The GABAB Receptor Agonist Baclofen Attenuates Cocaine- and Heroin-Seeking Behavior by Rats

Abstract

Conditioned stimuli paired with drugs of abuse can acquire motivational properties, and are capable of inducing drug-seeking behavior and relapse to cocaine use. Converging evidence implicates the mesolimbic dopamine (DA) system, through interactions with limbic afferents to the nucleus accumbens, in behavior controlled by conditioned stimuli. The GABA B receptor agonist baclofen has been shown to decrease break points in rats responding for cocaine under progressive ratio schedules and also to attenuate activation of limbic cortical areas in human cocaine addicts. The purpose of the present study was therefore to investigate the effects of baclofen on drug-associated cue-controlled cocaine-or heroin-seeking behavior by rats. Under the second-order schedule of reinforcement used in the present study, cocaine or heroin were available after a fixed time interval, while high rates of responding during the interdrug intervals were maintained by the response-contingent presentations of drug-associated conditioned reinforcers. Baclofen decreased stimulusmaintained responding for either heroin or cocaine, but decreased only cocaine intake under an FR1 schedule. These results therefore support preliminary clinical findings and suggest that drugs with GABA B receptor agonist properties may aid abstinence in human drug addicts by decreasing the propensity to cue-induced drug-seeking and relapse.

The GABAB Receptor-Positive Modulator GS39783 and the GABAB Receptor Agonist Baclofen Attenuate the Reward-Facilitating Effects of Cocaine: Intracranial Self-Stimulation Studies in the Rat

“…GABA B receptor agonists, such as baclofen, have been shown to decrease self-administration of cocaine under both a fixed ratio schedule (Roberts et al, 1996;Brebner et al, 1999;Xi and Stein, 1999) or a second-order schedule of reinforcement (Di Ciano and Everitt, 2003). Additionally, baclofen attenuates cocaine-conditioned locomotion in rats (Hotsenpiller and Wolf, 2003).…”

“…Additionally, baclofen attenuates cocaine-conditioned locomotion in rats (Hotsenpiller and Wolf, 2003). The antiaddictive properties of GABA B receptor agonists is not specific to cocaine as baclofen attenuates heroin self-administration under a second-order schedule of reinforcement (Di Ciano and Everitt, 2003). Further, the GABA B receptor agonists baclofen or CGP44532 attenuated self-administration of damphetamine (Brebner et al, 2005), alcohol (Colombo et al, 2002), and nicotine (Paterson et al, 2004a, b), in addition to decreasing amphetamine-induced rearing (Zhou et al, 2004).…”

“…Specifically, GABA B receptor activation via baclofen or other agonists attenuates many of the neurochemical and behavioral effects elicited by drugs of abuse. Baclofen administration reduces self-administration of d-amphetmaine (Brebner et al, 2005), nicotine (Fattore et al, 2002;Paterson et al, 2004a, b), heroin (Xi and Stein, 1999;Di Ciano and Everitt, 2003) alcohol (Colombo et al, 2002), and cocaine (Roberts et al, 1996;Brebner et al, 2000Brebner et al, , 2002b.…”

Effects of gabapentin on cocaine self-administration, cocaine-triggered relapse and cocaine-enhanced nucleus accumbens dopamine in rats

“…First, potentiation of GABA A receptor activity inhibits cocaine-induced seizures (Gasior et al, 1999) and cocaine-enhanced extracellular NAc DA (Giorgetti et al, 1998). Also, GABA B receptor agonists inhibit both cocaine self-administration (Roberts et al, 1996;Roberts, 2005) and cocaine-triggered reinstatement of drug-seeking behavior (Campbell et al, 1999;Di Ciano and Everitt, 2003). Second, elevation of extracellular GABA levels by inhibition of GABA degradation by γ-vinyl GABA (GVG) inhibits the rewarding effects of cocaine as assessed by intravenous self-administration, conditioned place preference and electrical brain stimulation reward (Kushner, 1997;Kushner et al, 1999;Dewey et al, 1998).…”

Positron Emission Tomography Molecular Imaging of Dopaminergic System in Drug Addiction

“…The GABA B receptor agonist baclofen dependently reduced the nicotine-, morphine-, and cocaine-evoked DA release in the shell of the NAc and also had been proposed as a potential therapeutic agent for the clinical treatment of several forms of drug addiction (Fadda et al, 2003). These drugs have shown promising results in animal studies (Dewey et al, 1998;Di Ciano and Everitt, 2003) and in preliminary clinical trials in cocaine-addicted subjects (Brodie et al, 2003;Gonzalez et al, 2003) and alcoholics (Johnson et al, 2003).…”