NEUROPHARMACOLOGICAL PROFILE OF NONPEPTIDE NEUROTENSIN ANTAGONISTS

Neurotensin, an endogenous peptide widely distributed throughout the b rain, fulfils neurotransmitter criteria When administered centrally, n eurotensin induces various effects and modulates the activity of the m esolimbic dopamine system. It antagonizes the behavioural action of do pamine in a manner similar, but not identical, to antipsychotic drugs. Neurotensin is even considered to be an endogenous neuroleptic. In fa ct, microinjection of neurotensin elicits different effects depending on both the dose and the cerebral structures into which the injection is made. Our work on the development of orally-active neurotensin anta gonists has led to the identification of SR 48692, the first non-pepti de antagonist of the neurotensin receptor, and some analogues. This sm all molecule reveals a surprising neuropharmacological profile. It ant agonizes turning behaviour induced in mice and rats (after striatal or ventral tegmental area administration of neurotensin, respectively), hypolocomotion induced by intracerebroventricular injection of neurote nsin in rats, and reverses the inhibitory effect of neurotensin (nucle us accumbens injection) on amphetamine-induced hyperlocomotion in rats . However, SR 48692 cannot reverse either dopamine release in the nucl eus accumbens evoked by neurotensin injection in ventral tegmental are a, or hypothermia and analgesia induced by intracerebroventricular inj ection of neurotensin. As direct and indirect dopamine agonists have b een reported to promote neurotensin release in the cortex, behavioural studies were performed using injection of apomorphine. In these exper iments, SR 48692 inhibited only turning and yawning. It did not antago nize other apomorphine-dependent effects such as climbing, hypothermia , hypo- or hyperlocomotion, penile erection and stereotypies. All toge ther, these data raise the question of the existence of neurotensin re ceptor subtypes and confirm that the nature of neurotensin and dopamin e interactions depends on the brain structures considered.