GABAB Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

Abstract

Exposure to cocaine induces selective behavioral and molecular adaptations. In rodents, acute cocaine induces increased locomotor activity, whereas prolonged drug exposure results in behavioral locomotor sensitization, which is thought to be a consequence of druginduced neuroadaptive changes. Recent attention has been given to compounds activating GABA B receptors as potential antiaddictive therapies. In particular, the principle of allosteric positive GABA B receptor modulators is very promising in this respect, as positive modulators lack the sedative and muscle relaxant properties of full GABA B receptor agonists such as baclofen. Here, we investigated the effects of systemic application of the GABA B receptor-positive modulator GS39783 (N,N 0 -dicyclopentyl-2-methylsulfanyl-5-nitropyrimidine-4, 6-diamine) in animals treated with acute and chronic cocaine administration. Both GS39783 and baclofen dose dependently attenuated acute cocaine-induced hyperlocomotion. Furthermore, both compounds also efficiently blocked cocaine-induced Fos induction in the striatal complex. In chronic studies, GS39783 induced a modest attenuation of cocaine-induced locomotor sensitization. Chronic cocaine induces the accumulation of the transcription factor DFosB and upregulates cAMP-response-element-binding protein (CREB) and dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). GS39783 blocked the induction/activation of DARPP-32 and CREB in the nucleus accumbens and dorsal striatum and partially inhibited DFosB accumulation in the dorsal striatum. In summary, our data provide evidence that GS39783 attenuates the acute behavioral effects of cocaine exposure in rodents and in addition prevents the induction of selective long-term adaptive changes in dopaminergic signaling pathways. Further investigation of GABA B receptor-positive modulation as a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse is therefore warranted.

GABAB Receptor-Positive Modulation-Induced Blockade of the Rewarding Properties of Nicotine Is Associated with a Reduction in Nucleus Accumbens ΔFosB Accumulation

“…These present results are consistent with previous data showing that GABA B receptor-positive modulator blocked the establishment but not the expression of behavioral sensitization to cocaine (Lhuillier et al, 2007). This absence of effects of GS39783 on the expression of CPP might be attributed to the inability of GABA B receptor-positive modulator to affect conditioned motivational properties of nicotine-paired cues.…”

“…in a suspension of 0.5% methylcellulose at a volume of 5 ml/kg 30 min before testing. Doses of GS39783 were chosen based on our previous data showing that GS39783 can reverse the behavioral and molecular effects of cocaine in this dose range (Slattery et al, 2005;Lhuillier et al, 2007). Furthermore, they are in line with the pharmacokinetic properties of GS39783 in terms of brain exposure (Smith et al, 2004).…”

“…Western blot analysis was carried out as described previously (Lhuillier et al, 2007). Primary antibodies used were rabbit anti-FosB (sc-48, 1:500; Santa Cruz Biotechnologies, Santa Cruz, CA) and rabbit anti-actin (A2066, 1:5000; Sigma Chemicals).…”

“…Hence, GS39783 lacks many of the behavioral and physiological side effects of full GABA B receptor agonists . Of particular interest, GS39783 reduces the behavioral effects of cocaine (Smith et al, 2004;Slattery et al, 2005;Lhuillier et al, 2007). However, to our knowledge, there are no investigations to date on the effects of GS39783 in animal models of nicotine reinforcement.…”

Efficacy and Tolerability of Baclofen in Substance Use Disorders: A Systematic Review

“…A possible strategy to potentiate the effects of baclofen may come from the use of PAMs. These compounds possess behavioral activity similar to that of the full GABA B receptor agonists, including in tests related to SUDs [97,178,179,180,181,182]. Preclinical studies have demonstrated that when coadministered with baclofen, PAMs enhance its potency, which could in theory minimize its side effects or imply the use of lower doses of baclofen [183,184].…”