Abstract

Due to persistent social problems caused by methamphetamine (METH) new therapeutic strategies need to be developed. Thus, we investigated the response of CNS neurotensin (NT) systems to METH self-administration (SA) and their interaction with basal ganglia dopamine (DA) pathways. Neurotensin is a peptide associated with inhibitory feedback pathways to nigrostriatal DA projections. We observed that NT levels decreased in rats during extinction of METH SA when lever pressing resulted in i.v. infusions of saline rather than METH. Thus, 6 hours after the first session of extinction, NT levels were 53%, 42% and 49% of corresponding controls in the anterior dorsal striatum, posterior dorsal striatum and the globus pallidus, respectively. NT levels were also significantly reduced in corresponding yoked rats in the anterior dorsal striatum (64% of control), but not the other structures examined. The reductions in NT levels in the anterior dorsal striatum particularly correlated with the lever pressing during the first session of extinction (r=0.745). These, and previously reported findings, suggest that the extinction-related reductions in NT levels were mediated by activation of D2 receptors. Finally, administration of the NTR1 agonist (PD149163; 0.25 or 0.5 mg/kg) diminished lever pressing during the first extinction session, while the NTR1 antagonist (SR48692; 0.3 mg/kg/administration) attenuated the reduction of lever pressing during the 2nd-4th days of extinction. In summary, these findings support the hypothesis that endogenous basal ganglia NT systems contribute to the elimination of contingent behavior during the early stages of the METH SA extinction process.