The neurotensin receptor antagonist SR 142948A blocks the efflux of dopamine evoked in nucleus accumbens by neurotensin ejection into the ventral tegmental area

Abstract.

The neuropeptide neurotensin (NT) exerts a wide range of central and peripheral effects. In particular, ejection of NT (10^–7 M, 65 nl) into the ventral tegmental area (VTA) in anaesthetised rats pre-treated with pargyline increases the dopamine (DA) efflux within the nucleus accumbens (NAcc) as measured by differential pulse amperometry (DPA) combined with carbon fibre electrodes. However, this effect is not blocked by systemic pre-treatment with the potent and selective non-peptide NT receptor antagonists SR 48692 and SR 142948A, at any dose studied. The present study was designed to determine the ability of these NT receptor antagonists to block the increase in DA efflux evoked within the NAcc when they are locally applied with the peptide into the VTA. The competitive N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoic acid (AP-5), applied into the VTA 1 min before NMDA, blocked the effect of NMDA on DA efflux concentration and volume dependently, thus demonstrating the suitability of our experimental procedure for characterizing both an agonist and an antagonist specific for receptors present on mesencephalic dopaminergic neurons and involved in the regulation of DA efflux within the NAcc. Intra-VTA application of SR 142948A blocked the NT-evoked increase in DA efflux within the NAcc dose dependently whereas SR 48692, at the concentration used, was inactive. These results suggest that NT regulates mesencephalic dopaminergic activity through NT receptors sensitive to SR 142948A, but possibly not to SR 48692.