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International audience; Cocaine addiction is a complex pathology inducing long-term neuroplastic changes that, in turn, contribute to maladaptive behaviors. This behavioral dysregulation is associated with transcriptional reprogramming in brain reward circuitry, although the mechanisms underlying this modulation remain poorly understood. The endogenous cannabinoid system may play a role in this process in that cannabinoid mechanisms modulate drug reward and contribute to cocaine-induced neural adaptations. In this study, we investigated whether cocaine self-administration induces long-term adaptations, including transcriptional modifications and associated epigenetic processes. We first examined endocannabinoid gene expression in reward-related brain regions of the rat following self-administered (0.33 mg/kg intravenous, FR1, 10 days) cocaine injections. Interestingly, we found increased Cnr1 expression in several structures, including prefrontal cortex, nucleus accumbens, dorsal striatum, hippocampus, habenula, amygdala, lateral hypothalamus, ventral tegmental area, and rostromedial tegmental nucleus, with most pronounced effects in the hippocampus. Endocannabinoid levels, measured by mass spectrometry, were also altered in this structure. Chromatin immunoprecipitation followed by qPCR in the hippocampus revealed that two activating histone marks, H3K4Me3 and H3K27Ac, were enriched at specific endocannabinoid genes following cocaine intake. Targeting CB1 receptors using chromosome conformation capture, we highlighted spatial chromatin re-organization in the hippocampus, as well as in the nucleus accumbens, suggesting that destabilization of the chromatin may contribute to neuronal responses to cocaine. Overall, our results highlight a key role for the hippocampus in cocaine-induced plasticity and broaden the understanding of neuronal alterations associated with endocannabinoid signaling. The latter suggests that epigenetic modifications contribute to maladaptive behaviors associated with chronic drug use.

Objectives Increased availability of high-calorie palatable food in most countries has resulted in overconsumption of these foods, suggesting that excessive eating is driven by pleasure, rather than metabolic need. The behavior contributes to the rise in eating disorders, obesity, and associated pathologies like diabetes, cardiac disease, and cancers. The mesocorticolimbic dopamine and homeostatic circuits are interconnected and play a central role in palatable food intake. The endocannabinoid system is expressed in these circuits and represents a potent regulator of feeding, but the impact of an obesogenic diet on its expression is not fully known. Methods Food intake and body weight were recorded in male Wistar rats over a 6-week free-choice regimen of high fat and sugar; transcriptional regulations of the endocannabinoid system were examined post-mortem in brain reward regions (prefrontal cortex, nucleus accumbens, ventral tegmental area, and arcuate nucleus). K-means cluster analysis was used to classify animals based on individual sensitivity to obesity and palatable food intake. Endocannabinoid levels were quantified in the prefrontal cortex and nucleus accumbens. Gene expression in dopamine and homeostatic systems, including ghrelin and leptin receptors, and classical homeostatic peptides, were also investigated. Results The free-choice high-fat -and sugar diet induced hyperphagia and obesity in rats. Cluster analysis revealed that the propensity to develop obesity and excessive palatable food intake was differently associated with dopamine and endocannabinoid system gene expression in reward and homeostatic brain regions. CB2 receptor mRNA was increased in the nucleus accumbens of high sugar consumers, whereas CB1 receptor mRNA was decreased in obesity prone rats. Conclusions Transcriptional data are consistent with observations of altered dopamine function in rodents that have access to an obesogenic diet and point to cannabinoid receptors as GPCR targets involved in neuroplasticity mechanisms associated with maladaptive intake of palatable food. Supplementary Information The online version contains supplementary material available at 10.1007/s00394-021-02613-0.

Coronavirus (COVID-19) lockdowns provided a unique opportunity to examine how changes in the social environment impact mental health and wellbeing. We addressed this issue by assessing how perceived social support across COVID-19 restrictions alters alcohol and cannabis use in emerging adults, a population vulnerable to adverse outcomes of substance use. Four hundred sixty-three young adults in Canada and the United States completed online questionnaires for three retrospective time points: Pre-Covid, Lockdown and Eased Restrictions. Sociodemographic factors, perceived social support, and substance use were assessed. Overall, alcohol use decreased while cannabis use increased during Lockdown. Interestingly, social support negatively predicted alcohol use and positively predicted cannabis use during Lockdown. These findings suggest a difference in motives underlying alcohol and cannabis use in emerging adults. Importantly, these changes were not sustained when restrictions eased, suggesting that emerging adults exhibit resiliency to the impacts of COVID-19 restrictions on substance use.

International audience; Binge eating in humans is driven by hedonic properties of food, suggesting that brain reward systems may contribute to this behaviour. We examined the role of mu opioid receptors (MOP) in binge eating by examining sweet solution intake in mice with genetic deletion of the MOP. Wildtype (WT) and MOP knockout (KO) mice had 4 hr access to food in the home cage combined with limited (4 hr) access to sucrose (17.1% w/v) or saccharin (.09% w/v), or continuous (24 hr) access to sucrose. Only limited access groups exhibited binge intake, measured as increased solution consumption during the first hour. KO mice consumed less solution and food during the first hour as well as less food each day compared to WT mice. Limited access groups consumed more food and gained more weight than continuous access groups, and the effect was magnified in saccharin-consuming mice. Indeed, the increased food consumption in animals given limited access to saccharin was so excessive that caloric intake of this group was significantly higher than either of the sucrose groups (limited or continuous access). Within this group, females consumed more food per bodyweight than males, highlighting important sex differences in feeding behaviours under restricted access schedules.

Delta opioid receptor (DOR) agonists alleviate nociceptive behaviors in various chronic pain models, including neuropathic pain, while having minimal effect on sensory thresholds in the absence of injury. The mechanisms underlying nerve injury-induced enhancement of DOR function are unclear. We used a peripheral nerve injury (PNI) model of neuropathic pain to assess changes in the function and localization of DORs in mice and rats. Intrathecal administration of DOR agonists reversed mechanical allodynia and thermal hyperalgesia. The dose-dependent thermal antinociceptive effects of DOR agonists were shifted to the left in PNI rats. Administration of DOR agonists produced a conditioned place preference in PNI, but not in sham, animals, whereas the DOR antagonist naltrindole produced a place aversion in PNI, but not in sham, mice, suggesting the engagement of endogenous DOR activity in suppressing pain associated with the injury. GTPγS autoradiography revealed an increase in DOR function in the dorsal spinal cord, ipsilateral to PNI. Immunogold electron microscopy and in vivo fluorescent agonist assays were used to assess changes in the ultrastructural localization of DORs in the spinal dorsal horn. In shams, DORs were primarily localized within intracellular compartments. PNI significantly increased the cell surface expression of DORs within lamina IV-V dendritic profiles. Using neonatal capsaicin treatment, we identified that DOR agonist-induced thermal antinociception was mediated via receptors expressed on primary afferent sensory neurons but did not alter mechanical thresholds. These data reveal that the regulation of DORs following PNI and suggest the importance of endogenous activation of DORs in regulating chronic pain states.

Neuron-derived 17β-estradiol (E2) alters synaptic transmission and plasticity in brain regions with endocrine and non-endocrine functions. Investigations into a modulatory role of E2 in synaptic activity and plasticity have mainly focused on the rodent hippocampal formation. In songbirds, E2 is synthesized by auditory forebrain neurons and promotes auditory signal processing and memory for salient acoustic stimuli; however, the modulatory effects of E2 on memory-related synaptic plasticity mechanisms have not been directly examined in the auditory forebrain. We investigated the effects of bidirectional E2 manipulations on synaptic transmission and long-term potentiation (LTP) in the rat primary auditory cortex (A1). Immunohistochemistry revealed widespread neuronal expression of the E2 biosynthetic enzyme aromatase in multiple regions of the rat sensory and association neocortex, including A1. In A1, E2 application reduced the threshold for in vivo LTP induction at layer IV synapses, whereas pharmacological suppression of E2 production by aromatase inhibition abolished LTP induction at layer II/III synapses. In acute A1 slices, glutamate and γ-aminobutyric acid (GABA) receptor-mediated currents were sensitive to E2 manipulations in a layer-specific manner. These findings demonstrate that locally synthesized E2 modulates synaptic transmission and plasticity in A1 and suggest potential mechanisms by which E2 contributes to auditory signal processing and memory.

Binge eating, the defining feature of binge eating disorder (BED), is associated with a number of adverse health outcomes as well as a reduced quality of life. Animals, like humans, selectively binge on highly palatable food suggesting that the behaviour is driven by hedonic, rather than metabolic, signals. Given the links to both reward processing and food intake, this study examined the contribution of the endocannabinoid system (ECS) to binge-like eating in rats. Separate groups were given intermittent (12 h) or continuous (24 h) access to 10% sucrose and food over 28 days, with only the 12 h access group displaying excessive sucrose intake within a discrete period of time (i.e., binge eating). Importantly, this group also exhibited alterations in ECS transcripts and endocannabinoid levels in brain reward regions, including an increase in cannabinoid receptor 1 (CB1R) mRNA in the nucleus accumbens as well as changes in endocannabinoid levels in the prefrontal cortex and hippocampus. We then tested whether different doses (1 and 3 mg/kg) of a CB1R antagonist, Rimonabant, modify binge-like intake or the development of a conditioned place preference (CPP) to sucrose. CB1R blockade reduced binge-like intake of sucrose and blocked a sucrose CPP, but only in rats that had undergone 28 days of sucrose consumption. These findings indicate that sucrose bingeing alters the ECS in reward-related areas, modifications that exacerbate the effect of CB1R blockade on sucrose reward. Overall, our results broaden the understanding of neural alterations associated with bingeing eating and demonstrate an important role for CB1R mechanisms in reward processing. In addition, these findings have implications for understanding substance abuse, which is also characterized by excessive and maladaptive intake, pointing towards addictive-like properties of palatable food.

The rewarding effect of opiates is mediated through dissociable neural systems in drug naïve and drug-dependent states. Neuroadaptations associated with chronic drug use are similar to those produced by chronic pain, suggesting that opiate reward could also involve distinct mechanisms in chronic pain and pain-naïve states. We tested this hypothesis by examining the effect of dopamine (DA) antagonism on morphine reward in a rat model of neuropathic pain.Neuropathic pain was induced in male Sprague-Dawley rats through chronic constriction (CCI) of the sciatic nerve; reward was assessed in the conditioned place preference (CPP) paradigm in separate groups at early (4-8 days post-surgery) and late (11-15 days post-surgery) phases of neuropathic pain. Minimal effective doses of morphine that produced a CPP in early and late phases of neuropathic pain were 6 mg/kg and 2 mg/kg respectively. The DA D1 receptor antagonist, SCH23390, blocked a morphine CPP in sham, but not CCI, rats at a higher dose (0.5 mg/kg), but had no effect at a lower dose (0.1 mg/kg). The DA D2 receptor antagonist, eticlopride (0.1 and 0.5 mg/kg), had no effect on a morphine CPP in sham or CCI rats, either in early or late phases of neuropathic pain. In the CPP paradigm, morphine reward involves DA D1 mechanisms in pain-naïve but not chronic pain states. This could reflect increased sensitivity to drug effects in pain versus no pain conditions and/or differential mediation of opiate reward in these two states.

Drug addiction affects approximately 10% of the population and these numbers are rising. Treatment and prevention of addiction are impeded by current diagnostic systems, such as DSM-5, which are based on outcomes rather than processes. Here, we review the importance of adopting a dimensional framework, specifically the Research Domain Criteria (RDoC), to identify protective and vulnerability mechanisms in addiction. We discuss how preclinical researchers should work within this framework to develop animal models based on domains of function. We highlight RDoC paradigms related to addiction and discuss how these can be used to investigate the biological underpinnings of an addiction cycle (i.e., binge/intoxication, negative affect, and craving). Using this information, we then outline the critical role of animal research in ongoing revisions to the RDoC matrix (specifically the functional significance of domains, constructs and subconstructs) and its contribution to the development and refinement of addiction theories. We conclude with an overview of the contribution that animal research has made to the development of pharmacological and behavioural treatments for addiction.

Pain is a multidimensional experience and negative affect, or how much the pain is “bothersome”, significantly impacts the sufferers' quality of life. It is well established that the κ opioid system contributes to depressive and dysphoric states, but whether this system contributes to the negative affect precipitated by the occurrence of chronic pain remains tenuous. Using a model of persistent pain, we show by quantitative real-time-PCR, florescencein situhybridization, Western blotting and GTPgS autoradiography an upregulation of expression and the function of κ opioid receptors (KORs) and its endogenous ligand dynorphin in the mesolimbic circuitry in animals with chronic pain compared with surgical controls. Usingin vivomicrodialysis and microinjection of drugs into the mesolimbic dopamine system, we demonstrate that inhibiting KORs reinstates evoked dopamine release and reward-related behaviors in chronic pain animals. Chronic pain enhanced KOR agonist-induced place aversion in a sex-dependent manner. Using various place preference paradigms, we show that activation of KORs drives pain aversive states in male but not female mice. However, KOR antagonist treatment was effective in alleviating anxiogenic and depressive affective-like behaviors in both sexes. Finally, ablation of KORs from dopamine neurons using AAV-TH-cre in KORloxPmice prevented pain-induced aversive states as measured by place aversion assays. Our results strongly support the use of KOR antagonists as therapeutic adjuvants to alleviate the emotional, tonic-aversive component of chronic pain, which is argued to be the most significant component of the pain experience that impacts patients' quality of life.SIGNIFICANCE STATEMENTWe show that KORs are sufficient to drive the tonic-aversive component of chronic pain; the emotional component of pain that is argued to significantly impact a patient's quality of life. The impact of our study is broadly relevant to affective disorders associated with disruption of reward circuitry and thus likely contributes to many of the devastating sequelae of chronic pain, including the poor response to treatment of many patients, debilitating affective disorders (other disorders including anxiety and depression that demonstrate high comorbidity with chronic pain) and substance abuse. Indeed, coexisting psychopathology increases pain intensity, pain-related disability and effectiveness of treatments (Jamison and Edwards, 2013).

Acute health consequences associated with coronavirus disease 2019 (COVID-19) infection have been thoroughly characterized; however, long-term impacts are not yet understood. Post-acute sequelae of COVID-19 (PASC), also known as Long COVID syndrome, is the persistence of COVID-19 symptoms long after viral infection. In addition to physical symptoms, those with PASC experience changes in mental health, but few studies have empirically examined these effects. The current study investigated mood and cognitive functioning in individuals who have recovered from COVID-19 infection. We recruited 100 male and female adults (M ​= ​30 years old) with no history of mood or cognitive impairment prior to the COVID-19 pandemic (Jan. 2020). Half of the subjects were healthy controls (i.e., no prior COVID-19 infection) and half had received a past COVID-19 diagnosis (ascertained by PCR or antibody test) but were no longer infectious. Participants completed self-reported measures of stress, depression, and anhedonia, as well as the Attention Network Test (ANT), a behavioural measure of attentional alerting, orienting and executive functioning. Relative to controls, depression and anhedonia were significantly higher in the past-COVID group. Selective impairment in attention was observed in the past-COVID group, marked by deficits in executive functioning while alerting and orienting abilities remained intact. Effects were most pronounced among individuals diagnosed 1–4 months prior to assessment. There were no group differences in pandemic-related experiences with respect to social interaction, social distancing, or isolation. The past-COVID group scored significantly higher on perceived stress; however, this did not moderate any effects observed on mood or cognition. These findings implicate a protracted reaction to the virus, possibly via prolonged inflammation, contributing to sustained mood dysregulation and cognitive impairment. Future research should examine the neural and physiological underpinnings of PASC, particularly mechanisms that promote psychiatric sequelae 1–4 months following diagnosis.

Background: Cannabinoid receptors play a key role in regulating numerous physiological processes, including immune function and reward signaling. Originally, endocannabinoid contributions to central nervous system processes were attributed to CB1 receptors, but technological advances have confirmed the expression of CB2 receptors in both neurons and glia throughout the brain. Mapping of these receptors is less extensive than for CB1 receptors, and it is still not clear how CB2 receptors contribute to processes that involve endocannabinoid signaling. Objectives: The goal of our study was to assess the effects of peripheral nerve injury and chronic morphine administration, two manipulations that alter endocannabinoid system function, on CB2 receptor expression in the spinal dorsal horn of rats. Methods: Twenty-four male Sprague Dawley rats were assigned to chronic constriction injury (CCI), sham surgery, or pain naïve groups, with half of each group receiving once daily injections of morphine (5 mg/kg) for 10 days. On day 11, spinal cords were isolated and prepared for fluorescent immunohistochemistry. Separate sections from the deep and superficial dorsal horn were stained for neuronal nuclei (NeuN), CD11b, or 4′,6-diamidino-2-phenylindole (DAPI) to mark neurons, microglia, and cell nuclei, respectively. Double labeling was used to assess colocalization of CB2 receptors with NeuN or microglial markers. Quantification of mean pixel intensity for each antibody was assessed using a fluorescent microscope, and CB2 receptor expressing cells were also counted manually. Results: Surgery increased DAPI cell counts in the deep and superficial dorsal horn, with CCI rats displaying increased CD11b labeling ipsilateral to the nerve injury. Surgery also decreased NeuN labeling in both regions, an effect that was blocked by morphine administration. CB2 receptors were expressed, predominantly, on NeuN-labeled cells with significant increases in CB2 receptor labeling across all surgery groups in both deep and superficial areas following morphine administration. Conclusions: Our findings provide supporting evidence for the expression of CB2 receptors on neurons and reveal upregulation of receptor expression in the dorsal spinal cord following surgery and chronic morphine administration, with the latter producing a larger effect. Synergistic effects of morphine-cannabinoid treatments, therefore, may involve CB2-mu opioid receptor interactions, pointing to novel therapeutic treatments for a variety of medical conditions.

Coronavirus disease 2019 (COVID-19) continues to ravage communities across the world. Despite its primary effect on the respiratory system, the virus does not solely impact those with underlying lung conditions as initially predicted. Indeed, prognosis is worsened (often fatal) in patients with pre-existing hyperinflammatory responses (e.g., hypertension, obesity and diabetes), yet the mechanisms by which this occurs are unknown. A number of psychological conditions are associated with inflammation, suggesting that these may also be significant risk factors for negative outcomes of COVID-19. In this review, we evaluate preclinical and clinical literature suggesting that chronic stress-induced hyperinflammation interacts synergistically with COVID-19-related inflammation, contributing to a potentially fatal cytokine storm syndrome. In particular, we hypothesize that both chronic stress and COVID-19-related hyperinflammation are a product of glucocorticoid insufficiency. We discuss the devastating effects of SARS-CoV-2 on structural and functional aspects of the biological stress response and how these induce exaggerated inflammatory responses, particularly interleukin (IL)-6 hypersecretion. We postulate that chronic stress should be considered a significant risk factor for adverse COVID-19-related health outcomes, given overlapping peripheral and central immune dysregulation in both conditions. We conclude by discussing how people with a history of chronic stress could mitigate their risk for COVID-19 complications, identifying specific strategies that can be implemented during self-isolation.

Rising rates of obesity in most industrialized countries are a major cause of serious medical conditions, including diabetes, heart disease, and mental health disorders. Binge eating, characterized by excessive consumption of highly palatable food within a short period of time, contributes significantly to these problems, even in individuals who are not diagnosed with binge eating disorder (BED). Over the last half century, the use of non-nutritive substitutes has been promoted as a means to reduce fat and sugar consumption, potentially minimizing obesity-related illnesses. Paradoxically, increased intake of artificial sweeteners is associated with weight gain, which may be linked to alterations in metabolic processes. Artificial sweeteners also increase food intake in both humans and rodents, raising intriguing possibilities that these substances are altering biological processes that underlie the homeostatic control of feeding. We explore this idea by summarizing the clinical and preclinical literature on behavioral and biological mechanisms of artificial sweeteners. As a starting point, we review evidence that non-nutritive sweeteners are rewarding in rodent models, then provide a comparison of neural systems mediating the rewarding properties of natural and artificial sweeteners. We then summarize data pointing to sexual dimorphism in behavioral and biological responses to sucrose, with preliminary evidence suggesting that responses to artificial sweeteners may follow a similar pattern. Finally, we provide an overview of the relationship between binge eating and substance use disorders, noting findings from animal studies that artificial sweeteners could contribute to this comorbidity.

Binge eating disorder (BED), characterized by excessive food consumption within a discrete period of time, is the most prevalent of all eating disorders, with higher rates in women than men. Chronic stress, particularly during adolescence, is a significant risk factor for BED in women, but the mechanism underlying this relationship remains elusive. We investigated the phenomenon by testing the impact of mid-adolescent intermittent physical stress (IPS) on binge-like intake of sucrose in adult female rats, assessing how the behavior changed across reproductive cycles. One hundred and nineteen Long-Evans rats were exposed to IPS (n = 59) or no stress (NS; n = 60) for 12 days during mid-adolescence (PD35–46). Binge-like eating was induced in adult animals using an intermittent access protocol: animals were provided with 12 h or 24 h access to sucrose, 12 h access to saccharin, or 12 h access to food over 28 days. After 1- or 28-day abstinence, compulsive responding for sucrose was measured using a conditioned suppression paradigm. Rats given 12 h access to sucrose developed binge-like intake, measured as increased consumption during the first hour; the effect was magnified in IPS animals and most pronounced during proestrous. Solution intake in IPS rats was predicted by open arm entries in the elevated plus maze, suggesting that increased risk-taking behavior is associated with greater binge-like eating. IPS blocked conditioned suppression after 28 days of abstinence, pointing to a role of mid-adolescent stress in compulsivity. Collectively, these findings emphasize the impact of stress on the emergence of binge eating in females and suggest that intervention programs for women with a history of adolescent adversity should be investigated as a means to reduce risk for BED.

The scientific study of animal cognition has roots in both experimental psychology and evolutionary biology, with researchers often working in related disciplines such as neuroscience, computing science, or ecology. The interdisciplinary nature of the endeavor is both a strength and a challenge for the field. We begin this review with a brief history of comparative cognition and cognitive ecology, focusing on cognitive processes as a mechanistic link between ethology and behaviorism. We then present a "snapshot" of modern-day undergraduate courses in Canada, the United States of America, and the United Kingdom that focus on animal cognition, highlighting the various course names and host departments. We emphasize the value of keeping (or adding) this subject material within curricula, either as independent courses or as enhanced material in other courses. We also present pedagogical approaches to teaching animal cognition that include techniques in large lecture-based courses and in smaller courses that emphasize hands-on experiential learning. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Binge eating disorder is the most common eating disorder, but its underlying etiology is poorly understood. Both humans and animals exhibit binge-like intake of highly-palatable food, suggesting that the behavior is driven by the rewarding properties of food, rather than homeostatic signals. Food reward is regulated, in part, by endogenous opioid mechanisms which, themselves, may be altered by excessive eating. We examined this hypothesis by testing whether binge-like sucrose intake modifies the subsequent development of a conditioned place preference (CPP) to sucrose and morphine in both female and male adult rats. Separate groups were given intermittent (12h) or continuous (24 h) access to a sweet solution (10% sucrose or 0.1% saccharin) and food in their home cage over 28 days. Intermittent sucrose access induced binge-like intake, defined as increased consumption within the first hour; importantly, daily sucrose intake was similar for continuous and intermittent access groups. In a later test, all rats developed a conditioned place preference (CPP) to 15% sucrose with the exception of female and male rats given 12-h intermittent access to sucrose. In a separate experiment, all groups displayed a CPP to morphine (4 mg/kg). These findings demonstrate that binge-like sucrose intake, not just increased consumption, disrupts reward processing without affecting stimulus-reward learning. This fits with clinical evidence of hypo-reward responsivity in patients with binge eating disorder.

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.

Persistent and intrusive memories define a number of psychiatric disorders, including posttraumatic stress disorder and substance use disorder. In the latter, memory for drug-paired cues plays a critical role in sustaining compulsive drug use as these are potent triggers of relapse. As with many drugs, cocaine-cue associated memory is strengthened across presentations as cues become reliable predictors of drug availability. Recently, the targeting of cocaine-associated memory through disruption of the reconsolidation process has emerged as a potential therapeutic strategy; reconsolidation reflects the active process by which memory is re-stabilized after retrieval. In addition, a separate line of work reveals that neuroinflammatory markers, regulated by cocaine intake, play a role in memory processes. Our review brings these two literatures together by summarizing recent findings on cocaine-associated reconsolidation and cocaine-induced neuroinflammation. We discuss the interactions between reconsolidation processes and neuroinflammation following cocaine use, concluding with a new perspective on treatment to decrease risk of relapse to cocaine use.

Both the lateral septum (LS) and anterior hypothalamus (AHA) regulate behavioural defense. We tested whether those two interconnected structures act in serial in that regard. Infusions of the GABAA agonist muscimol into one side of the LS and the contralateral (but not ipsilateral) AHA suppressed rats' burying in the shock-probe test whereas none of our muscimol infusion approaches altered their open-arm avoidance in the elevated plus-maze. These results suggest that the LS-AHA circuit serves a specialized role in defensive responses towards discrete, localizable threat stimuli but not towards potential threats.

Anhedonia, a deficit in reward processing, is an endophenotype of several neuropsychiatric conditions. Despite its prevalence and debilitating effects, treatments for anhedonia are lacking, primarily because its underlying mechanisms are poorly understood. Dopamine (DA) has been implicated in anhedonia through its role in reward-related learning; glucocorticoid systems may also be involved in that anhedonia is often preceded by chronic stress. This study investigated DA and glucocorticoid systems in anhedonia using a rat version of the probabilistic reward task (PRT). Adult male Wistar rats were trained on the PRT and then tested following: (1) activation or inhibition of DA activity induced by amphetamine (AMPH) or pramipexole (PRAMI) injections, (2) chronic mild stress (CMS), or (3) glucocorticoid system activation (dexamethasone (DEX)) or inhibition (mifepristone (MIFE)). AMPH increased and PRAMI decreased response bias, pointing to enhanced and diminished reward responsiveness with DA agonism and antagonism, respectively. CMS reduced response bias but only in a subpopulation of rats. DEX also decreased response bias, suggesting that glucocorticoid processes contribute to anhedonia, although glucocorticoid inhibition (MIFE) had no effect. None of the manipulations altered the ability to detect and respond to reward-paired stimuli. These results confirm a role of DA in anhedonia and elucidate the contribution of the glucocorticoid system to this effect. In addition, chronic stress may interfere with normal DA functioning, leading to impaired reward-related learning in some animals. These findings may direct future treatment of anhedonia by targeting DA and glucocorticoid systems, as well as a possible interaction between the two.

Binge eating disorder (BED) is characterized by periods of excessive food intake combined with subjective feelings of loss of control. We examined whether sucrose bingeing itself leads to uncontrolled or compulsive responding and whether this effect is magnified following a period of abstinence. We then assessed dopamine (DA) modulation of inhibitory synaptic transmission in the oval bed nucleus of the stria terminalis (ovBNST) as a neural correlate of compulsive responding and whether this behavioral effect could be disrupted by DA blockade in the ovBNST. Over 28 days, male Long–Evans rats (n = 8–16 per group) had access to 10% sucrose and food (12 or 24 h), 0.1% saccharin and food (12 h), or food alone (12 h). Compulsive responding was assessed following 1 or 28 days of sucrose abstinence using a conditioned suppression paradigm. Only rats given 12 h access to sucrose developed binge-like intake, manifested as copious intake within the first hour; compulsive responding was significantly elevated in this group following 28 days of abstinence. In parallel, the effect of DA on ovBNST inhibitory transmission switched from a reduction to a potentiation; the effect, although observable after 1 day, was more pronounced and sustained following 28 days of abstinence. Intra-ovBNST infusions of a DA D1 receptor antagonist (0.8 µg/µl SCH-23390) reversed the blockade of conditioned suppression, thereby confirming the causal relationship between ovBNST DA modulation of γ-aminobutyric acid transmission and alterations in conditioned suppression following binge-like intake of sucrose.

© 2016 American College of Neuropsychopharmacology. Opioid dependence is accompanied by neuroplastic changes in reward circuitry leading to a negative affective state contributing to addictive behaviors and risk of relapse. The current study presents a neuroimmune mechanism through which chronic opioids disrupt the ventral tegmental area (VTA) dopaminergic circuitry that contributes to impaired reward behavior. Opioid dependence was induced in rodents by treatment with escalating doses of morphine. Microglial activation was observed in the VTA following spontaneous withdrawal from chronic morphine treatment. Opioid-induced microglial activation resulted in an increase in brain-derived neurotrophic factor (BDNF) expression and a reduction in the expression and function of the K + Cl-co-Transporter KCC2 within VTA GABAergic neurons. Inhibition of microglial activation or interfering with BDNF signaling prevented the loss of Cl-extrusion capacity and restored the rewarding effects of cocaine in opioid-dependent animals. Consistent with a microglial-derived BDNF-induced disruption of reward, intra-VTA injection of BDNF or a KCC2 inhibitor resulted in a loss of cocaine-induced place preference in opioid-naïve animals. The loss of the extracellular Cl-gradient undermines GABA A-mediated inhibition, and represents a mechanism by which chronic opioid treatments can result in blunted reward circuitry. This study directly implicates microglial-derived BDNF as a negative regulator of reward in opioid-dependent states, identifying new therapeutic targets for opiate addictive behaviors.

Impulsive action is mediated through several neurochemical systems, although it is not clear which role each of these plays in the inability to withhold inappropriate responses. Manipulations of the opioid system alter impulsive action in rodents, although the effects are not consistent across tasks. Previously, we speculated that these discrepancies reflect differences in the cognitive mechanisms that control responding in each task. We investigated whether the effect of morphine, a mu opioid receptor (MOR) agonist, on impulsive action depends on the ability of the subjects to time the interval during which they must inhibit a response. Male Long–Evans rats were trained in a response inhibition (RI) task to withhold responding for sucrose during a 4- or 60-s delay; impulsive action was assessed as increased responding during the delay. The rats were tested following an injection of morphine (0, 1, 3, 6 mg/kg). In a subsequent experiment, the effects of morphine (6 mg/kg) plus the MOR antagonist naloxone (0, 0.3, 1, 3 mg/kg) were investigated. Morphine increased impulsive action, but had different effects in the two conditions: the drug increased the proportion of premature responses as the 4-s interval progressed and produced a general increase in responding across the 60-s interval. Naloxone blocked all morphine-induced effects. The finding that morphine increases impulsive action in a fixed-delay RI task contrasts with our previous evidence which shows no effect in the same task with a variable delay. Thus, MORs disrupt impulsive action only when rats can predict the delay to respond.

In addition to sensory disturbances, neuropathic pain is associated with an ongoing and persistent negative affective state. This condition may be reflected as altered sensitivity to rewarding stimuli. We examined this hypothesis by testing whether the rewarding properties of morphine are altered in a rat model of neuropathic pain. Neuropathic pain was induced by chronic constriction of the common sciatic nerve. Drug reward was assessed using an unbiased, three-compartment conditioned place preference (CPP) paradigm. The rats underwent two habituation sessions beginning 6 days after surgery. Over the next 8 days, they were injected with drug or vehicle and were confined to one CPP compartment for 30 min. On the following test day, the rats had access to all three compartments for 30 min. Consistent with the literature, systemic administration of morphine dose-dependently increased the CPP in pain-naive animals. In rats with neuropathic pain, however, the dose-dependent effects of morphine were in a bell-shaped curve, with a low dose of morphine (2 mg/kg) producing a greater CPP than a higher dose of morphine (8 mg/kg). In a separate group of animals, acute administration of morphine reversed mechanical allodynia in animals with neuropathic pain at the same doses that produced a CPP. The increased potency of systemic morphine to produce a CPP in animals with neuropathic pain suggests that the motivation for opioid-induced reward is different in the two states. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Both impulsivity and stress are risk factors for substance abuse, but it is not clear how these two processes interact to alter susceptibility for the disorder. The aim of this project was to examine the pharmacology of a stress-impulsivity interaction in rats. To do so, we tested the effects of yohimbine on impulsive action and then assessed whether behavioural changes could be reduced by antagonists at different receptor subtypes. Male Long-Evans rats were injected with various doses of yohimbine (0-5.0 mg/kg) before testing in the response-inhibition task. In subsequent experiments, yohimbine (2.5 mg/kg) was injected following pretreatment with the following receptor antagonists: corticotropin-releasing factor receptor 1, antalarmin (0-20 mg/kg); glucocorticoid, mifepristone (0-30 mg/kg); noradrenergic (NA) α1, prazosin (0-2 mg/kg); NA α2, guanfacine (0-0.5 mg/kg); NA β2, propranolol (0.5-2.0 mg/kg); dopamine D1/5, SCH 39166 (0-0.0625 mg/kg); μ opioid, naloxone (0-2 mg/kg); or 5-HT2A, M100907 (0.005-0.05 mg/kg). In all experiments, impulsive action was measured as increased premature responding. Yohimbine dose dependently increased impulsive action, but the effect was not reversed by antagonist pretreatment. None of the drugs altered any other behavioural measure. We conclude that stress-impulsivity interactions are likely mediated by a synergy of multiple neurotransmitter systems.

Ambiguous biochemical and subjective responses to alcohol may relate to preexisting individual differences in alcohol expectations, experience, or impulsivity. This study examined cortisol and alpha-amylase responses to alcohol and their association with trait impulsivity, alcohol expectancy, and subjective reports of alcohol's effects. Eighty-seven males assigned to an alcohol, sober, or placebo group provided biochemical and self-report measures. Both cortisol and alpha-amylase increased following alcohol administration. Impulsivity correlated with cortisol changes, and the greatest rise in cortisol correlated with high stimulating effects in the alcohol group. These findings emphasize the importance of individual differences in alcohol responses and support a relationship between hormonal responses and alcohol use.

The objective of this study was to test the hypothesis that prenatal exposure to ethanol, through maternal consumption of an aqueous ethanol solution, induces neurobehavioral deficits and increases ethanol preference in offspring. Pregnant Dunkin-Hartley-strain guinea pigs were given 24-h access to an aqueous ethanol solution (5%, v/v) sweetened with sucralose (1 g/l), or water sweetened with sucralose (1 g/l), throughout gestation. Spontaneous locomotor activity was measured in the offspring on postnatal day (PD) 10. The offspring underwent either ethanol preference testing using a two-bottle-choice paradigm beginning on PD 40 or Morris water maze testing using a hidden moving platform design beginning on PD 60. Maternal consumption of a 5% (v/v) ethanol solution (average daily dose of 2.3±0.1 g of ethanol/kg maternal body weight; range: 1.8-2.8 g/kg) decreased offspring birth weight, increased spontaneous locomotor activity, and increased preference for an aqueous ethanol solution. In the Morris water maze test, sucralose-exposed offspring decreased escape latency on the second day of testing, whereas the ethanol-exposed offspring showed no improvement. These data demonstrate that moderate maternal consumption of ethanol produces hyperactivity, enhances ethanol preference, and impairs learning and memory in guinea pig offspring.

Background: Most adults in Western society consume alcohol regularly without negative consequences. For a small subpopulation, however, drinking can quickly progress to excessive and chronic intake. Given the dangers associated with alcohol abuse, it is critical to identify traits that may place an individual at risk for developing these behaviors. To that end, we used a rat model to determine whether anxiety-related behaviors, novelty seeking, or cognitive flexibility predict excessive alcohol drinking under both limited and continuous access conditions. Methods: Adult male rats were assessed in a series of behavioral tasks (elevated plus maze [EPM], locomotor activity, and discrimination/reversal learning in a Y-maze) followed by 6 weeks of daily, 1-hour access to alcohol in a free-choice, 2-bottle paradigm (10% alcohol vs. tap water). Next, subjects were given the opportunity to consume alcohol for 72 hours in drinking chambers that permit separate measures of each drinking bout. Half of the animals experienced a 2-week deprivation period between the limited and continuous access sessions. Results: Time spent on the open arms of the EPM, but not novelty seeking or discrimination/reversal learning, predicted alcohol consumption during limited, 1-h/d access sessions to alcohol. Anxiety-related behavior also predicted the escalation of intake when animals were given 72 hours of continuous access to alcohol. Bout size, but not frequency, was responsible for the increased consumption by high-anxiety subjects during this period. Finally, intake during limited access sessions predicted intake during continuous access, but only in subjects with low intake during limited access. Conclusions: These findings confirm that preexisting anxiety-related behavior predicts alcohol intake under several schedules of alcohol access. Moreover, when access is unlimited, the high-anxiety-related group exhibited an increase in bout size, but not frequency, of drinking. In addition, we show that modest intake when alcohol is restricted may or may not progress to excessive intake when the drug is freely available.

This experiment used both biological and self-report measures to examine how alcohol modifies stress responses, and to test whether the interaction between these two factors alters risk-taking in healthy young adults. Participants were divided into stress or no-stress conditions and then further divided into one of three beverage groups. The alcohol group consumed a binge-drinking level of alcohol; the placebo group consumed soda, but believed they were consuming alcohol; the sober group was aware that they were not consuming alcohol. Following beverage consumption, the stress group was subjected to the Trier Social Stress Test (TSST) while the no-stress group completed crossword puzzles; all participants subsequently completed a computerized risk-taking task. Exposure to the TSST significantly increased salivary levels of the hormone cortisol and the enzyme alpha-amylase, as well as subjective self-ratings of anxiety and tension. In the stress condition, both placebo and intoxicated groups reported less tension and anxiety, and exhibited a smaller increase in cortisol, following the TSST than did the sober group. Thus, the expectation of receiving alcohol altered subjective and physiological responses to the stressor. Neither alcohol nor stress increased risk taking, however the sober group demonstrated lower risk-taking on the computer task on the second session. These findings clearly demonstrate that the expectation of alcohol (placebo) alters subsequent physiological responses to stress.

There is widespread consensus that stress induces dramatic physiological changes, but no agreement on the quantitative parameters that are appropriate to measure these responses. More importantly, the interpretation of various stress measurements, and how individual responses should be evaluated, has not been properly addressed. Even the definition of baseline, against which stress responses must be measured, is not clearly established. The current experiment sought to address these shortcomings by comparing the predictive value of different calculated parameters for psychosocial and physiological measures of stress across individuals. Subjects were 29 male and 59 female healthy undergraduate students with saliva samples collected over a 3-h interval that included a Trier Social Stress Test. Salivary cortisol and alpha-amylase response were analyzed using the absolute concentration, the percent change in concentration, the area under the curve (Pruessner et al., 2003), and the arrival index (change from arrival to 1 h after arrival). The arrival index correlated with the subsequent stress response for both cortisol (r = 0.76, p

Background: Conditioned reward is a classic measure of drug-induced brain changes in animal models of addiction. The process can be examined in humans using the Conditioned Pattern Preference (CPP) task, in which participants associate nonverbal cues with reward but demonstrate low awareness of this conditioning. Previously, we reported that alcohol intoxication does not affect CPP acquisition in humans, but our data indicated that prior drug use may impact conditioning scores. Methods: To test this possibility, the current study examined the relationship between self-reported alcohol use and preference conditioning in the CPP task. Working memory was assessed during conditioning by asking participants to count the cues that appeared at each location on a computer screen. Participants (69 female and 23 male undergraduate students) completed the Alcohol Use Disorders Identification Test (AUDIT) and the Rutgers Alcohol Problem Index (RAPI) as measures of hazardous drinking. Results: Self-reported hazardous drinking was significantly correlated with preference conditioning in that individuals who scored higher on these scales exhibited an increased preference for the reward-paired cues. In contrast, hazardous drinking did not affect working memory errors on the CPP task. Conclusions: These findings support evidence that repeated drug use sensitizes neural pathways mediating conditioned reward and point to a neurocognitive disposition linking substance misuse and responses to reward-paired stimuli. The relationship between hazardous drinking and conditioned reward is independent of changes in cognitive function, such as working memory.

Binge drinking on university campuses is associated with social and health-related problems. To determine the factors that may predict this behavior, we collected information on alcohol use, alcohol expectations, and impulsivity from 428 undergraduate students attending a Canadian university. The subjective effects of a binge drinking dose of alcohol were assessed in a subset of participants. In the larger sample, 72% of students reported drinking at or above binge drinking thresholds on a regular basis. Men reported alcohol consumption per drinking occasion, which was consistent with other studies, but the frequency of drinking occasions among women was higher than in earlier studies, suggesting that consumption in women may be increasing. Compared with men, women reported different expectations of alcohol, specifically related to sociability and sexuality. Self-reported impulsivity scores were related, albeit weakly, to drinking behaviors and to expectations in both the sexes. Finally, intoxicated binge drinkers reported feeling less intoxicated, liking the effects more, and wanting more alcohol than did non-binge drinkers receiving an equivalent dose of alcohol. These results have implications for sex-specific prevention strategies for binge drinking on university campuses.

Full Disclosure: We have recently authored an undergraduate textbook entitled Comparative Cognition (Olmstead and Kuhlmeier, 2015). Our motivation to write this book did not result from a perceived lack of undergraduate interest in the topic, but rather overenrolled courses for which we did not have a textbook. A key difference between our approach—largely shared by fellow commenters Brodbeck and Brodbeck (2015) and McMillan and Sturdy (2015)—and that of Abramson (2015), is our willingness to work under the title “comparative cognition.” We have been trained under various titles (e.g., biological anthropology, behavioral ecology, ethology, cognitive psychology, developmental psychology, and behavioral neuroscience) and have witnessed the continued emergence of comparative cognition as the logical intersection of these disciplines. Though, still considered a narrowly focused field by Abramson, we propose instead that comparative cognition has broadened (or perhaps always was broad, see Hulse et al., 1978; Wasserman, 1981), and encompasses, without conflict, Abramson's defining features of comparative psychology. Our point here goes beyond an argument about semantics, though it is important to be clear about our use of “comparative cognition,” Take, for example, a statement in the commentary by Bielert and Gallup (2015): “In particular, comparative cognition is quite similar to comparative psychology aside from restricting its research questions and measures to those specific to information processing (Shettleworth, 2010).” We do not see this “restriction” in scope in the modern practice of comparative cognition research. Instead, researchers consider the ways that general learning mechanisms may be constrained by early developing (perhaps innate) behavioral or perceptual biases, conceptual abilities, and/or non-conceptual processes. So yes, comparative cognition is open to the possibility of cognitive processes, but it actively tests for them. It also goes far beyond comparing behavioral responses of “species X” to that of humans (an anthropocentric approach that only a subset of researchers adopt, often with appropriate consideration of phylogenetics), and gone are the days of studying only a few, unrelated species. To use one metric: at the 2015 meeting of the Comparative Cognition Society, research with over 20 different species was presented. Shettleworth (2009), a pioneer and leader in the field, noted that comparative cognition research in the first decade of the twenty-first century was characterized by an increasing number of species examined and more synergy with related fields, such as behavioral ecology. A scholar of comparative cognition—and we think Shettleworth would agree with this based on her 2010 book—should be knowledgeable about sensory systems, behavioral tenets including general associative learning mechanisms, memory, and proposed cognitive mechanisms that are implicated in such areas as categorization, spatial navigation, number, timing, prosocial behavior, communication, and social learning, all the while considering an evolutionary, developmental, and neuroscientific framework. It's a tall order, but what an exciting field! In our experience, undergraduates agree. Like fellow commenters Furlong et al. (2015), we see the “missing” undergraduates every week—200 of them this term alone in a second year survey course: Introduction to Comparative Cognition. Many of these students will take our upper level laboratory courses that focus on specialized topics within the field of comparative cognition. The majority of these students specialize in other areas of psychology such as developmental, clinical, or cognitive psychology, a number are biology or life science majors, and a handful come from complementary disciplines such as computer science or philosophy. And yes, occasionally students seek out graduate study in laboratories specifically focused on comparative cognition. Regardless, we trust that they all pursue their chosen area of study with a greater appreciation and engagement in the basic, comparative science that informs so many fields of study.

The analgesic effect of opioids is enhanced, and tolerance is attenuated, by ultra-low doses (nanomolar to picomolar) of an opioid antagonist, an effect that is mediated by preventing the receptor from coupling to Gs proteins. Recently, we demonstrated a cannabinoid-opioid interaction at the ultra-low dose level, suggesting that the effect might not be specific to opioid receptors. The purpose of this study was to examine, both behaviorally and mechanistically, whether the cannabinoid CB1 receptor was also sensitive to ultra-low dose effects. Antinociception was tested in rats after an injection of either vehicle, the CB1 receptor agonist WIN 55 212-2 (WIN), an ultra-low dose of the CB1 receptor antagonist rimonabant (SR 141716), or a combination of WIN and the ultra-low-dose rimonabant. In the acute experiment, tail-flick latencies were recorded at 10-min intervals for 90 min; in the chronic experiment, tail-flick latencies were recorded 10 min after a daily injection over 7 days. Ultra-low dose rimonabant extended the duration of WIN-induced antinociception. WIN produced maximal tolerance by day 7, whereas WIN+ultra-low dose rimonabant continued to produce strong antinociception, demonstrating that ultra-low dose rimonabant prevented the development of WIN-induced tolerance. Animals chronically treated with WIN alone had CB1 receptors predominantly coupling to Gs receptors in the striatum, whereas the vehicle, ultra-low dose rimonabant, and WIN+ultra-low dose rimonabant groups had CB1 receptors predominantly coupling to Gi receptors. Cannabinoid-induced tolerance is thus associated with a G protein coupling switch from the inhibitory Gi protein to the excitatory Gs protein, an effect which is prevented by the ultra-low dose rimonabant.

Background: The impact of alcohol on implicit, emotional learning is not well understood, partly because family history, drug use, and task demands influence these processes. The conditioned pattern preference (CPP) task provides a more ecologically valid means to investigate implicit cognition in the lab because it has low demand awareness and relies on learning to associate nonverbal cues with reward. Methods: This study examined the effects of acute alcohol intoxication on implicit learning using the CPP task in 83 intoxicated and 69 sober young adults. Information on individual drug use, family history, impulsivity, and alcohol expectancies was also collected. Results: Alcohol intoxication affected explicit, but not implicit learning on the CPP task. In addition, participants who reported a positive family history of addiction (FH+) or individual recreational drug use did not exhibit a preference for cues previously paired with reward. Conclusions: Preference formation on the CPP task recruits motivational neurocircuitry, an effect that is unaltered by alcohol. Group differences in implicit emotional learning on this task may represent neurocognitive differences in individuals at risk for addiction.

This research tests the hypothesis that specific forms of adversity in early life map onto behavioral signs analogous to depression versus anxiety in later life. Male and female rats were exposed to either severe sporadic stress or chronic mild stress during the childhood-adolescent period, and their behavior was tested in adulthood. Males in the severe sporadic stress group showed exaggerated anxiety-related behaviors, as indicated by increases in shock-probe burying and escape-like responses (jumps) from the open arms of the elevated plus-maze. Females exposed to severe sporadic stress displayed no change in burying behavior but did display increases in escape behavior. These same females also exhibited behaviors analogous to depression that manifested as decreased sucrose consumption. The chronic mild stress regime produced effects only in females, including reduced burying, decreased sucrose consumption, and an exaggerated corticosterone response to cold-water immersion stress. Findings reiterate the importance of early life experience to the development of adult psychopathologies and emphasize the need to consider both the type of early experience and gender differences in these analyses.

Chronic pain attenuates midbrain dopamine (DA) transmission, as evidenced by a decrease in opioid-evoked DA release in the ventral striatum, suggesting that the occurrence of chronic pain impairs reward-related behaviors. However, mechanisms by which pain modifies DA transmission remain elusive. Usingin vivomicrodialysis and microinjection of drugs into the mesolimbic DA system, we demonstrate in mice and rats that microglial activation in the VTA compromises not only opioid-evoked release of DA, but also other DA-stimulating drugs, such as cocaine. Our data show that loss of stimulated extracellular DA is due to impaired chloride homeostasis in midbrain GABAergic interneurons. Treatment with minocycline or interfering with BDNF signaling restored chloride transport within these neurons and recovered DA-dependent reward behavior. Our findings demonstrate that a peripheral nerve injury causes activated microglia within reward circuitry that result in disruption of dopaminergic signaling and reward behavior. These results have broad implications that are not restricted to the problem of pain, but are also relevant to affective disorders associated with disruption of reward circuitry. Because chronic pain causes glial activation in areas of the CNS important for mood and affect, our findings may translate to other disorders, including anxiety and depression, that demonstrate high comorbidity with chronic pain.

Compulsion and impulsivity are both primary features of drug addiction. Based on decades of animal research, we have a detailed understanding of the factors (both environmental and physiological) that influence compulsive drug use, but still know relatively little about the impulsive aspects of drug addiction. This review outlines our current knowledge of the relationship between impulsivity and drug addiction, focusing on cognitive and motor impulsivity, which are particularly relevant to this disorder. Topics to be discussed include the influence of chronic drug administration on impulsivity, the mechanisms that may explain drug-induced impulsivity, and the role of individual differences in the development of impulsive drug use. In addition, the manner in which contemporary theories of drug addiction conceptualize the relationship between impulsivity and compulsion is examined. Most importantly, this review emphasizes a critical role for animal research in understanding the role of impulsivity in the development and maintenance of drug addiction.

Ultra-low-dose opioid antagonists enhance opiate analgesia and attenuate tolerance and withdrawal.To determine whether ultra-low-dose naltrexone (NTX) coadministration alters the rewarding effects of opiates or the aversive effects of opiate withdrawal.We used the conditioned place preference (CPP) and conditioned place aversion (CPA) paradigms to assess whether ultra-low-dose NTX alters the acute rewarding effects of oxycodone or morphine, or the aversive aspect of withdrawal from either drug. To assess the dose response for ultra-low-dose NTX, a range of NTX doses (0.03-30 ng/kg) was tested in the oxycodone CPP experiment. In order to avoid tolerance or sensitization effects, we used single conditioning sessions and female rats, as females are more sensitive to the conditioning effects of these drugs.Ultra-low-dose NTX (5 ng/kg) blocked the CPP to morphine (5 mg/kg) and the CPA to withdrawal from chronic morphine (5 mg/kg, for 7 days). Coadministration of ultra-low-dose NTX (30 pg/kg) also blocked the CPA to withdrawal from chronic oxycodone administration (3 mg/kg, for 7 days). The effects of NTX on the CPP to oxycodone (3 mg/kg) revealed a biphasic dose response. The two lowest doses (0.03 and 0.3 ng/kg) blocked the CPP, the middle dose (3 ng/kg) was ineffective, and oxycodone combined with the highest dose (30 ng/kg) produced a trend toward a CPP.Ultra-low-dose NTX coadministration blocks the acute rewarding effects of analgesic doses of oxycodone or morphine as well as the anhedonia of withdrawal from chronic administration.

Opiates produce analgesia by activating mu opioid receptor-linked inhibitory G protein signaling cascades and related ion channel interactions that suppress cellular activities by hyperpolarization. After chronic opiate exposure, an excitatory effect emerges contributing to analgesic tolerance and opioid-induced hyperalgesia. Ultra-low-dose opioid antagonist co-treatment blocks the excitatory effects of opiates in vitro, as well as opioid analgesic tolerance and dependence, as was demonstrated here with ultra-low-dose naloxone combined with morphine. While the molecular mechanism for the excitatory effects of opiates is unclear, a switch in the G protein coupling profile of the mu opioid receptor and adenylyl cyclase activation by Gbetagamma have both been suggested. Using CNS regions from rats chronically treated with vehicle, morphine, morphine+ultra-low-dose naloxone or ultra-low-dose naloxone alone, we examined whether altered mu opioid receptor coupling to G proteins or adenylyl cyclase activation by Gbetagamma occurs after chronic opioid treatment. In morphine-naïve rats, mu opioid receptors coupled to Go in striatum and to both Gi and Go in periaqueductal gray and spinal cord. Although chronic morphine decreased Gi/o coupling by mu opioid receptors, a pronounced coupling to Gs emerged coincident with a Gbetagamma interaction with adenylyl cyclase types II and IV. Co-treatment with ultra-low-dose naloxone attenuated both the chronic morphine-induced Gs coupling and the Gbetagamma signaling to adenylyl cyclase, while increasing Gi/o coupling toward or beyond vehicle control levels. These findings provide a molecular mechanism underpinning opioid tolerance and dependence and their attenuation by ultra-low-dose opioid antagonists.

Drug addiction can be considered an impulse control disorder in that addicts exhibit increased impulsivity on both behavioural and self-report measures. We investigated whether chronic cocaine affects delay of gratification and/or behavioural disinhibition in rats using the delayed reinforcement and Go/No-go paradigms. Animals were treated with saline or cocaine (15 mg/kg) three times per day for 14 days; all behavioural tests occurred prior to daily injections. To assess the effectiveness of the cocaine treatment, sucrose intake, behavioural sensitization and serotonin (5-HT)-dependent (dorsal raphe-stimulated) cortical activation were also measured. Chronic cocaine caused a transient (days 7-8) increase in impulsivity in the delayed reinforcement paradigm, but did not influence behaviour in the Go/No-go paradigm. As expected, chronic cocaine increased behavioural sensitization scores, although it did not affect sucrose consumption. Although, cocaine treatment did not affect dorsal raphe-stimulated electrocorticographic activation, the serotonergic receptor antagonist methiothepin (0.1 mg/kg) was more effective in blocking cortical activation in cocaine- than in saline-treated animals. The electrocorticographic changes may be the result of a pre-synaptic 5-HT deficit and the compensatory supersensitivity of post-synaptic 5-HT receptors. Given the differential time courses of the behavioural and electrocorticographic data, however, this change probably does not mediate the effects of chronic cocaine in the delayed reinforcement paradigm.

Aims: To examine the moderating effects of alcohol myopia on cognitive impulsivity in humans using the delay- discounting paradigm. Methods: Seventy-six male undergraduate students were randomly assigned to sober, placebo or alcohol conditions. In the delay-discounting task, participants made a series of hypothetical choices between a small, immediate reward and a large, delayed reward. To test the predictions of alcohol myopia theory, participants completed a standard version of the task or one containing cues which impelled the impulsive choice (i.e. preference for the small, immediate reward). Participants also completed a personality measure of impulsivity and the go/no-go task, which assesses motor impulsivity. Results: Intoxicated participants tended to discount delayed rewards at lower rates than sober participants, and blood alcohol level was inversely correlated with delay discounting. The impelling cues did not moderate the effects of alcohol on delay discounting. Conclusions: Alcohol intoxication does not always increase cognitive impulsivity and may lead to more cautious decision-making under certain conditions.