GABA(B) receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self-administration of alcohol and cocaine

Drugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug-induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug-seeking behavior. To evaluate the impact of GABA(B) receptors on addiction-related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABA(B) receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward-related behaviors induced by ethanol and cocaine. A novel compound (S)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-4-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (ORM-27669) was found to be a GABA(B) PAM of low efficacy as agonist, whereas the reference compound (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) had a different allosteric profile being a more potent PAM in the calcium-based assay and an agonist, coupled with potent PAM activity, in the [S-35] GTP gamma S binding assay in rat and human recombinant receptors. Using autoradiography, the high-efficacy rac-BHFF and the low-efficacy ORM-27669 potentiated the effects of baclofen on [S-35] GTP gamma S binding with identical brain regional distribution. Treatment of mice with baclofen, rac-BHFF, or ORM-27669 failed to induce glutamate receptor neuroplasticity in the VTA DA neurons. Pretreatment with rac-BHFF at non-sedative doses effectively reversed both ethanol- and cocaine-induced plasticity and attenuated cocaine i.v. self-administration and ethanol drinking. Pretreatment with ORM-27669 only reversed ethanol-induced neuroplasticity and attenuated ethanol drinking but had no effects on cocaine-induced neuroplasticity or self-administration. These findings encourage further investigation of GABA(B) receptor PAMs with different efficacies in addiction models to develop novel treatment strategies for drug addiction.Peer reviewe

Alcohol intake in two different mouse drinking models after recovery from the lipopolysaccharide-induced sickness reaction

Neuroinflammation may play an important role in the development of alcohol addiction. Recent pre-clinical reports suggest that enhanced innate immune system signaling increases consumption of alcohol. Our aim was to study whether consequences of lipopolysaccharide (LPS)-induced sickness reaction increase long-term alcohol intake. Adult male C57BL/6j mice, housed in individually ventilated cages, were injected with LPS intraperitoneally (i.p.) and allowed to recover from an acute sickness reaction for 1 week before analysis of their alcohol intake in two different drinking models. Effects of LPS challenge were tested in a continuous two-bottle free choice test with increasing concentrations of alcohol and in a drinking in the dark (DID) binge model. In addition, the effect of repeatedly administered LPS during abstinence periods between binge drinking was analyzed in the DID model. In addition, the DID model was used to study the effects of the microglia inhibitor minocycline (50 mg/kg/day, 4 days) and purinergic P2X7 receptor antagonist Brilliant Blue G (75 mg/kg/day, 7 days) on alcohol intake. In contrast to previous findings, pretreatment with a 1-mg/kg dose of LPS did not significantly increase ethanol consumption in the continuous two-bottle choice test. As a novel finding, we report that increasing the LPS dose to 1.5 mg/kg reduced consumption of 18 and 21% (v/v) ethanol. In the DID model, pretreatment with LPS (0.2-1.5 mg/kg) did not significantly alter 15% or 20% ethanol consumption. Neither did repeated LPS injections affect binge alcohol drinking. Minocycline reduced alcohol, but also water, intake regardless of LPS pretreatment. No data on effects of P2X7 antagonists on alcohol consumption have been previously published; therefore, we report here that subchronic Brilliant Blue G had no effect on alcohol intake in the DID model. As a conclusion, further studies are needed to validate this LPS model of the interaction between immune system activation and alcohol consumption. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe