Opioid misuse is at historically high levels in the United States. Opioid addiction is a chronic disease characterized by cyclical periods of compulsive drug use and seeking, quitting, and the emergence of a persistent negative emotional state (e.g., anxiety, pain, dysphoria) during abstinence. We tested the hypothesis that neural circuits mediating reward and negative emotional states have a key role in learning that contributes to the maintenance of compulsive opioid seeking. We found that when given alone, cues previously paired with withdrawal-induced aversive states can increase operant responding for heroin, promote reinstatement of lever pressing behavior following extinction, and alter pain sensitivity in heroin dependent rats. Using functional magnetic resonance imaging, we identified several cortical and subcortical brain regions that are activated by presentation of these cues in the absence of heroin, including extended amygdala and hypothalamic stress circuitries. These results point to novel targets for therapeutic intervention, specifically brain circuits of negative emotional learning. Follow up studies are using molecular imaging (e.g., immunohistochemistry and in situ hybridization) to characterize these circuits, which represent a potentially powerful source of motivation in addiction. We hypothesized that repeated, intense cycles of opioid intoxication and withdrawal lead to glucocorticoid-dependent downregulation of hypothalamic-pituitary-adrenal (HPA) axis function and sensitization of extrahypothalamic stress systems and that these allostatic changes contribute to negative emotional states that drive compulsive drug taking and seeking. We found that chronic administration of the glucocorticoid receptor (GR) antagonist mifepristone blocked the development of compulsive-like heroin taking and seeking in rat models of drug dependence. Chronic mifepristone treatment also prevented the emergence of heroin withdrawal-induced hyperalgesia. Importantly, mifepristone had no effects on drug taking and seeking in nondependent rats. Moreover, acute treatment with mifepristone or the selective GR antagonist CORT113176 reduced drug intake in rats already dependent on opioids. Because similar results were found in alcohol dependence and mifepristone reduced craving and drinking in humans with alcohol use disorders, we propose that opioid and alcohol dependence share a similar mechanism of action in terms of dysregulation of the HPA axis and sensitization of brain stress systems and that glucocorticoid-mediated plasticity represents a novel target for the treatment of stress-related psychiatric disorders. Glucocorticoid receptors (GRs) are transcription factors and their activity depend on the association of GR with co-regulators, such as steroid receptor co-regulator 1 (SRC-1). SRC-1 has two splice variants that have opposite effects on gene transcription, SRC-1a is inhibitory and SRC-1e is stimulatory, particularly the expression of corticotropin-releasing factor (CRF). It is well known that CRF transmission in the extended amygdala (a stress/arousal-related circuitry) is involved in compulsive-like drug taking and seeking. We tested the hypothesis that opioid dependent rats would have increased activity of CRF transmission in the central nucleus of the amygdala and that biasing the splicing of SRC-1 towards SRC-1a in the central amygdala would block compulsive-like drug taking and seeking. Using CRF-Cre rats, we found that the number of action potential of CRF cells is remarkably increased in rats allowed long access (12 h/session; LgA) to heroin self-administration (dependent rats) compared with rats allowed short access (1 h/session; ShA) to heroin self-administration and drug nave rats, indicating a gain in CRF transmission in the central amygdala in opioid dependence. Using an antisense oligonucleotide approach, we discovered that biasing splice variant of SRC-1 towards SRC-1a in the central amygdala significantly decreased heroin self-administration in LgA rats. Importantly, antisense oligonucleotide infusion in ShA rats had no behavioral effects. These results suggest SRC-1 as a novel potential target for the treatment of opioid-use disorder. Because animal models of opioid dependence are fundamental for studying the etiology of addictive behaviors and because of the wide availability of transgenic mouse lines and genetic tools that are available in mice, we tested the hypothesis that extended access to heroin self-administration leads to increases in heroin intake and the motivation to obtain heroin and produces somatic signs of opioid dependence in both male and female mice. Adult C57BL/6J mice were trained to nosepoke (fixed-ratio 1) to obtain intravenous heroin in six daily 1-h sessions (30-60 g/kg/infusion). The mice were divided into short access (ShA; 1 h) and long access (LgA; 6 h) groups. Immediately after the 10th escalation session, the mice received a challenge dose of naloxone (1 mg/kg), and somatic signs of withdrawal were recorded. The mice were then tested under a 6 h progressive-ratio schedule of reinforcement to measure the motivation to obtain heroin. The mice readily acquired intravenous heroin self-administration. LgA mice escalated their drug intake in the first hour across sessions, exhibited an increase in the motivation to obtain heroin, and had significantly higher scores of somatic signs of naloxone-precipitated opioid withdrawal compared with ShA mice. Female mice exhibited increases in heroin intake and the motivation to obtain heroin compared with male mice. Male and female mice exhibited similar levels of somatic signs of withdrawal. Because of the wide availability of genetically modified mouse lines, the present mouse model may be particularly useful for better understanding genetic and sex differences that underlie the transition to compulsive-like opioid taking and seeking. We have previously developed a model of opioid dependence by inhalation in rats that does not require surgery, and thus, we sought to develop such a model in mice. Mice readily learned to self-administer fentanyl vapor over 1-h sessions and to discriminate between the active and inactive nosepoke holes. Mice self-titrated their fentanyl vapor intake to the dose of vaporized fentanyl, i.e., the number of fentanyl vapor deliveries was inversely related to the fentanyl concentration. Mice that received passive fentanyl vapor exposure at 3, 10, and 30 mg/ml exhibited a concentration-dependent increase in the latency to nociception (i.e., an analgesic effect) and blood fentanyl concentrations were directly correlated with the concentration of delivered fentanyl vapor. Alcohol use disorder continues to be a major public health issue worldwide and new treatments are urgently needed. We tested the effects of oxytocin on compulsive-like alcohol drinking using systemic injection and intranasal delivery. Rats were trained to lever press for access to alcohol (i.e., operant conditioning). Some of the animals were made dependent on alcohol via chronic, intermittent alcohol vapor exposure (dependent rats). This procedure results in a dramatic increase in alcohol self-administration and motivation to obtain alcohol. Nondependent rats were exposed to air without alcohol. We observed that systemic injections and intranasal delivery of oxytocin substantially reduced alcohol consumption in dependent but not in nondependent rats. We further demonstrated that central but not peripheral oxytocin receptor agonism decreased alcohol self-administration in dependent rats. We are currently validating viral vector tools to bring under experimental control (e.g., through optogenetic manipulation) specific cells that produce oxytocin or produce the oxytocin receptor. With these tools, we will identify experimentally the neurocircuitry that me
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