Attenuation of cocaine-seeking by GABAB receptor agonists baclofen and CGP44532 but not the GABA reuptake inhibitor tiagabine in baboons

Abstract

The current study evaluated the effects of drugs that increase GABA levels by activation of GABA(B) receptors (baclofen and CGP44532) or by inhibition of GABA reuptake (tiagabine) on the reinstatement of extinguished lever responding produced by priming doses of cocaine in baboons (i.e., cocaine-seeking). Cocaine self-injection was established and maintained under a fixed ratio (FR10) schedule of reinforcement during daily 2h sessions. Lever responding was extinguished by substituting vehicle (saline) for cocaine until the number of self-injections decreased to 10 or less per session for two consecutive sessions (defined as extinction). Once extinction occurred, priming doses of cocaine (0.1-3.2mg/kg, i.v.) were administered during extinction conditions. Administration of priming doses of cocaine significantly increased cocaine-seeking in a dose-dependent manner. Cocaine-seeking produced by priming doses of cocaine were attenuated by pretreatment with baclofen (N=5) or CGP44532 (N=5) but not tiagabine (N=3). The doses of baclofen (0.32 mg/kg), and CGP445532 (0.32 mg/kg) that reduced cocaine-seeking produced by cocaine priming doses did not reinstate cocaine-seeking and did not produce overt effects when administered alone. These data indicate that GABA(B) agonists may reduce relapse to cocaine taking.

Behavioral Effects of γ-Hydroxybutyrate, Its Precursor γ-Butyrolactone, and GABAB Receptor Agonists: Time Course and Differential Antagonism by the GABAB Receptor Antagonist 3-Aminopropyl(diethoxymethyl)phosphinic Acid (CGP35348)

“…At concentrations described as clinically relevant, GHB disinhibits and baclofen inhibits ventral tegmental dopamine neurons . It has been suggested that GHB is more likely to activate the dopamine system implicated in addiction, whereas baclofen, which may be useful to reduce a relapse to taking cocaine (Weerts et al, 2007), may have more pronounced anticraving effects . GHB and baclofen differ also in their effects on neurotransmission at glutamate receptors (Li et al, 2007).…”

Cataleptic effects of γ-hydroxybutyrate (GHB) and baclofen in mice: mediation by GABAB receptors, but differential enhancement by N-methyl-d-aspartate (NMDA) receptor antagonists

“…When applied at clinically relevant concentrations, GHB disinhibits and baclofen inhibits ventral tegmental dopamine neurons ). This suggests that GHB would be more likely than baclofen to activate the dopamine system implicated in addiction and that baclofen, which may be useful to reduce relapse to cocaine-taking (e.g., Weerts et al 2007), may have more pronounced anti-craving effects than GHB . GHB and baclofen also differ in their effects on excitatory neuro-transmission at NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) subtypes of glutamate receptors in neocortex (Li et al 2007).…”

Evidence-based treatments of addiction

“…Other medications block cocaine reward in animal studies (but not yet reliably demonstrated in humans) by increasing GABA-inhibitory effects on reward pathways such as ventral tegmental-ventral striatal DA pathways. These include medications such as topiramate (Kampman et al 2004), vigabatrin (Brodie et al 2005) and baclofen (Weerts et al 2007). …”