivity. This effect was blocked by the co-administration of an oxytocin antagonist. Additionally, we found no effect of peripheral oxytocin administration on any task. To identify potential cognitive mechanisms of central oxytocin's effect on decision-making, we determined if central or peripheral oxytocin affects reward sensitivity using an intracranial self-stimulation task, and motivation using a progressive ratio task. These results showed that at the dosage that affects decision-making, central oxytocin had a mild and short-lasting effect on motivation, but no observable effect on reward sensitivity. This pattern of results suggests that oxytocin may selectively reduce risky decisions in male rats, even at dosages that have no major effects on reward processing and motivation. These findings highlight a potentially novel role for oxytocin in non-social cognitive processes and expand our understanding of the mechanism by which oxytocin may regulate social behavior.

The acute effects of cannabidiol on the neural correlates of reward anticipation and feedback in healthy volunteers.

BACKGROUND: Cannabidiol has potential therapeutic benefits for people with psychiatric disorders characterised by reward function impairment. There is existing evidence that cannabidiol may influence some aspects of reward processing. However, it is unknown whether cannabidiol acutely affects brain function underpinning reward anticipation and feedback. HYPOTHESES: We predicted that cannabidiol would augment brain activity associated with reward anticipation and feedback. METHODS: We administered a single 600 mg oral dose of cannabidiol and matched placebo to 23 healthy participants in a double-blind, placebo-controlled, repeated-measures design. We employed the monetary incentive delay task during functional magnetic resonance imaging to assay the neural correlates of reward anticipation and feedback. We conducted whole brain analyses and region-of-interest analyses in pre-specified reward-related brain regions. RESULTS: The monetary incentive delay task elicited expected brain activity during reward anticipation and feedback, including in the insula, caudate, nucleus accumbens, anterior cingulate and orbitofrontal cortex. However, across the whole brain, we did not find any evidence that cannabidiol altered reward-related brain activity. Moreover, our Bayesian analyses showed that activity in our regions-of-interest was similar following cannabidiol and placebo. Additionally, our behavioural measures of motivation for reward did not show a significant difference between cannabidiol and placebo. DISCUSSION: Cannabidiol did not acutely affect the neural correlates of reward anticipation and feedback in healthy participants. Future research should explore the effects of cannabidiol on different components of reward processing, employ different doses and administration regimens, and test its reward-related effects in people with psychiatric disorders.

Sex differences in nicotine-induced impulsivity and its reversal with bupropion in rats.

BACKGROUND: Enhancement in cognitive impulsivity and the resulting alterations in decision making serve as a contributing factor for the development and maintenance of substance-use disorders. Nicotine-induced increases in impulsivity has been previously reported in male humans and rodents. Although the potential for sex differences in nicotine-induced impulsivity has not been examined. AIMS AND METHODS: In the present study, male and female Sprague Dawley rats were submitted to a delay discounting task, in which several consecutive measures of self-control were taken. Firstly, rats were tested with vehicle, and next with nicotine doses of 0.4 and 0.8 mg/kg. Thereafter, chronic treatment with bupropion started, and the animals were tested again. Half the animals continued to receive 0.8 mg/kg of nicotine, while the rest received nicotine and also a daily dose of 30 mg/kg of bupropion. RESULTS: When the animals were first tested with nicotine, female rats showed a significant nicotine dose dependent increase of impulsive behaviour, whereas male rats only showed a decrease on their elections of the larger but delayed reward under the highest dose of 0.8 mg/kg of nicotine. Treatment with bupropion blocked the effect of nicotine on decision making in female rats, as they showed results close to their baseline levels. On the other hand, bupropion did not affect the nicotine-induced delay discounting in male rats. CONCLUSION: These findings demonstrate sexually dimorphic effects of nicotine on cognitive impulsivity which may help to shed light on nicotine use vulnerabilities observed in women.

Risk-based decision making in rats: Modulation by sex and amphetamine.

Decision-making is a complex process essential to daily adaptation in many species. Risk is an inherent aspect of decision-making and it is influenced by gonadal hormones. Testosterone and 17ß-estradiol may modulate decision making and impact the mesocorticolimbic dopamine pathway. Here, we explored sex differences, the effect of gonadal hormones and the dopamine agonist amphetamine on risk-based decision making. Intact or gonadectomised (GDX) male and female rats underwent to a probabilistic discounting task. High and low doses of testosterone propionate (1.0 or 0.2 mg) and 17ß-estradiol benzoate (0.3 µg) were administered to assess acute effects on risk-based decision making. After 3-days of washout period, intact and GDX rats received high or low (0.5 or 0.125 mg/kg) doses of amphetamine and re-tested in the probabilistic discounting task. Under baseline conditions, males made more risky choices during probability discounting compared to female rats, particularly in the lower probability blocks, but GDX did not influence risky choice. The high, but not the low dose, of testosterone modestly reduced risky decision making in GDX male rats. Conversely, 17ß-estradiol had no significant effect on risky choice regardless of GDX status in either sex. Lastly, a higher dose of amphetamine increased risky decision making in both intact males and females, but had no effect in GDX rats. These findings demonstrated sex differences in risk-based decision making, with males showing a stronger bias toward larger, uncertain rewards. GDX status influenced the effects of amphetamine, suggesting different dopaminergic regulation in risk-based choices among males and females.

Developmental exposure to 17α-hydroxyprogesterone caproate impairs adult delayed reinforcement and reversal learning in male and female rats.

Women with a history of unexplained miscarriage are frequently prescribed the synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC) during the middle trimester of pregnancy. However, little is known about the long-term behavioural effects of 17-OHPC. Work in rodents suggests that the developing brain is sensitive to progestins. Neonatal 17-OHPC impairs adult performance in set-shifting and delay discounting. The present study tested the effects of 17-OHPC (0.5 mg kg-1 ) or vehicle administration from postnatal days 1-14 on cognitive function in adulthood in rats. Cognitive function was assessed in males and females (n = 8-10 per group) by operant responding for sugar pellets, measuring delayed reinforcement or reversal learning. For delayed reinforcement, the rat must wait 15 seconds for pellets after responding on a lever. Delay is signalled by a light or is unsignalled. For reversal learning, the rat must respond on the lever under a stimulus light, and then learn to respond on the unlit lever. For delayed reinforcement, rats earned more pellets under signalled vs unsignalled conditions. Likewise, males made more responses and earned more pellets compared to females. Under signalled conditions, 17-OHPC-treated rats earned fewer pellets than controls. For reversal learning, the results were similar. Females required more trials than males to respond correctly for the new rule, and 17-OHPC-treated rats required more trials than controls. This suggests that 17-OHPC exposure during development may impair cognitive function. Considering that questions have been raised as to the efficacy of 17-OHPC to prevent miscarriage, it may be necessary to rethink the use of progestin therapy during pregnancy.

Sex-dependent associations between addiction-related behaviors and the microbiome in outbred rats.

BACKGROUND: Multiple factors contribute to the etiology of addiction, including genetics, sex, and a number of addiction-related behavioral traits. One behavioral trait where individuals assign incentive salience to food stimuli ("sign-trackers", ST) are more impulsive compared to those that do not ("goal-trackers", GT), as well as more sensitive to drugs and drug stimuli. Furthermore, this GT/ST phenotype predicts differences in other behavioral measures. Recent studies have implicated the gut microbiota as a key regulator of brain and behavior, and have shown that many microbiota-associated changes occur in a sex-dependent manner. However, few studies have examined how the microbiome might influence addiction-related behaviors. To this end, we sought to determine if gut microbiome composition was correlated with addiction-related behaviors determined by the GT/ST phenotype. METHODS: Outbred male (N=101) and female (N=101) heterogeneous stock rats underwent a series of behavioral tests measuring impulsivity, attention, reward-learning, incentive salience, and locomotor response. Cecal microbiome composition was estimated using 16S rRNA gene amplicon sequencing. Behavior and microbiome were characterized and correlated with behavioral phenotypes. Robust sex differences were observed in both behavior and microbiome; further analyses were conducted within sex using the pre-established goal/sign-tracking (GT/ST) phenotype and partial least squares differential analysis (PLS-DA) clustered behavioral phenotype. RESULTS: Overall microbiome composition was not associated to the GT/ST phenotype. However, microbial alpha diversity was significantly decreased in female STs. On the other hand, a measure of impulsivity had many significant correlations to microbiome in both males and females. Several measures of impulsivity were correlated with the genus Barnesiella in females. Female STs had notable correlations between microbiome and attentional deficient. In both males and females, many measures were correlated with the bacterial families Ruminocococcaceae and Lachnospiraceae. CONCLUSIONS: These data demonstrate correlations between several addiction-related behaviors and the microbiome specific to sex.

Effects of opioid/cannabinoid mixtures on impulsivity and memory in rhesus monkeys.

The opioid epidemic underscores the need for safer and more effective treatments for pain. Combining opioid receptor agonists with drugs that relieve pain through nonopioid mechanisms could be a useful strategy for reducing the dose of opioid needed to treat pain, thereby reducing risks associated with opioids alone. Opioid/cannabinoid mixtures might be useful in this context; individually, opioids and cannabinoids have modest effects on cognition, and it is important to determine whether those effects occur with mixtures. Delay discounting and delayed matching-to-sample tasks were used to examine effects of the mu-opioid receptor agonist morphine (0.32-5.6 mg/kg), the cannabinoid CB1/CB2 receptor agonist CP55940 (0.0032-0.1 mg/kg), and morphine/CP55940 mixtures on impulsivity (n = 3) and memory (n = 4) in rhesus monkeys. Alone, each drug decreased rate of responding without modifying choice in the delay-discounting task, and morphine/CP55940 mixtures reduced choice of one pellet in a delay dependent manner, with monkeys instead choosing delayed delivery of the larger number of pellets. With the exception of one dose in one monkey, accuracy in the delayed matching-to-sample task was not altered by either drug alone. Morphine/CP55940 mixtures decreased accuracy in two monkeys, but the doses in the mixture were equal to or greater than doses that decreased accuracy or response rate with either drug alone. Rate-decreasing effects of morphine/CP55940 mixtures were additive. These data support the notion that opioid/cannabinoid mixtures that might be effective for treating pain do not have greater, and might have less, adverse effects compared with larger doses of each drug alone.

Ventral striatum supports Methylphenidate therapeutic effects on impulsive choices expressed in temporal discounting task.

Methylphenidate (MPH) is a dopamine transporter (DAT) inhibitor used to treat attention-deficit/hyperactivity-disorder (ADHD). ADHD patients make impulsive choices in delay discounting tasks (DDT) and MPH reduces such impulsivity, but its therapeutic site of action remains unknown. Based on the high density of DAT in the striatum, we hypothesized that the striatum, especially the ventral striatum (VS) and caudate nucleus which both encode temporal discounting, can be preferential MPH action sites. To determine whether one of these striatal territories is predominantly involved in the effect of MPH, we trained monkeys to make choices during DDT. First, consistent with clinical observations, we found an overall reduction of impulsive choices with a low dose of MPH administered via intramuscular injections, whereas we reported sedative-like effects with a higher dose. Then, using PET-imaging, we found that the therapeutic reduction of impulsive choices was associated with selective DAT occupancy of MPH in the VS. Finally, we confirmed the selective involvement of the VS in the effect of MPH by testing the animals' impulsivity with microinjections of the drug in distinct striatal territories. Together, these results show that the therapeutic effect of MPH on impulsive decisions is mainly restricted to its action in the VS.