Abstract

Cocaine-primed reinstatement is an animal model of drug relapse. The neurocircuitry underlying cocaine-primed reinstatement includes a decrease in GABA in the ventral pallidum (VP) that is inhibited by a μ opioid receptor antagonist, suggesting that opioid peptides colocalized with GABA in the projection from the nucleus accumbens to the VP may mediate this effect. Neurotensin is also colocalized with GABA and has been shown to increase GABA release in several brain regions. Therefore, the present study determined whether neurotensin increases GABA release in the VP, antagonizes cocaine-induced decreases in GABA, and prevents reinstatement of cocaine seeking. In vivo microdialysis revealed that the neurotensin agonist neurotensin peptide fragment 8–13 [NT(8–13)] increased GABA in the VP in a neurotensin receptor and tetrodotoxin-dependent manner and blocked the cocaine-induced decrease in GABA. NT(8–13) (3 nmol) microinjected into the VP prevented cue-induced reinstatement without affecting cocaine self-administration. In contrast, 3 nmol NT(8–13) potentiated cocaine-primed reinstatement. The neurotensin antagonist SR142948 (2-[[[5-(2,6-dimethoxyphenyl)-1-[4-[[[3-(dimethylamino)propyl]methylamino]carbonyl]-2-(1-methylethyl)phenyl]-1H -pyrazol-3-yl]carbonyl]amino]-tricyclo-[3.3.1.13,7]decane-2-carboxylic acid) had no effect on any behavioral measure when infused in the VP at the dose tested but attenuated cocaine-primed reinstatement when administered systemically. In contrast to reinstatement, NT(8–13) did not alter the motor response to acute cocaine or the development of motor sensitization by chronic cocaine. Three conclusions can be drawn from these data: 1) neurotensin promotes GABA release in the VP and correspondingly inhibits cue-induced reinstatement, 2) neurotensin and cocaine interact in a manner that countermands the neurotensin-induced increase in GABA and promotes reinstatement, and 3) endogenous release of neurotensin in the VP is not necessary for reinstatement.