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Substance use disorders are prevalent, causing extensive morbidity and mortality worldwide. Evidence-based treatments are of low to moderate effect size. Growth in the neurobiological understanding of addiction (e.g., craving) along with technological advancements in neuromodulation have enabled an evaluation of neurosurgical treatments for substance use disorders. Deep brain stimulation (DBS) involves surgical implantation of leads into brain targets and subcutaneous tunneling to connect the leads to a programmable implanted pulse generator (IPG) under the skin of the chest. DBS allows direct testing of neurobiologically-guided hypotheses regarding the etiology of substance use disorders in service of developing more effective treatments. Early studies, although with multiple limitations, have been promising. Still the authors express caution regarding implementation of DBS studies in this population and emphasize the importance of safeguards to ensure patient safety and meaningful study results. In this perspectives article, we review lessons learned through the years of planning an ongoing trial of DBS for methamphetamine use disorder. [ABSTRACT FROM AUTHOR]

Two experiments examined how 5- and 10-year-olds revised their category representations when exposed to exemplars that were congruent or incongruent with existing knowledge. Findings indicated that judgments about feature co-occurrent within the learned category were influenced by both stereotypical beliefs and exemplar observation. Stereotypical beliefs had a greater influence on co-occurrent judgments in the knowledge-subtyping than in standard conditions. Effects generalized to judgments about features not presented during training. (Author/KB)

The present study investigated the role of the α1-containing GABAA receptors in the neurobehavioral actions of alcohol. In Experiment 1, mice lacking the α1 subunit (α1 (−/−)) were tested for their capacity to initiate operant-lever press responding for alcohol or sucrose. Alcohol intake in the home cage was also measured. In Experiment 2, the α1 (−/−) mice were injected with a range of alcohol doses (0.875–4.0 g/kg; i.p.) to evaluate the significance of the α1 subunit in alcohol's stimulant actions. In Experiment 3, we determined if the alcohol-induced stimulant effects were regulated via dopaminergic (DA) or benzodiazepine (BDZ)-dependent mechanisms. To accomplish this, we investigated the capacity of DA (eticlopride, SCH 23390) and BDZ (flumazenil, βCCt) receptor antagonists to attenuate the alcohol-induced stimulant actions. Compared with wild-type mice (α1 (+/+)), the null mutants showed marked reductions in both EtOH and sucrose-maintained responding, and home-cage alcohol drinking. The null mutants also showed significant increases in locomotor behaviors after injections of low–moderate alcohol doses (1.75–3.0 g/kg). βCCt, flumazenil, eticlopride, and SCH 23390 were able to attenuate the alcohol-induced stimulation in mutant mice, in the absence of intrinsic effects. These data suggest the α1 receptor plays an important role in alcohol-motivated behaviors; however, it also appears crucial in regulating the reinforcing properties associated with normal ingestive behaviors. Deleting the α1 subunit of the GABAA receptor appears to unmask alcohol's stimulatory effects; these effects appear to be regulated via an interaction of both DA- and GABAA BDZ-dependent mechanisms.Neuropsychopharmacology (2007) 32, 137–152. doi:10.1038/sj.npp.1301097; published online 17 May 2006 [ABSTRACT FROM AUTHOR]

Rationale. Previously, we reported that the GABAA receptor containing α5 subunit played a significant role in the reinforcing actions of EtOH in rats selectively bred to consume alcohol. However, the role of the α5 receptor in regulating the neurobehavioral effects of EtOH in outbred rats is not known. Objective. In the present study, RY024, a novel benzodiazepine (BDZ) inverse agonist with high affinity (Kd~ 0.40 nM) and selectivity (~67.3-fold) for the α5 receptor, was investigated for its capacity to antagonize EtOH’s reinforcing, motor impairing, and sedative effects in Long-Evans rats. Methods. Rats were trained to lever press for EtOH under a fixed-ratio 1 schedule of reinforcement. Subsequent studies evaluated EtOH’s motor-impairing effects in an oscillating bar task, while EtOH’s sedative effects were measured in the open field. Results. RY024 (0.125-3.5 mg/kg; IP) markedly reduced EtOH-maintained responding with no effects on water responding, except for the highest dose. RY024 (3.0-15 mg/kg; IP) also reversed the motor impairing effects of a moderate (0.75 g/kg), and intoxicating EtOH dose (1.25 g/kg) in the absence of intrinsic effects. Finally, RY024 (7.5 mg/kg) attenuated the sedation produced by the 1.25 g/kg EtOH dose; however, it failed to attenuate the sedation induced by the 0.75 g/kg EtOH dose. Given alone, RY024 exhibited intrinsic effects in the open field. Conclusion. The results suggest the GABAA receptor containing α5 subtype plays an important role in regulating the reinforcing, motor-impairing, and sedative effects of alcohol in outbred rats. [ABSTRACT FROM AUTHOR]

The present study tested the hypothesis that GABAA and opioid receptors within the central nucleus of the amygdala (CeA) regulate ethanol (EtOH), but not sucrose-maintained responding. To accomplish this, βCCt, a mixed benzodiazepine (BDZ) agonist-antagonist with binding selectivity at the α1 subunit-containing GABAA receptor, and the nonselective opioid antagonist, naltrexone, were bilaterally infused directly into the CeA of alcohol-preferring rats. The results demonstrated that in HAD-1 and P rat lines, βCCt (5-60 µg) reduced EtOH-maintained responding by 56-89% of control levels. On day 2, βCCt (10-40 µg) continued to suppress EtOH maintained responding in HAD-1 rats by as much as 60-85% of control levels. Similarly, naltrexone (0.5-30 µg) reduced EtOH-maintained responding by 56-75% of control levels in P rats. βCCt and naltrexone exhibited neuroanatomical and reinforcer specificity within the CeA. Specifically, no effects on EtOH-maintained responding were observed following infusion into the caudate putamen (CPu), a locus several millimeters dorsal to the CeA. Additionally, responding maintained by sucrose, when presented concurrently with ethanol (EtOH) or presented alone, was not altered by βCCt. Naltrexone reduced sucrose-maintained responding only under the 5 µg dose condition when sucrose was presented alone, however, it did not alter sucrose responding when given concurrently with EtOH. These results support the hypothesis that GABAA and opioid receptors within the CeA can selectively regulate EtOH-maintained responding. The CeA may represent a novel target site in the development of prototypical GABAA and opioidergic receptor ligands, which selectively reduce alcohol abuse in humans. [ABSTRACT FROM AUTHOR]

The exact opioid-sensitive receptors participating in EtOH-seeking behaviors remains unclear. Previous studies have reported higher densities of µ-opioid receptor binding in the nucleus accumbens (NACC) of P relative to NP rats; however, no differences were seen in δ-receptor binding. In contrast to the NACC, substantially lower levels of µ-receptor binding have been observed in the ventral tegmental area (VTA) of both P and NP rats, albeit no line differences have been observed. In the present study, opioid receptors in the NACC, VTA, and hippocampus were evaluated for their capacity to regulate both EtOH- and saccharin-motivated behaviors in the genetically selected alcohol-preferring (P) rat. To accomplish this, nalmefene, an opiate antagonist with preferential binding affinity for the µ-opioid receptor was unilaterally or bilaterally infused during concurrent availability of 1 h daily EtOH (10% v/v) and saccharin (0.025 or 0.050% w/v) solutions. Rats performed under a two-lever fixed ratio (FR) schedule in which four responses on one lever produced the EtOH solution, and four on a second lever produced the saccharin solution. The results demonstrated that when responding maintained by both EtOH and saccharin are matched at basal levels, unilateral (1-60 µg) or bilateral (0.5-10 µg) microinjections of nalmefene into the NACC produced selective dose-dependent reductions on responding maintained by EtOH. Unilateral (40, 60 µg) and bilateral (10 µg) VTA infusions were also observed to selectively reduced EtOH responding; however, greater nalmefene doses were required and the magnitude of suppression on EtOH responding was markedly less compared with the NACC. The greater sensitivity of nalmefene to suppress EtOH responding in the NACC is likely due to the greater number of opioid receptors in the NACC relative to the VTA. Only bilateral infusion of the 40 µg dose in the NACC and VTA suppressed responding maintained by both EtOH and saccharin. In contrast, intrahippocampal infusions dose dependently suppressed EtOH- and saccharin-maintained responding over a range of doses (1-20 µg). The present study provides evidence that nalmefene suppresses EtOH-motivated behaviors via blockade of opioid receptors within the NACC and VTA, and under various dose conditions both reinforcer and neuroanatomical specificity can be observed. [ABSTRACT FROM AUTHOR]

It has been hypothesized that alcohol addiction is mediated, at least in part, by specific γ-aminobutyric acidA (GABAA) receptors within the ventral pallidum (VP). Among the potential GABAA receptor isoforms regulating alcohol-seeking behaviors within the VP, the GABAA α1 receptor subtype (GABAA1) appears pre-eminent. In the present study, we developed β-carboline-3-carboxylate-t-butyl ester (βCCt), a mixed agonist-antagonist benzodiazepine (BDZ) site ligand, with binding selectivity at the A1 receptor to explore the functional role of VPA1 receptors in the euphoric properties of alcohol. The in vivo actions of βCCt were then determined following microinfusion into the VP, a novel alcohol reward substrate that primarily expresses the A1 receptor. In two selectively bred rodent models of chronic alcohol drinking (HAD-1, P rats), bilateral microinfusion of βCCt (0.5-40 µg) produced marked reductions in alcohol-reinforced behaviors. Further, VP infusions of βCCt exhibited both neuroanatomical and reinforcer specificity. Thus, no effects on alcohol-reinforced behaviors were observed following infusion in the nucleus accumbens (NACC)/caudate putamen (CPu), or on response maintained by saccharin. Parenteral-administered βCCt (1-40 mg/kg) was equally effective and selective in reducing alcohol-reinforced behaviors in P and HAD-1 rats. Additional tests of locomotor activity revealed that βCCt reversed the locomotor sedation produced by both chlordiazepoxide (10 mg/kg) and EtOH (1.25 g/kg), but was devoid of intrinsic effects when given alone. Studies in recombinant receptors expressed in Xenopus oocytes revealed that βCCt acted as a low-efficacy partial agonist at α3β3γ2 and α4β3γ2 receptors and as a low-efficacy inverse agonist at α1β3γ2, α2β3γ2, and α5β3γ2 receptors. The present study indicates that βCCt is capable of antagonizing the reinforcing and the sedative properties of alcohol. These anti-alcohol properties of βCCt are primarily mediated via the GABAA1 receptor. βCCt may represent a prototype of a pharmacotherapeutic agent to effectively reduce alcohol drinking behavior in human alcoholics. [ABSTRACT FROM AUTHOR]

The present study investigated the role of the alpha1-containing GABA(A) receptors in the neurobehavioral actions of alcohol. In Experiment 1, mice lacking the alpha1 subunit (alpha1 (-/-)) were tested for their capacity to initiate operant-lever press responding for alcohol or sucrose. Alcohol intake in the home cage was also measured. In Experiment 2, the alpha1 (-/-) mice were injected with a range of alcohol doses (0.875-4.0 g/kg; i.p.) to evaluate the significance of the alpha1 subunit in alcohol's stimulant actions. In Experiment 3, we determined if the alcohol-induced stimulant effects were regulated via dopaminergic (DA) or benzodiazepine (BDZ)-dependent mechanisms. To accomplish this, we investigated the capacity of DA (eticlopride, SCH 23390) and BDZ (flumazenil, betaCCt) receptor antagonists to attenuate the alcohol-induced stimulant actions. Compared with wild-type mice (alpha1 (+/+)), the null mutants showed marked reductions in both EtOH and sucrose-maintained responding, and home-cage alcohol drinking. The null mutants also showed significant increases in locomotor behaviors after injections of low-moderate alcohol doses (1.75-3.0 g/kg). betaCCt, flumazenil, eticlopride, and SCH 23390 were able to attenuate the alcohol-induced stimulation in mutant mice, in the absence of intrinsic effects. These data suggest the alpha1 receptor plays an important role in alcohol-motivated behaviors; however, it also appears crucial in regulating the reinforcing properties associated with normal ingestive behaviors. Deleting the alpha1 subunit of the GABA(A) receptor appears to unmask alcohol's stimulatory effects; these effects appear to be regulated via an interaction of both DA- and GABA(A) BDZ-dependent mechanisms.

Background: Previous research has implicated the alpha5-containing GABAA receptors of the hippocampus in the reinforcing properties of alcohol. In the present study, a selective GABAA alpha5 benzodiazepine inverse agonist (e.g., RY 023) was used in a series of in vivo and in vitro studies to determine the significance of the alpha5-receptor in the neurobehavioral actions of alcohol., Methods: In experiment one, systemic injections of RY 023 (1 to 10 mg/kg IP) dose-dependently reduced ethanol-maintained responding by 52% to 86% of controls, whereas bilateral hippocampal infusions (0.3 to 20 microg) reduced responding by 66% to 84% of controls. Saccharin responding was reduced only with the highest intraperitoneal (e.g., 10 mg) and microinjected (e.g., 20 microg) doses. In experiment two, RY 023 (3.0 to 15 mg/kg IP) reversed the motor-impairing effects of a moderate dose of alcohol (0.75 g/kg) on an oscillating bar task in the absence of intrinsic effects. In the open field, RY 023 (3.0 to 7.5 mg/kg) produced intrinsic effects alone but attenuated the suppression of the 1.25 g/kg ethanol dose. Because the diazepam-insensitive receptors (e.g., alpha4 and alpha6) have been suggested to play a role in alcohol motor impairing and sedative actions, experiment three compared the efficacy of RY 023 with Ro 15-4513 and two prototypical benzodiazepine antagonists (e.g., flumazenil and ZK 93426) across the alpha4beta3gamma2-, alpha5beta3gamma2-, and alpha6beta3gamma2-receptor subtypes in Xenopus oocytes., Results: RY 023 produced classic inverse agonism at all receptor subtypes, whereas Ro15-4513 and the two antagonists displayed a neutral or agonistic profile at the diazepam-insensitive receptors., Conclusions: Overall, the results extend our previous findings by demonstrating that an alpha5-subtype ligand is capable of attenuating not only the rewarding action of alcohol but also its motor impairing and sedative effects. We propose that these actions are mediated in part by the alpha5-receptors of the hippocampus. The hippocampal alpha5-receptors could represent novel targets in understanding the neuromechanisms regulating the neurobehavioral actions of alcohol in humans.

The present study tested the hypothesis that GABA(A) and opioid receptors within the central nucleus of the amygdala (CeA) regulate ethanol (EtOH), but not sucrose-maintained responding. To accomplish this, betaCCt, a mixed benzodiazepine (BDZ) agonist-antagonist with binding selectivity at the alpha1 subunit-containing GABA(A) receptor, and the nonselective opioid antagonist, naltrexone, were bilaterally infused directly into the CeA of alcohol-preferring rats. The results demonstrated that in HAD-1 and P rat lines, betaCCt (5-60 microg) reduced EtOH-maintained responding by 56-89% of control levels. On day 2, betaCCt (10-40 microg) continued to suppress EtOH maintained responding in HAD-1 rats by as much as 60-85% of control levels. Similarly, naltrexone (0.5-30 microg) reduced EtOH-maintained responding by 56-75% of control levels in P rats. betaCCt and naltrexone exhibited neuroanatomical and reinforcer specificity within the CeA. Specifically, no effects on EtOH-maintained responding were observed following infusion into the caudate putamen (CPu), a locus several millimeters dorsal to the CeA. Additionally, responding maintained by sucrose, when presented concurrently with ethanol (EtOH) or presented alone, was not altered by betaCCt. Naltrexone reduced sucrose-maintained responding only under the 5 microg dose condition when sucrose was presented alone, however, it did not alter sucrose responding when given concurrently with EtOH. These results support the hypothesis that GABA(A) and opioid receptors within the CeA can selectively regulate EtOH-maintained responding. The CeA may represent a novel target site in the development of prototypical GABA(A) and opioidergic receptor ligands, which selectively reduce alcohol abuse in humans.

We investigated the potential role of the alpha1-containing GABA(A) receptor in regulating the reinforcing properties of alcohol. To accomplish this, we developed 3-propoxy-beta-carboline hydrochloride (3-PBC), a mixed agonist-antagonist benzodiazepine site ligand with binding selectivity at the alpha1 receptor. We then tested the capacity of 3-PBC to block alcohol-maintained responding in the ventral pallidum (VP), a novel alcohol reward substrate, which primarily expresses the alpha1-receptor isoform. Our results demonstrated that bilateral microinfusion of 3-PBC (0.5-40 microg) in the anterior and medial VP produced marked reductions in alcohol-maintained responding in a genetically selected rodent model of alcohol drinking. The VP infusions showed both neuroanatomical and reinforcer specificity because no effects were seen in sites dorsal to the VP (e.g., nucleus accumbens, caudate putamen). The saccharin-maintained responding was reduced only with the highest dose (40 microg). Parenteral injections of 3-PBC (1-20 mg/kg) also showed a similar selectivity on alcohol-maintained responding. Complementary in vitro studies revealed that 3-PBC exhibited a low partial agonist efficacy profile at recombinant diazepam-sensitive receptors (e.g., alpha1beta3gamma2, alpha2beta3gamma, and alpha3beta3gamma2). The selective suppression of 3-PBC on alcohol-maintained responding after central and parenteral administrations, together with its low-efficacy agonist profile, suggest that the reduction in alcohol-maintained behaviors was not attributable to a general suppression on consummatory behaviors. These results demonstrate that the alpha1-containing GABA(A) receptors in both the anterior and medial VP are important in regulating the reinforcing properties of alcohol. These receptors represent novel targets in the design and development of pharmacotherapies for alcohol-dependent subjects.