Baclofen attenuates conditioned locomotion to cues associated with cocaine administration and stabilizes extracellular glutamate levels in rat nucleus accumbens

We have used cocaine-conditioned locomotion in rats as an animal model for cocaine-conditioned responses that contribute to drug craving and relapse in human addicts. The purpose of the present study was to examine the ability of the GABA_B agonist, baclofen, to attenuate such associative responses. First, experiments were conducted to identify a dose range of baclofen that did not impede exploratory or spontaneous behavior. This dose range was used during testing for conditioned locomotion specific to a flashing light and metronome, which were previously associated with administration of cocaine (PAIRED group) or saline (UNPAIRED group). At 2.0 mg/kg, baclofen attenuated conditioned locomotion in PAIRED subjects to the level of UNPAIRED subjects receiving saline or 2.0 mg/kg baclofen. Considering the importance of glutamate transmission in the nucleus accumbens (NAc) during associative responses to reward-related stimuli, the effect of baclofen on extracellular levels of glutamate in the NAc was tested with microdialysis. Baclofen (2.0 mg/kg) did not alter basal glutamate levels. However, baclofen pretreatment prevented the predatory odor, 2,5-dihydro-2,4,5-trimethylthiazoline, from increasing glutamate levels. This is the first report of baclofen modulating extracellular levels of glutamate in the NAc. Baclofen may prove to have general utility for suppressing stimulus-evoked increases in NAc glutamate levels. This could explain its ability to prevent cocaine-conditioned responses. In summary, our results suggest that enhancing GABA_B transmission inhibits cocaine-conditioned responses, possibly by suppressing glutamate transmission in the NAc. A better understanding of interactions between GABA and glutamate transmission in the NAc may lead to the development of pharmacotherapies for cocaine craving.