An epigenetic mechanism for over-consolidation of fear memories.

Excessive fear is a hallmark of anxiety disorders, a major cause of disease burden worldwide. Substantial evidence supports a role of prefrontal cortex-amygdala circuits in the regulation of fear and anxiety, but the molecular mechanisms that regulate their activity remain poorly understood. Here, we show that downregulation of the histone methyltransferase PRDM2 in the dorsomedial prefrontal cortex enhances fear expression by modulating fear memory consolidation. We further show that Prdm2 knock-down (KD) in neurons that project from the dorsomedial prefrontal cortex to the basolateral amygdala (dmPFC-BLA) promotes increased fear expression. Prdm2 KD in the dmPFC-BLA circuit also resulted in increased expression of genes involved in synaptogenesis, suggesting that Prdm2 KD modulates consolidation of conditioned fear by modifying synaptic strength at dmPFC-BLA projection targets. Consistent with an enhanced synaptic efficacy, we found that dmPFC Prdm2 KD increased glutamatergic release probability in the BLA and increased the activity of BLA neurons in response to fear-associated cues. Together, our findings provide a new molecular mechanism for excessive fear responses, wherein PRDM2 modulates the dmPFC -BLA circuit through specific transcriptomic changes.

Increased impulsivity in rats as a result of repeated cycles of alcohol intoxication and abstinence.

Impulsivity is a risk factor for alcoholism, and long-term alcohol exposure may further impair impulse control in a manner that propels problematic alcohol use. The present study employed the rat 5-choice serial reaction time task (5-CSRTT) to measure behavioral inhibition and attentional capacity during abstinence from repeated 5-day cycles of alcohol liquid diet consumption. Task performance was not disrupted following the first cycle of alcohol exposure; however, evidence of impaired behavioral inhibition emerged following the third cycle of alcohol exposure. In comparison with controls, alcoholic rats exhibited deficits in inhibitory control during cognitively challenging 5-CSRTT tests employing variable intertrial interval (varITI). This behavioral disruption was not present during early abstinence (3 days) but was evident by 7 days of abstinence and persisted for at least 34 days. Interestingly, renewed alcohol consumption ameliorated these disruptions in impulse control, although deficient behavioral inhibition re-emerged during subsequent abstinence. Indices of increased impulsivity were no longer present in tests conducted after 49 days of abstinence. Alcohol-related impairments in impulse control were not evident in sessions employing highly familiar task parameters regardless of the abstinence period, and control experiments confirmed that performance deficits during the challenge sessions were unlikely to result from alcohol-related disruption in the adaptation to repeated varITI testing. Together, the current findings demonstrate that chronic intermittent alcohol consumption results in decreased behavioral inhibition in rats that is temporally similar to clinical observations of disrupted impulsive control in abstinent alcoholics performing tasks of behavioral inhibition.

Activation of GABAB receptors in central amygdala attenuates activity of PKCδ + neurons and suppresses punishment-resistant alcohol self-administration in rats.

Alcohol use despite negative consequences is a core phenomenon of alcohol addiction. We recently used alcohol self-administration that is resistant to footshock punishment as a model of this behavior, and found that activity of PKCδ + GABAergic neurons in the central amygdala (CeA) is a determinant of individual susceptibility for punishment resistance. In the present study, we examined whether activation of GABAB receptors in CeA can attenuate the activity of PKCδ + neurons in this region, and whether this will result in suppression of punishment- resistant alcohol self-administration in the minority of rats that show this behavior. Systemic administration of the clinically approved GABAB agonist baclofen (1 and 3 mg/kg) dose- dependently reduced punishment-resistant alcohol self-administration. Bilateral microinjections of baclofen into CeA (64 ng in 0.3 µl/side) reduced the activity of PKCδ + neurons, as measured by Fos expression. This manipulation also selectively suppressed punished alcohol self-administration in punishment-resistant rats. Expression analysis indicated that virtually all CeA PKCδ + neurons express the GABAB receptor. Using in vitro electrophysiology, we found that baclofen induced hyperpolarization of CeA neurons, reducing their firing rate in response to depolarizing current injections. Together, our findings provide a potential mechanism that contributes to the clinical efficacy of baclofen in alcohol addiction. Therapeutic use of baclofen itself is limited by problems of tolerance and need for dose escalation. Our findings support a mechanistic rationale for developing novel, improved alcohol addiction medications that target GABAB receptors, and that lack these limitations, such as e.g., GABAB positive allosteric modulators (PAM:s).

µ-Opioid receptors in the nucleus accumbens shell region mediate the effects of amphetamine on inhibitory control but not impulsive choice.

Acute challenges with psychostimulants such as amphetamine affect impulsive behavior in both animals and humans. With regard to amphetamine, it is important to unravel how this drug affects impulsivity since it is not only a widely abused recreational drug but also regularly prescribed to ameliorate maladaptive impulsivity. Therefore, we studied the effects of amphetamine in two rat models of impulsivity, the five-choice serial reaction time task and the delayed-reward task, providing measures of inhibitory control and impulsive choice, respectively. We focused on the role of opioid receptor activation in amphetamine-induced impulsivity as there is ample evidence indicating an important role for endogenous opioids in several behavioral and neurochemical effects of amphetamine. Results showed that amphetamine-induced inhibitory control deficits were dose-dependently attenuated by the preferential µ-opioid receptor antagonist naloxone, but not by the selective δ-opioid receptor antagonist naltrindole or κ-opioid receptor antagonist nor-BNI (nor-binaltorphimine dihydrochloride). In contrast, naloxone did not affect amphetamine-induced improvements in impulsive decision making. Naloxone also completely prevented inhibitory control deficits induced by GBR 12909 [1-(2-[bis(4-fluorophenyl)methoxy] ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride], a selective dopamine transporter inhibitor. Intracranial infusions of naloxone, the selective µ-opioid receptor antagonist CTAP (H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)), morphine, and the selective µ-opioid receptor agonist DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin acetate salt) revealed that µ-opioid receptor activation in the shell rather than the core subregion of the nucleus accumbens (NAc) modulates inhibitory control and subserves the effect of amphetamine thereon. Together, these results indicate an important role for NAc shell µ-opioid receptors in the regulation of inhibitory control, probably via an interaction between these receptors and the mesolimbic dopamine system.

Contributions of face processing, social anhedonia and mentalizing to the expression of social autistic-like traits.

Introduction: Quantitative autistic-like traits (QATs) are a constellation of traits that mirror those of clinical autism and are thought to share the same mechanisms as the condition. There is great interest in identifying the genetic and neurobiological basis of QATs, but progress is hindered by the composite nature of these clinically based constructs. Social QATs are defined according to the diagnostic criteria for autism, comprising multiple potential neural mechanisms that may contribute to varying degrees. The objective of this study was to decompose social QATs into more specific constructs, in line with the Research Domain Criteria (RDoC). We chose constructs with trait-like properties and known or suggested significance for autistic social function: (1) social anhedonia, (2) prosopagnosia (face blindness), and (3) mentalizing (attributing mental states to images of eyes). We hypothesized that these constructs may all contribute to observed variance in social QATs. Methods: We recruited 148 adults with a broad range of QATs (mean age 37.9 years, range 18-69; 50% female; 5.4% autistic) to an experimental behavioral study conducted online. We estimated social QATs using the social factor of the Comprehensive Autistic Traits Inventory. We used the Oxford Face Matching Task and the Reading the Mind in the Eyes Test to measure face matching ability and mentalizing, respectively. Social anhedonia traits were measured with the Anticipatory and Consummatory Interpersonal Pleasure Scale, and prosopagnosic traits with the 20-item Prosopagnosia Index. A combination of frequentist and Bayesian statistics was used to test the social constructs as predictors of social QATs. Results: We found that social anhedonic traits, prosopagnosic traits, and face matching performance were likely predictors of social QATs, whereas mentalizing showed limited contribution. Conclusion: The findings support prosopagnosic and anhedonic traits, but not mentalizing deficits, as dimensional predictors of individual differences in social function across the autistic spectrum. Further, the study strongly suggests that social reward systems and face processing networks play significant and independent roles in autistic-like social function.

Preconception paternal morphine exposure leads to an impulsive phenotype in male rat progeny.

RATIONALE: Identifying the long-term neurocognitive implications of opioid addiction may further our understanding of the compulsive nature of this brain disorder. The aim of this study was to examine the effects of paternal adolescent opiate exposure on cognitive performance (visual attention, impulsivity, and compulsivity) in the next generation. METHODS: Male Wistar rats received escalating doses of morphine (2.5-25 mg/kg, s.c.) or saline for 10 days during adolescence (P30-39). In adulthood (P70-80), these rats were allowed to mate with drug-naive females. Male offspring from morphine- and saline-exposed sires, once in adulthood, were trained and tested in the 5-choice serial reaction time test (5-CSRTT) to evaluate their cognitive abilities under baseline, drug-free conditions as well as following acute (1, 3, 5 mg/kg morphine) and subchronic morphine (5 mg/kg morphine for 5 days) treatment. Behavioral effects of the opioid receptor antagonist naloxone were also assessed. RESULTS: Morphine-sired offspring exhibited delayed learning when the shortest stimulus duration (1 s) was introduced, i.e., when cognitive load was highest. These subjects also exhibited a reduced ability to exert inhibitory control, as reflected by increased premature and perseverative responding under drug-free baseline conditions in comparison to saline-sired rats. These impairments could not be reversed by administration of naloxone. Moreover, impulsive behavior was further enhanced in morphine-sired rats following acute and subchronic morphine treatment. CONCLUSION: Paternal opiate exposure during adolescence was found to primarily impair inhibitory control in male progeny. These results further our understanding of the long-term costs and risk of opioid abuse, extending across generations.

The orexin-1 receptor antagonist SB-334867 reduces motivation, but not inhibitory control, in a rat stop signal task.

There is considerable clinical interest in the neuropeptide orexin/hypocretin for its ability to regulate motivation and reward as well as arousal and wakefulness. For instance, antagonists for the orexin-1 receptor (OxR1) are thought to hold great promise for treating drug addiction and disorders associated with overeating, as these compounds repeatedly have been found to suppress seeking of various drugs of abuse as well as highly palatable foods in preclinical models. Given the hypothesized role of OxR1 signaling in cue-driven motivation, an outstanding question is whether pharmacologically blocking this receptor affects cognitive functioning. Response inhibition - the ability to cancel ongoing behavior - is one aspect of cognitive control that may be particularly relevant. Response inhibition deficits are commonly associated with a range of psychiatric disorders and neurological diseases, including substance use disorders and obesity. Moreover, OxR1 signaling recently has been implicated in waiting impulsivity, another aspect of inhibitory control. Here, we investigated the effects of the OxR1 antagonist SB-334867 on response inhibition in a rat version of the stop-signal reaction time task. Results show that acutely blocking OxR1 had minimal effects on response inhibition or attentional functioning. In contrast, this manipulation reduced motivation to perform the task and earn food rewards, consistent with other recent findings. These results add to the growing body of literature implicating OxR1 in the regulation of motivation and suggest that effects of pharmacological compounds such as SB-334867 on drug-seeking behavior are not related to effects on response inhibition.

Opposing Influence of Sensory and Motor Cortical Input on Striatal Circuitry and Choice Behavior.

The striatum is the main input nucleus of the basal ganglia and is a key site of sensorimotor integration. While the striatum receives extensive excitatory afferents from the cerebral cortex, the influence of different cortical areas on striatal circuitry and behavior is unknown. Here, we find that corticostriatal inputs from whisker-related primary somatosensory (S1) and motor (M1) cortex differentially innervate projection neurons and interneurons in the dorsal striatum and exert opposing effects on sensory-guided behavior. Optogenetic stimulation of S1-corticostriatal afferents in ex vivo recordings produced larger postsynaptic potentials in striatal parvalbumin (PV)-expressing interneurons than D1- or D2-expressing spiny projection neurons (SPNs), an effect not observed for M1-corticostriatal afferents. Critically, in vivo optogenetic stimulation of S1-corticostriatal afferents produced task-specific behavioral inhibition, which was bidirectionally modulated by striatal PV interneurons. Optogenetic stimulation of M1 afferents produced the opposite behavioral effect. Thus, our results suggest opposing roles for sensory and motor cortex in behavioral choice via distinct influences on striatal circuitry.

Cannabinoid modulation of executive functions.

Executive functions are higher-order cognitive processes such as attention, behavioural flexibility, decision-making, inhibitory control, planning, time estimation and working memory that exert top-down control over behaviour. In addition to the role of cannabinoid signaling in other cognitive functions such as mnemonic processes, interest in its involvement in executive functions has arisen more recently. Here, we will briefly review some of the recent findings indicating a modulatory role of cannabinoid action on executive functioning. In addition, a growing body of evidence suggests that in particular adolescents are more vulnerable for the deleterious effects of drugs of abuse such as cannabis on cognitive functioning. Therefore, in this paper we will also briefly discuss some recent developments in this research field.

The role of CB1 receptors in psychostimulant addiction.

Recent studies have implicated the endocannabinoid (eCB) system in the neuronal mechanisms underlying substance dependence. Here, we review results of studies using cannabinoid receptor subtype 1 (CB1) knockout mice as well as CB1 antagonists to elucidate the role of this neurotransmitter system in psychostimulant addiction. The overall picture is that CB1 receptors appear not to be involved in psychostimulant reward, nor in the development of dependence to such substances. In contrast, the eCB system appears to play a role in the persistence of psychostimulant addiction. In particular, CB1 receptors have been found to play a cardinal role in mediating reinstatement of previously extinguished drug-seeking behavior upon re-exposure to the drug or drug-associated cues. The anatomical loci as well as the neuronal mechanisms of the relapse-preventing effects of CB1 antagonists are still poorly understood, although interactions of the eCB system with afferent glutamatergic and possibly dopaminergic projections to the nucleus accumbens are most likely involved. In addition, CB1 receptors seem to modulate drug-related memories, in line with the hypothesized role of the eCB system in memory-related plasticity. Together, these findings suggest that modulators of the eCB system represent a promising novel type of therapy to treat drug addiction.

Response contingency directs long-term cocaine-induced neuroplasticity in prefrontal and striatal dopamine terminals.

Exposure to addictive substances such as cocaine is well-known to alter brain organisation. Cocaine-induced neuroadaptations depend on several factors, including drug administration paradigm. To date, studies addressing the consequences of cocaine exposure on dopamine transmission have either not been designed to investigate the role of response contingency or focused only on short-term neuroplasticity. We demonstrate a key role of response contingency in directing long-term cocaine-induced neuroplasticity throughout projection areas of the mesocorticolimbic dopamine system. We found enhanced electrically-evoked [(3)H]dopamine release from superfused brain slices of nucleus accumbens shell and core, dorsal striatum and medial prefrontal cortex three weeks after cessation of cocaine self-administration. In yoked cocaine rats receiving the same amount of cocaine passively, sensitised dopamine terminal reactivity was only observed in the nucleus accumbens core. Control sucrose self-administration experiments demonstrated that the observed neuroadaptations were not the result of instrumental learning per se. Thus, long-term withdrawal from cocaine self-administration is associated with widespread sensitisation of dopamine terminals throughout frontostriatal circuitries.

Dissociated sequential activity and stimulus encoding in the dorsomedial striatum during spatial working memory.

Several lines of evidence suggest that the striatum has an important role in spatial working memory. The neural dynamics in the striatum have been described in tasks with short delay periods (1-4 s), but remain largely uncharacterized for tasks with longer delay periods. We collected and analyzed single unit recordings from the dorsomedial striatum of rats performing a spatial working memory task with delays up to 10 s. We found that neurons were activated sequentially, with the sequences spanning the entire delay period. Surprisingly, this sequential activity was dissociated from stimulus encoding activity, which was present in the same neurons, but preferentially appeared towards the onset of the delay period. These observations contrast with descriptions of sequential dynamics during similar tasks in other brains areas, and clarify the contribution of the striatum to spatial working memory.

On the Role of Cannabinoid CB1- and µ-Opioid Receptors in Motor Impulsivity.

Previous studies using a rat 5-choice serial reaction time task have established a critical role for dopamine D2 receptors in regulating increments in motor impulsivity induced by acute administration of the psychostimulant drugs amphetamine and nicotine. Here we investigated whether cannabinoid CB1 and/or µ-opioid receptors are involved in nicotine-induced impulsivity, given recent findings indicating that both receptor systems mediate amphetamine-induced motor impulsivity. Results showed that the cannabinoid CB1 receptor antagonist SR141716A, but not the opioid receptor antagonist naloxone, reduced nicotine-induced premature responding, indicating that nicotine-induced motor impulsivity is cannabinoid, but not opioid receptor-dependent. In contrast, SR141716A did not affect impulsivity following a challenge with the dopamine transporter inhibitor GBR 12909, a form of drug-induced impulsivity that was previously found to be dependent on µ-opioid receptor activation. Together, these data are consistent with the idea that the endogenous cannabinoid, dopamine, and opioid systems each play important, but distinct roles in regulating (drug-induced) motor impulsivity. The rather complex interplay between these neurotransmitter systems modulating impulsivity will be discussed in terms of the differential involvement of mesocortical and mesolimbic neurocircuitry.

Characterization of the effects of reuptake and hydrolysis inhibition on interstitial endocannabinoid levels in the brain: an in vivo microdialysis study.

The present experiments employed in vivo microdialysis to characterize the effects of commonly used endocannabinoid clearance inhibitors on basal and depolarization-induced alterations in interstitial endocannabinoid levels in the nucleus accumbens of rat brain. Compounds targeting the putative endocannabinoid transporter and hydrolytic enzymes (FAAH and MAGL) were compared. The transporter inhibitor AM404 modestly enhanced depolarization-induced increases in 2-arachidonoyl glycerol (2-AG) levels but did not alter levels of N-arachidonoyl-ethanolamide (anandamide, AEA). The transport inhibitor UCM707 did not alter dialysate levels of either endocannabinoid. The FAAH inhibitors URB597 and PF-3845 robustly increased AEA levels during depolarization without altering 2-AG levels. The MAGL inhibitor URB602 significantly enhanced depolarization-induced increases in 2-AG, but did not alter AEA levels. In contrast, the MAGL inhibitor JZL184 did not alter 2-AG or AEA levels under any condition tested. Finally, the dual FAAH/MAGL inhibitor JZL195 significantly enhanced depolarization-induced increases in both AEA and 2-AG levels. In contrast to the present observations in rats, prior work in mice has demonstrated a robust JZL184-induced enhancement of depolarization-induced increases in dialysate 2-AG. Thus, to further investigate species differences, additional tests with JZL184, PF-3845, and JZL195 were performed in mice. Consistent with prior reports, JZL184 significantly enhanced depolarization-induced increases in 2-AG without altering AEA levels. PF-3845 and JZL195 produced profiles in mouse dialysates comparable to those observed in rats. These findings confirm that interstitial endocannabinoid levels in the brain can be selectively manipulated by endocannabinoid clearance inhibitors. While PF-3845 and JZL195 produce similar effects in both rats and mice, substantial species differences in JZL184 efficacy are evident, which is consistent with previous studies.

The relationship between impulsive choice and impulsive action: a cross-species translational study.

Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.

Cannabinoid CB1 receptor activation mediates the opposing effects of amphetamine on impulsive action and impulsive choice.

It is well known that acute challenges with psychostimulants such as amphetamine affect impulsive behavior. We here studied the pharmacology underlying the effects of amphetamine in two rat models of impulsivity, the 5-choice serial reaction time task (5-CSRTT) and the delayed reward task (DRT), providing measures of inhibitory control, an aspect of impulsive action, and impulsive choice, respectively. We focused on the role of cannabinoid CB1 receptor activation in amphetamine-induced impulsivity as there is evidence that acute challenges with psychostimulants activate the endogenous cannabinoid system, and CB1 receptor activity modulates impulsivity in both rodents and humans. Results showed that pretreatment with either the CB1 receptor antagonist/inverse agonist SR141716A or the neutral CB1 receptor antagonist O-2050 dose-dependently improved baseline inhibitory control in the 5-CSRTT. Moreover, both compounds similarly attenuated amphetamine-induced inhibitory control deficits, suggesting that CB1 receptor activation by endogenously released cannabinoids mediates this aspect of impulsive action. Direct CB1 receptor activation by Δ9-Tetrahydrocannabinol (Δ9-THC) did, however, not affect inhibitory control. Although neither SR141716A nor O-2050 affected baseline impulsive choice in the DRT, both ligands completely prevented amphetamine-induced reductions in impulsive decision making, indicating that CB1 receptor activity may decrease this form of impulsivity. Indeed, acute Δ9-THC was found to reduce impulsive choice in a CB1 receptor-dependent way. Together, these results indicate an important, though complex role for cannabinoid CB1 receptor activity in the regulation of impulsive action and impulsive choice as well as the opposite effects amphetamine has on both forms of impulsive behavior.

Extracellular matrix plasticity and GABAergic inhibition of prefrontal cortex pyramidal cells facilitates relapse to heroin seeking.

Successful treatment of drug addiction is hampered by high relapse rates during periods of abstinence. Neuroadaptation in the medial prefrontal cortex (mPFC) is thought to have a crucial role in vulnerability to relapse to drug seeking, but the molecular and cellular mechanisms remain largely unknown. To identify protein changes that contribute to relapse susceptibility, we investigated synaptic membrane fractions from the mPFC of rats that underwent 21 days of forced abstinence following heroin self-administration. Quantitative proteomics revealed that long-term abstinence from heroin self-administration was associated with reduced levels of extracellular matrix (ECM) proteins. After extinction of heroin self-administration, downregulation of ECM proteins was also present in the mPFC, as well as nucleus accumbens (NAc), and these adaptations were partially restored following cue-induced reinstatement of heroin seeking. In the mPFC, these ECM proteins are condensed in the perineuronal nets that exclusively surround GABAergic interneurons, indicating that ECM adaptation might alter the activity of GABAergic interneurons. In support of this, we observed an increase in the inhibitory GABAergic synaptic inputs received by the mPFC pyramidal cells after the re-exposure to heroin-conditioned cues. Recovering levels of ECM constituents by metalloproteinase inhibitor treatment (FN-439; i.c.v.) prior to a reinstatement test attenuated subsequent heroin seeking, suggesting that the reduced synaptic ECM levels during heroin abstinence enhanced sensitivity to respond to heroin-conditioned cues. We provide evidence for a novel neuroadaptive mechanism, in which heroin self-administration-induced adaptation of the ECM increased relapse vulnerability, potentially by augmenting the responsivity of mPFC GABAergic interneurons to heroin-associated stimuli.

Acute effects of morphine on distinct forms of impulsive behavior in rats.

RATIONALE: Disturbances in impulse control are key features of substance abuse disorders, and conversely, many drugs of abuse are known to elicit impulsive behavior both clinically and preclinically. To date, little is known with respect to the involvement of the opioid system in impulsive behavior, although recent findings have demonstrated its involvement in delay discounting processes. The aim of the present study was to further investigate the role of the opioid system in varieties of impulsivity. MATERIALS AND METHODS: To this end, groups of rats were trained in the five-choice serial reaction time task (5-CSRTT) and stop-signal task (SST), operant paradigms that provide measures of inhibitory control and response inhibition, respectively. In addition, another group of rats was trained in the delayed reward paradigm, which measures the sensitivity towards delay of gratification and as such assesses impulsive choice. RESULTS AND DISCUSSION: Results demonstrated that morphine, a selective micro-opioid receptor agonist, primarily impaired inhibitory control in the 5-CSRTT by increasing premature responding. In addition, in keeping with previous data, morphine decreased the preference for the large over small reward in the delayed reward paradigm. The effects of morphine on measures of impulsivity in both the 5-CSRTT and delayed reward paradigm were blocked by naloxone, a micro-opioid receptor antagonist. Naloxone by itself did not alter impulsive behavior, suggesting limited involvement of an endogenous opioid tone in impulsivity. Response inhibition measured in the SST was neither altered by morphine nor naloxone, although some baseline-dependent effects of morphine on response inhibition were observed. CONCLUSION: In conclusion, the present data demonstrate that acute challenges with morphine modulate distinct forms of impulsive behavior, thereby suggesting a role for the opioid system in impulsivity.