Mu and Delta Opioid Receptors Oppositely Regulate Motor Impulsivity in the Signaled Nose Poke Task

Impulsivity is a primary feature of many psychiatric disorders, most notably attention deficit hyperactivity disorder and drug addiction. Impulsivity includes a number of processes such as the inability to delay gratification, the inability to withhold a motor response, or acting before all of the relevant information is available. These processes are mediated by neural systems that include dopamine, serotonin, norepinephrine, glutamate and cannabinoids. We examine, for the first time, the role of opioid systems in impulsivity by testing whether inactivation of the mu- (Oprm1) or delta- (Oprd1) opioid receptor gene alters motor impulsivity in mice. Wild-type and knockout mice were examined on either a pure C57BL6/J (BL6) or a hybrid 50% C57Bl/6J–50% 129Sv/pas (HYB) background. Mice were trained to respond for sucrose in a signaled nose poke task that provides independent measures of associative learning (responses to the reward-paired cue) and motor impulsivity (premature responses). Oprm1 knockout mice displayed a remarkable decrease in motor impulsivity. This was observed on the two genetic backgrounds and did not result from impaired associative learning, as responses to the cue signaling reward did not differ across genotypes. Furthermore, mutant mice were insensitive to the effects of ethanol, which increased disinhibition and decreased conditioned responding in wild-type mice. In sharp contrast, mice lacking the Oprd1 gene were more impulsive than controls. Again, mutant animals showed no deficit in associative learning. Ethanol completely disrupted performance in these animals. Together, our results suggest that mu-opioid receptors enhance, whereas delta-opioid receptors inhibit, motor impulsivity. This reveals an unanticipated contribution of endogenous opioid receptor activity to disinhibition. In a broader context, these data suggest that alterations in mu- or delta-opioid receptor function may contribute to impulse control disorders

Dissociation between morphine-induced spinal gliosis and analgesic tolerance by ultra-low-dose α2-adrenergic and cannabinoid CB1-receptor antagonists.

Long-term use of opioid analgesics is limited by tolerance development and undesirable adverse effects. Paradoxically, spinal administration of ultra-low-dose (ULD) G-protein-coupled receptor antagonists attenuates analgesic tolerance. Here, we determined whether systemic ULD α2-adrenergic receptor (AR) antagonists attenuate the development of morphine tolerance, whether these effects extend to the cannabinoid (CB1) receptor system, and if behavioral effects are reflected in changes in opioid-induced spinal gliosis. Male rats were treated daily with morphine (5 mg/kg) alone or in combination with ULD α2-AR (atipamezole or efaroxan; 17 ng/kg) or CB1 (rimonabant; 5 ng/kg) antagonists; control groups received ULD injections only. Thermal tail flick latencies were assessed across 7 days, before and 30 min after the injection. On day 8, spinal cords were isolated, and changes in spinal gliosis were assessed through fluorescent immunohistochemistry. Both ULD α2-AR antagonists attenuated morphine tolerance, whereas the ULD CB1 antagonist did not. In contrast, both ULD atipamezole and ULD rimonabant attenuated morphine-induced microglial reactivity and astrogliosis in deep and superficial spinal dorsal horn. So, although paradoxical effects of ULD antagonists are common to several G-protein-coupled receptor systems, these may not involve similar mechanisms. Spinal glia alone may not be the main mechanism through which tolerance is modulated

Recreational Drug Use and Impulsivity in a Population of Canadian Undergraduate Drinkers

The consumption of drugs during young adulthood may be particularly detrimental given important neurodevelopmental changes occurring during this period. As impulsivity may lead to substance use and substance use to the commission of seemingly impulsive acts, an improved understanding of the relationship between alcohol use, other substance use and impulsivity in young adults is important. We gathered information on self-reported impulsivity, recreational drug use, and drinking habits of 205 (105 female) undergraduate students. Results showed that 64% of the students reported using marijuana at least once and these individuals were more likely to report binge drinking. Polysubstance use, defined as using marijuana and at least one other illicit substance, was reported by 20% of students. These individuals reported more drinking occasions per month and had higher levels of trait impulsivity. Rates of recreational drug use were similar to those reported in recent national surveys, suggesting an increase in experimentation with specific illicit drugs. Given that a majority of undergraduate drinkers reported marijuana use and its association with binge drinking, future research should clarify the relationship between marijuana use and binge consumption of alcohol and prevention efforts should consider the conjoint targeting of marijuana and binge drinking. The associations between polysubstance use, binge-level alcohol consumption and elevated self-reported impulsivity suggests that perceived trait impulsivity across multiple domains may predispose to excessive use of multiple substances. Longitudinal studies should examine the contribution of impulsivity to the initiation and experimentation with illicit drugs and the influence of specific substances on impulsivity

CB1 Agonism Alters Addiction-Related Behaviors in Mice Lacking Mu or Delta Opioid Receptors

Opioids are powerful analgesics but the clinical utility of these compounds is reduced by aversive outcomes, including the development of affective and substance use disorders. Opioid systems do not function in isolation so understanding how these interact with other neuropharmacological systems could lead to novel therapeutics that minimize withdrawal, tolerance, and emotional dysregulation. The cannabinoid system is an obvious candidate as anatomical, pharmacological, and behavioral studies point to opioid-cannabinoid interactions in the mediation of these processes. The aim of our study is to uncover the role of specific cannabinoid and opioid receptors in addiction-related behaviors, specifically nociception, withdrawal, anxiety, and depression. To do so, we tested the effects of a selective CB1 agonist, arachidonyl-2-chloroethylamide (ACEA), on mouse behavior in tail immersion, naloxone-precipitated withdrawal, light-dark, and splash tests. We examined cannabinoid-opioid interactions in these tests by comparing responses of wildtype (WT) mice to mutant lines lacking either Mu or Delta opioid receptors. ACEA, both acute or repeated injections, had no effect on nociceptive thresholds in WT or Mu knockout (KO) mice suggesting that analgesic properties of CB1 agonists may be restricted to chronic pain conditions. The opioid antagonist, naloxone, induced similar levels of withdrawal in all three genotypes following ACEA treatment, confirming an opioidergic contribution to cannabinoid withdrawal. Anxiety-like responses in the light-dark test were similar across WT and KO lines; neither acute nor repeated ACEA injections modified this behavior. Similarly, administration of the Delta opioid receptor antagonist, naltrindole, alone or in combination with ACEA, did not alter responses of WT mice in the light-dark test. Thus, there may be a dissociation in the effect of pharmacological blockade vs. genetic deletion of Delta opioid receptors on anxiety-like behavior in mice. Finally, our study revealed a biphasic effect of ACEA on depressive-like behavior in the splash test, with a prodepressive state induced by acute exposure, followed by a shift to an anti-depressive state with repeated injections. The initial pro-depressive effect of ACEA was absent in Mu KO mice. In sum, our findings confirm interactions between opioid and cannabinoid systems in withdrawal and reveal reduced depressive-like symptoms with repeated CB1 receptor activation

Shift in the Intrinsic Excitability of Medial Prefrontal Cortex Neurons following Training in Impulse Control and Cued-Responding Tasks

Impulse control is an executive process that allows animals to inhibit their actions until an appropriate time. Previously, we reported that learning a simple response inhibition task increases AMPA currents at excitatory synapses in the prelimbic region of the medial prefrontal cortex (mPFC). Here, we examined whether modifications to intrinsic excitability occurred alongside the synaptic changes. To that end, we trained rats to obtain a food reward in a response inhibition task by withhold responding on a lever until they were signaled to respond. We then measured excitability, using whole-cell patch clamp recordings in brain slices, by quantifying action potentials generated by the injection of depolarizing current steps. Training in this task depressed the excitability of layer V pyramidal neurons of the prelimbic, but not infralimbic, region of the mPFC relative to behavioral controls. This decrease in maximum spiking frequency was significantly correlated with performance on the final session of the task. This change in intrinsic excitability may represent a homeostatic mechanism counterbalancing increased excitatory synaptic inputs onto those neurons in trained rats. Interestingly, subjects trained with a cue that predicted imminent reward availability had increased excitability in infralimbic, but not the prelimbic, pyramidal neurons. This dissociation suggests that both prelimbic and infralimbic neurons are involved in directing action, but specialized for different types of information, inhibitory or anticipatory, respectively

Neural mechanisms underlying a conditioned place preference induced by morphine

The present study used the conditioned place preference (CPP) paradigm to examine the neural mechanisms underlying morphine's rewarding effect in the rat. Of thirteen sites tested with intra-cerebral morphine injections, only the ventral tegmental area (VTA) and periaqueductal gray (PAG) produced a CPP, suggesting that morphine's rewarding effect is initiated by an action at these sites. The CPPs induced by intra-VTA and intra-PAG morphine may be produced by different mechanisms because animals conditioned with these two injections exhibited different patterns of behaviour during testing. Injections of a quaternary opioid antagonist into either the VTA or PAG blocked a CPP to systemic morphine, confirming that opiate-induced reward is mediated via opioid receptors in these sites. Lesions of the pedunculopontine tegmental nucleus (PPT$rm sb{g}),$ ventral striatum (VS), PAG, or fornix reduced a CPP to morphine, although PAG and fornix lesioned animals displayed a CPP when tested in a drugged state. These findings suggest that PPT$rm sb{g}$ and VS lesions reduce the rewarding effect of morphine, and that PAG and fornix lesions disrupt the ability to retrieve information about the relationship between conditioned and unconditioned stimuli

Effects of pedunculopontine tegmental nucleus lesions on morphine-induced conditioned place preference and analgesia in the formalin test

It has been proposed that analgesia in the formalin test is mediated through forebrain systems associated with reinforcement, whereas motor responses necessary for the expression of pain are organized at the level of the brainstem. Because it is located in the brainstem and connected with both limbic reward systems and motor structures, the pedunculopontine tegmental nucleus (PPTg) is a site where reward signals might influence the expression of pain. Experiment 1 confirmed that NMDA-induced lesions of the PPTg block the development of a conditioned place preference to morphine. Subsequently, morphine-induced analgesia was found to be reduced, but not eliminated. The reduction of reward was not significantly correlated with loss of choline acetyltransferase containing neurons in the PPTg. In Experiment 2, PPTg lesions did not affect morphine analgesia in drug naive animals, but produced motor abnormalities and blocked the morphine-induced depression of spontaneous motor activity and catalepsy