Effects of neurotensin gene knockout in mice on the behavioral effects of cocaine

Rationale: The neuropeptide neurotensin (NT), which has been implicated in the modulation of dopamine signaling, is expressed in a subset of dopamine neurons and antagonism of the NT receptor has been reported to reduce psychostimulant-induced behavior. Gene knockout (KO) of the neurotensin/ neuromedin N precursor provides an approach to delineating possible roles of endogenous NT in psychostimulant-induced responses. Objectives: Involvement of NT in cocaine responses was examined by comparing acute and conditioned locomotor responses, conditioned place preference, and sensitization in wild-type (WT), heterozygous, and homozygous NT KO mice. Results: NT KO mice did not differ from their WT or heterozygous littermates in either baseline or acute cocaine-stimulated locomotor activity. The locomotor stimulant effects of cocaine were slightly prolonged in these mice under some, but not all, experimental conditions. The rewarding effects of cocaine as assessed in the conditioned place preference and conditioned locomotion paradigms were also similar between genotypes at all cocaine doses tested. Conclusions: These results suggest that endogenous NT is not involved in cocaine-mediated behaviors in most circumstances, but under some conditions, a slight prolongation of the effects of cocaine was observed in the absence of endogenous NT.