Baclofen and naltrexone, but not N-acetylcysteine, affect voluntary alcohol drinking in rats regardless of individual levels of alcohol intake.

In humans, there is profound individual variation in the risk of alcohol use disorder (AUD). Because GABA, opioid and glutamate neurotransmission have been implicated in AUD, functional differences in these neural systems may underlie the individual vulnerability to AUD. We therefore determined the effects of drugs affecting GABA, opioid and glutamatergic neurotransmission on alcohol consumption in rats that differed in baseline alcohol intake. Subgroups of low-, medium- and high-alcohol-drinking rats were selected on the basis of alcohol consumption using an intermittent alcohol access procedure. The subgroups were treated with the GABAB receptor agonist baclofen, the opioid receptor antagonist naltrexone and the cysteine precursor N-acetylcysteine, and the effects on alcohol intake and preference were determined. Both baclofen and naltrexone reduced alcohol consumption, but N-acetylcysteine did not. These effects were comparable for low-, medium- and high-alcohol-drinking rats. However, there was a substantial degree of individual variation in the responsivity to baclofen and naltrexone, across the subgroups. Taken together, these results suggest that variation in alcohol consumption does not predict the responsivity to baclofen and naltrexone. This implies that individual variability in alcohol consumption on the one hand and sensitivity to treatment with these drugs on the other hand represent separate processes that likely involve distinct biological mechanisms.

Genetic Variability in Adenosine Deaminase-Like Contributes to Variation in Alcohol Preference in Mice.

BACKGROUND: A substantial part of the risk for alcohol use disorder is determined by genetic factors. We previously used chromosome substitution (CSS) mice, to identify a quantitative trait loci (QTL) for alcohol preference on mouse chromosome 2. The aim of this study was to identify candidate genes within this QTL that confer the risk for alcohol preference. METHODS: In order to delineate the neurobiological underpinnings of alcohol consumption, we expanded on the QTL approach to identify candidate genes for high alcohol preference in mice. We narrowed down a QTL for alcohol preference on mouse chromosome 2, that we previously identified using CSS mice, to 4 candidate genes in silico. Expression levels of these candidate genes in prefrontal cortex, amygdala, and nucleus accumbens-brain regions implicated in reward and addiction-were subsequently compared for the CSS-2 and the C57BL/6J host strain. RESULTS: We observed increased expression of adenosine deaminase-like (Adal) in all 3 regions in CSS-2 mice. Moreover, we found that the adenosine deaminase inhibitor EHNA reduced the difference in alcohol preference between CSS-2 and C57BL/6J mice. CONCLUSIONS: This study identifies Adal as a genetically protective factor against alcohol consumption in mice, in which elevated Adal levels contribute to low alcohol preference.

Mu-opioid receptors are not involved in acute cocaine-induced locomotor activity nor in development of cocaine-induced behavioral sensitization in mice.

Although mu-opioid receptors have been extensively investigated for their role in drug reinforcement, little is known about the contribution of these receptors to the acute and sensitized locomotor response to cocaine. In this study mu-opioid receptor involvement in acute cocaine-induced locomotor activity and in the development of cocaine-induced behavioral sensitization was evaluated using mu-opioid receptor knockout mice and chronic naltrexone (NTX) pretreatment as models. In addition, co-administration of the specific mu-opioid receptor antagonist CTOP with repeated saline or cocaine injections was used to establish the involvement of mu-opioid receptors in sensitization to the locomotor stimulant effects of cocaine. The acute locomotor response to cocaine (3, 10, 20, or 30 mg/kg i.p.) of mu-opioid receptor knockout or chronic NTX pretreated mice was not different from the cocaine response of their respective controls. With respect to cocaine-induced behavioral sensitization, induced by daily injections of 20 mg/kg cocaine for 11 subsequent days, mu-opioid receptor knockout mice developed behavioral sensitization to the locomotor stimulant effects of cocaine (challenge 10 mg/kg i.p.) comparable to wild-type littermates and the mu-opioid receptor antagonist CTOP did not affect cocaine-induced sensitization either. However, mice that were pretreated with NTX exhibited augmented cocaine-induced behavioral sensitization relative to placebo pretreated controls, which may be ascribed to increased delta-opioid receptor levels as has been described for chronic NTX pretreated mice. The present findings suggest that mu-opioid receptors are not required for the acute locomotor response to cocaine nor are they essential for the development of cocaine-induced behavioral sensitization.

Enhanced morphine withdrawal and micro -opioid receptor G-protein coupling in A2A adenosine receptor knockout mice.

Much evidence supports the hypothesis that A2A adenosine receptors play an important role in the expression of morphine withdrawal and that the dopaminergic system might also be involved. We have evaluated morphine withdrawal signs in wild-type and A2A receptor knockout mice and shown a significant enhancement in some withdrawal signs in the knockout mice. In addition, micro -opioid and dopamine D2 receptor autoradiography, as well as micro -opioid receptor-stimulated guanylyl 5'-[gamma-[35S]thio]-triphosphate ([35S]GTPgammaS) autoradiography was carried out in brain sections of withdrawn wild-type and knockout mice. No significant changes in D2 and micro -opioid receptor binding were observed in any of the brain regions analysed. However, a significant increase in the level of micro receptor-stimulated [35S]GTPgammaS binding was observed in the nucleus accumbens of withdrawn knockout mice. These data indicate that the A2A receptor plays a role in opioid withdrawal related to functional receptor activation.