• Energy Research

A growing number of studies suggest that gamma-aminobutyric acid type-B (GABA(B)) receptor agonists reduce alcohol use and craving.This study was designed to further clarify behavioral mechanism(s) by which GABA(B) agonists may decrease alcohol reinforcement.Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABA(B) agonist baclofen (0-17 mg/kg, IP) or SKF 97541 (0-1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABA(B) agonists was examined in ethanol naive and self-administering mice.Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABA(B) agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABA(B) agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABA(B) agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol.GABA(B) agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABA(B) agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABA(B) positive modulation. These data question the safety of prescribing GABA(B) agonists to alcoholics since these drugs may potentiate ethanol's sedative/hypnotic effects during relapse.

Background: Protein kinase C (PKC) is a family of isoenzymes that regulate a variety of functions in the central nervous system including neurotransmitter release, ion channel activity, and cell differentiation. Growing evidence suggests that specific isoforms of PKC influence a variety of behavioral, biochemical, and physiological effects of ethanol in mammals. The purpose of this study was to determine whether acute ethanol exposure alters phosphorylation of conventional PKC isoforms at a threonine 674 (p‐cPKC) site in the hydrophobic domain of the kinase, which is required for its catalytic activity.Methods: Male rats were administered a dose range of ethanol (0, 0.5, 1, or 2 g/kg, intragastric) and brain tissue was removed 10 minutes later for evaluation of changes in p‐cPKC expression using immunohistochemistry and Western blot methods.Results: Immunohistochemical data show that the highest dose of ethanol (2 g/kg) rapidly increases p‐cPKC immunoreactivity specifically in the nucleus accumbens (core and shell), lateral septum, and hippocampus (CA3 and dentate gyrus). Western blot analysis further showed that ethanol (2 g/kg) increased p‐cPKC expression in the P2 membrane fraction of tissue from the nucleus accumbens and hippocampus. Although p‐cPKC was expressed in numerous other brain regions, including the caudate nucleus, amygdala, and cortex, no changes were observed in response to acute ethanol. Total PKCγ immunoreactivity was surveyed throughout the brain and showed no change following acute ethanol injection.Conclusions: These results suggest that ethanol rapidly promotes phosphorylation of cPKC in limbic brain regions, which may underlie effects of acute ethanol on the nervous system and behavior.

Sensitivity to the stimulant and rewarding effects of alcohol may be genetically-correlated traits that predispose individuals to developing an alcohol use disorder.

The Group I family of metabotropic glutamate receptors includes subtype 1 (mGlu1) and subtype 5 (mGlu5) receptors. This family of receptors has generated interest as potential targets for different areas of therapeutic development, including intervention for alcohol and drug abuse. Most of this interest is driven by findings showing involvement of mGlu5 receptors in the regulation of drug self-administration; however, studies examining the role of mGlu1 receptors in drug self-administration are limited. The purpose of this work was to examine the role of mGlu1 receptor antagonism in the maintenance of ethanol self-administration and the self-administration of an alternate non-drug reward, sucrose. Male alcohol-preferring inbred (iP) rats were trained to self-administer ethanol (15% v/v) vs. water on a concurrent schedule of reinforcement, and the effect of the mGlu1 receptor antagonist JNJ16259685 (0.1 - 1.0 mg/kg IP) was evaluated on self-administration. The rats were then trained to self-administer sucrose (0.4% w/v) vs. water, and the same dose range of JNJ16259685 was tested. Locomotor activity was tested in a separate assessment to evaluate potential non-specific motor effects of the antagonist. Ethanol self-administration was dose-dependently reduced by JNJ16259685. This reduction was likely due to a motor impairment as the lowest effective dose (0.1 mg/kg) significantly reduced locomotor behavior. Sucrose self-administration was reduced by the highest JNJ16259685 dose (1.0 mg/kg), and this reduction was also likely due to a motor impairment. Interestingly, ethanol self-administration was more sensitive to mGlu1 receptor antagonism than sucrose self-administration as lower JNJ16259685 doses reduced ethanol reinforced-responding and motor behavior. Together these results suggest that mGlu1 receptors do not play a specific role in modulating ethanol self-administration, or the self-administration of an alternate non-drug reward (i.e., sucrose).

The mammalian adolescent period is characterized by enhanced vulnerability to drug-induced neuroadaptations. Epidemiological evidence indicates that individuals who start drinking alcohol during adolescence are four times more likely to develop alcohol dependence in adulthood, but little is known about the adaptive mechanism(s) that may underlie this observation. Behavioral sensitization in rodents is a model of neurobehavioral plasticity that occurs following repeated drug exposure and may underlie components of addiction.

Rats were trained using a two-lever drug discrimination procedure to press one lever following systemic administration of ethanol (1.0 mg/kg, IP) and another lever following IP injections of saline. After determination of an ethanol generalization curve (0.25-1.25 g/kg, IP), rats were surgically implanted with bilateral stainless steel guide cannulae that terminated in the lateral ventricles. Following surgery, the generalization curve was redetermined and did not differ from presurgery values. Then, generalization to bilateral intracerebroventricular (ICV) injections of ethanol (600.0 and 900.0 mM, 1.0 microliter/side) were administered alone and in combination with IP injections of ethanol. The ICV ethanol injections produced partial generalization, but the combination of ICV ethanol (600.0 and 900.0 mM) with IP ethanol (0.25 and 0.50 g/kg) injections were two- to threefold more potent then IP injections alone. Response rates were unaffected by any dose of ethanol tested. These data suggest central mediation of ethanol's discriminative stimulus function due to: 1) increased potency of systemically administered ethanol by centrally administered ethanol, and 2) partial generalization between centrally and peripherally administered ethanol.

AbstractBackgroundA prominent therapeutic indication for alcohol use disorder (AUD) is reduction in chronic repetitive alcohol use. Glutamate α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptors (AMPARs) regulate chronic alcohol self‐administration in preclinical models. Recent evidence indicates that the expression and function of AMPARs require the transmembrane AMPAR regulatory protein γ‐8 (TARP γ‐8). This study evaluated the preclinical efficacy of JNJ‐55511118, a novel, selective, high‐affinity inhibitor of TARP γ‐8‐bound AMPARs, in reducing chronic operant alcohol self‐administration.MethodsSeparate groups of male and female C57BL/6J mice (n = 8/sex/group) were trained to lever press for sweetened alcohol (9% v/v + sucrose 2% w/v) or sucrose only (2% w/v) in operant conditioning chambers using an FR‐4 schedule of reinforcement. After a 40‐day baseline, JNJ‐55511118 (0, 1, and 10 mg/kg, p.o.) was administered in randomized order 1 h before self‐administration sessions. Parameters of operant behavior including response rate, total reinforcers, and head entries in the drinking troughs were computer recorded.ResultsDuring baseline, responding to alcohol, but not sucrose, was greater in female than male mice. In male mice, both doses of JNJ‐55511118 decreased multiple parameters of alcohol self‐administration but did not reduce behavior‐matched sucrose‐only self‐administration. JNJ‐55511118 had no effect on sweetened alcohol or sucrose self‐administration in female mice. Subsequent tests of motor function showed that the lowest effective dose of JNJ‐55511118 (1 mg/kg) had no effect on open‐field activity in male mice.ConclusionsThis study shows for the first time that TARP γ‐8‐bound AMPARs regulate a behavioral pathology associated with addiction. The preclinical efficacy of JNJ‐55511118 in reducing alcohol self‐administration in male mice suggests that inhibition of TARP γ‐8‐bound AMPARs is a novel and highly significant neural target for developing medications to treat AUD and other forms of addiction.

Recent work has identified a role for metabotropic glutamate receptor subtype 5 (mGlu5) in the discriminative stimulus properties of investigator-administered ethanol. The purpose of this study was to determine if mGlu5 receptors modulate the discriminative stimulus properties of self-administered ethanol. Results show that the mGlu5 receptor antagonist 6-Methyl-2-(phenylethynyl)pyridine (MPEP; 10 mg/kg) inhibited the discriminative stimulus properties of consumed ethanol during a self-administration test session. Further, 10 mg/kg MPEP increased and 1 mg/kg MPEP decreased the amount of self-administered ethanol required to produce full substitution. These results indicate that mGlu5 receptors are involved in the expression of the discriminative stimulus properties of self-administered ethanol.