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BACKGROUND: Alcohol use disorder (AUD) is a leading preventable cause of death. The central amygdala (CeA) is a hub for stress and AUD, while dysfunction of the noradrenaline (NA) stress system is implicated in AUD relapse. METHODS: Here we investigated whether alcohol (ethanol) dependence and protracted withdrawal alter noradrenergic regulation of the amygdala in rodents and humans. Male adult rats were housed under control conditions, subjected to chronic intermittent ethanol vapor exposure (CIE) to induce dependence, or withdrawn from CIE for two weeks, and ex vivo electrophysiology, biochemistry (catecholamine quantification by HPLC), in situ hybridization and behavioral brain-site specific pharmacology studies were performed. We also used qRT-PCR to assess gene expression of the α1(B), β1, and β2 adrenergic receptor in human post-mortem brain tissue from men diagnosed with AUD and matched controls. RESULTS: We found that α1 receptors potentiate CeA GABAergic transmission and drive moderate alcohol intake in control rats. In dependent rats, β receptors disinhibit a subpopulation of CeA neurons, contributing to their excessive drinking. Withdrawal produces CeA functional recovery with no change in local noradrenaline tissue concentrations, though there are some long-lasting differences in the cellular patterns of adrenergic receptor mRNA expression. Additionally, post-mortem brain analyses reveal increased α1B receptor mRNA in the amygdala of humans with AUD. CONCLUSIONS: Thus, CeA adrenergic receptors are key neural substrates of AUD. Identification of these novel mechanisms that drive alcohol drinking, particularly during the alcohol-dependent state, support ongoing new medication development for AUD.

Prescription opioids, such as oxycodone, are potent analgesics that are used to treat and manage pain. However, oxycodone is one of the most commonly abused prescription drugs. Finding an effective strategy to prevent prescription opioid use disorder is urgent. Orexin receptors (OrxR1 and OrxR2) have been implicated in the regulation of motivation, arousal, and stress, making them possible targets for the treatment of substance use disorder. To study the significance of environmental stimuli in maintaining the vulnerability to relapse to oxycodone use, resistance to the extinction of oxycodone-seeking behavior that was elicited by an oxycodone-related stimulus was examined. Rats were trained to self-administer oxycodone in the presence of a contextual/discriminative stimulus (SD). Using this procedure, the rats readily acquired oxycodone self-administration and exhibited increases in physical signs of opioid withdrawal. Following extinction, response-reinstating effects of re-exposure to the SD perseverated. We then tested whether OrxR blockade prevents oxycodone intake and relapse. The effects of the OrxR1 antagonist SB334867 and OrxR2 antagonist TCSOX229 on oxycodone self-administration were tested. SB334867 significantly decreased oxycodone self-administration, whereas TCSOX229 did not produce any effect. To investigate whether OrxR1 and OrxR2 blockade prevents oxycodone seeking, the rats were tested for the ability of SB334867 and TCSOX229 to prevent the SD-induced conditioned reinstatement of oxycodone-seeking behavior. SB334867 decreased oxycodone-seeking behavior, whereas TCSOX229 was ineffective. These results suggest that OrxR1 antagonism prevents excessive prescription opioid use and relapse and might be beneficial for the treatment of prescription opioid use disorder.

Originally studied for its role in energy homeostasis, the paraventricular nucleus of the thalamus (PVT) has recently gained attention because of its involvement in the modulation of drug-directed behavior. The posterior part of the PVT (pPVT) is connected with brain structures that modulate motivated behavior, and we tested whether the pPVT plays a pivotal role in cocaine seeking. The aim of the present study was to investigate whether transient inactivation of the pPVT prevents cue-induced reinstatement of cocaine seeking but not natural reward seeking. Male Wistar rats were trained to associate a discriminative stimulus (S(+)) with the availability of cocaine or a highly palatable conventional reinforcer, sweetened condensed milk (SCM). Following extinction, the cocaine S(+) and SCM S(+) elicited comparable levels of reinstatement. Intra-pPVT administration of the γ-aminobutyric acid-A (GABAA) and GABAB receptor agonists muscimol and baclofen (0.06 and 0.6mM, respectively) prior to the presentation of the cocaine or SCM S(+) completely prevented the reinstatement of cocaine seeking, with no statistically significant effects on SCM seeking. These data show that the pPVT plays an important role in neuronal mechanisms that drive cocaine-seeking behavior.

Background Rats with extended daily cocaine access show escalating cocaine self-administration and behavioral signs of dependence. Regulation of glutamatergic transmission by metabotropic glutamate receptors has emerged as a mechanism in the addictive actions of drugs of abuse. We examined here whether neuroadaptive dysregulation of metabotropic glutamate receptor function is a factor in escalating cocaine self-administration. Methods Rats with 1 hour daily cocaine access (short access [ShA]) versus 6-hour access (long access [LgA]) were tested for differences in the effects of the metabotropic glutamate receptor 2/3 (mGluR2/3) agonist (−)-2-oxa-4-aminobicylco(3.1.0)hexane-4,6-dicarboxylic acid (LY379268) and the metabotropic glutamate receptor 5 (mGluR5) antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on cocaine-reinforced progressive-ratio responding and differences in expression levels and functional activity of mGluR2/3 and mGluR5. Results The LgA groups showed higher progressive-ratio breakpoints than ShA groups. LY379268 (0–3 mg/kg subcutaneous) dose-dependently lowered breakpoints in the LgA group but reduced breakpoints only at 3 mg/kg in the ShA group. Consistent with this behavioral effect, functional mGluR2/3 activity was significantly elevated following LgA cocaine exposure. MTEP (0–3 mg/kg intraperitoneal) reduced breakpoints in the ShA group only. Long access cocaine exposure was associated with decreased mGluR5 expression, accompanied by reduced functional mGluR5 activity in the nucleus accumbens. A downward trend developed in mGluR5 protein expression in the medial prefrontal cortex and hippocampus. Conclusions Functional upregulation of mGluR2/3 and downregulation of mGluR5 are likely factors in the transition to cocaine dependence. The differential behavioral effects of LY379268 and MTEP in rats with a history of long access to cocaine have implications for the treatment target potential of mGluR2/3 and mGluR5.

Background Growing evidence supports a role of metabotropic glutamate receptors (mGluRs) in ethanol reinforcement, ethanol seeking, and ethanol withdrawal. To extend the understanding of the role of mGluRs in the addiction-relevant effects of ethanol as well as of the treatment target potential of these receptors for alcohol abuse, the effects of a selective mGlu2/3 agonist (LY379268) and a selective mGlu5 antagonist (MTEP) were tested on two processes central to alcohol addiction: ethanol reinforcement and stress-induced reinstatement of ethanol seeking in rats with a history of ethanol dependence. Methods Following operant ethanol self-administration training, male Wistar rats were made dependent by intragastric ethanol intubations. Ethanol dependence was confirmed by the presence of somatic withdrawal signs. Following 2 weeks of withdrawal, stable ethanol self-administration was reestablished, and the effects of LY379268 (0–3 mg/kg subcutaneous) and MTEP (0–3 mg/kg, intraperitoneal) on ethanol self-administration were determined in both nondependent and postdependent rats. A second set of rats underwent extinction training and then was tested for the effects of LY379268 or MTEP on reinstatement of ethanol seeking induced by footshock stress. Results LY379268 and MTEP dose-dependently reduced both ethanol self-administration and reinstatement of ethanol seeking induced by footshock stress. Additionally, LY379268 was more effective than MTEP in inhibiting both behaviors in postdependent than in nondependent animals. Conclusions These findings suggest that neuroadaptation associated with chronic ethanol exposure or withdrawal alters the sensitivity of mGlu2/3 receptors, with implications for the understanding of the neural basis of alcohol dependence and the treatment target potential of these receptors.

Background There has been a recent upsurge of interest in the role of hypothalamic feeding peptides, in particular, orexin (hypocretin), in drug-seeking behavior. However, the potential role of other hypothalamic feeding peptides, such as cocaine- and amphetamine-regulated transcript (CART), in conditioned reinstatement has yet to be explored. Methods Animals were exposed to environmental stimuli previously associated with ethanol availability (EtOH S + ), and sections from the hypothalamus and paraventricular thalamus (PVT), a recipient of CART and orexin innervation, were dual labeled for Fos-protein and either CART or orexin. Results Significantly larger numbers of Fos-positive arcuate nucleus CART and hypothalamic orexin neurons were seen in animals exposed to the EtOH S + compared with nonreward S − animals. Presentation of the EtOH S + also increased numbers of Fos-positive PVT neurons. Fos-positive PVT neurons were observed to be closely associated with orexin and CART terminal fields. Conclusions Taken together, these findings suggest that activation of hypothalamic neuropeptide systems may be a common mechanism underlying drug-seeking behavior.

N -[1-(2-benzo[ b ]thiophenyl)cyclohexyl]piperidine (BTCP), a potent dopamine reuptake inhibitor, substitutes for the reinforcing effects of cocaine and meets other criteria for possible agonist pharmacotherapeutic potential. The purpose of this study was to determine (1) whether BTCP modifies reinstatement of cocaine-seeking elicited by cocaine-related environmental stimuli and (2) whether this compound produces priming effects. Male Wistar rats were trained to associate discriminative stimuli (S D ) with cocaine availability (0.25 mg/infusion) versus non-reward and then were subjected to repeated extinction sessions during which the reinforcer and S D were withheld. Subsequent presentation of the cocaine S D produced recovery of cocaine-seeking. BTCP (2.5–30 mg/kg; i.p.) did not attenuate the conditioned reinstatement induced by the cocaine S D but, rather, potentiated this effect at 10 mg/kg. To test whether BTCP, by itself, exerts priming effects, different groups of rats were trained to self-administer cocaine (0.25 mg/infusion) for 2 weeks. After a 2-week extinction period, BTCP (5, 10 and 20 mg/kg, i.p.) reinstated cocaine-seeking, showing that BTCP not only increases cocaine-seeking induced by cocaine-related stimuli but also produces priming effects following abstinence. The results suggest that, in cocaine abstinent rats, BTCP produces cocaine-like effects.

N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP) is a phencyclidine (PCP) derivative that acts as a potent dopamine (DA) reuptake inhibitor. Earlier studies have shown that BTCP can substitute for the reinforcing effects of cocaine. Therefore, the aim of the study was to further characterize the reinforcing effects of BTCP. The reinforcing actions of BTCP were compared to those of cocaine at equimolar concentrations in drug-naive rats. Two groups of animals were implanted with jugular catheters and trained to intravenously self-administer BTCP or cocaine (0.25 mg/infusion) on a fixed-ratio five schedule (FR 5) of reinforcement. Both BTCP and cocaine produced comparable inverted U-shaped dose-effect curves on this schedule over doses of 0.03, 0.06, 0.125, and 0.25 mg/infusion. Two doses (0.125 and 0.25 mg/infusion) that produced reliable self-administration in all the animals for cocaine and BTCP were then tested on a progressive-ratio schedule. At each dose, BTCP supported higher breaking points (BPs) than cocaine. The results demonstrate that rats readily acquire responding maintained by BTCP and suggest that BTCP may have greater reinforcing effects than cocaine at equimolar concentrations.

N -[1-(2-Benzo( b )thiophenyl)cyclohexyl]piperidine (BTCP) and cocaine inhibit dopamine (DA) uptake but bind to different sites on the transporter. Their dose-dependent effects (i.p. administration) on extracellular DA levels in the rat striatum were measured by in vivo microdialysis. Both drugs dose-dependently increased DA levels with a maximum effect 60 min post injection. BTCP (20 mg/kg) had a greater peak effect than cocaine (40 mg/kg). For doses inducing similar behavioral effects (cocaine, 20 mg/kg; BTCP, 10 mg/kg) similar DA increases were observed in the striatum and the nucleus accumbens. Although both drugs bind on the DA transporter on different sites and induce different behavioral effects when administered chronically, their acute administration increased striatal DA level in a similar way.