FACILITATION OF GABA RELEASE BY NEUROTENSIN IS ASSOCIATED WITH A REDUCTION OF DOPAMINE RELEASE IN RAT NUCLEUS-ACCUMBENS

The main aim of the present study was to investigate the effects of local perfusion with the tridecapeptide neurotensin on extracellular GABA and dopamine levels in the nucleus accumbens of the halothane-anaesthetized rat, using in vivo microdialysis. In an initial set of characterization studies we examined the Na+ dependence of neurotransmitter release by local perfusion with ouabain, veratridine and tetrodotoxin. Local perfusion with the Nac ATPase inhibitor ouabain (10 mu M) or the Naf channel agonist veratridine (20 mu M) perfused into the nucleus accumbens increased both extracellular GABA and dopamine levels. The Na+ channel antagonist tetrodotoxin (1 mu M) consistently decreased (24% of basal) dopamine levels, while even at 10 mu M it did not affect GABA. However, tetrodotoxin (10 mu M) abolished the veratridine-induced increase in both GABA and dopamine, demonstrating that Na+-dependent neuronal activity is involved in this release mechanism. In a second set of experiments a hypothesis for a functional link between neurotensin, dopamine and GABA in the medial nucleus accumbens was tested. Towards this aim, the effects of local perfusion with different neurotensin concentrations on GABA and dopamine release were investigated. Local perfusion with a high 1 mu M concentration of neurotensin into the nucleus accumbens increased both GABA (210% of basal value) and dopamine (145% of basal) release. However, a low (10 nM) concentration of neurotensin again increased GABA release (160% of basal), but decreased that of dopamine (75% of basal value). Furthermore, the local perfusion with the GABA, receptor antagonist bicuculline abolished the neurotensin (10 nM) induced inhibition of dopamine release without affecting the increase in GABA release. These findings suggest that neurotensin modulates both GABA and dopamine neurotransmission in the nucleus accumbens. They provide strong evidence that the inhibition of dopamine release induced by the 10 nM dose of neurotensin is mediated by increased GABA release, possibly via a direct activation of high-affinity neurotensin receptors located on accumbens GABA neurons, known to contain the dopamine receptors.