Neurotensin (NT), a tridecapeptide included in the family of recently discovered brain-gut peptides, has been suggested to function as a neurotransmitter. Recent evidence indicates that NT interacts with dopaminergic systems in the CNS. The neuropharmacologic profile of centrally administered NT shares many similarities with that of peripherally administered neuroleptics (antipsycotic agents), leading to the suggestion that NT may be an endogenous neuroleptic. One area of potential interaction which has not been adequately investigated concerns the effect of NT on dopamine (DA) release from presynaptic terminal projections of the nigrostriatal and mesolimbic dopaminergic systems (striatum and nucleus accumbens, respectively). The proposed experiments represent the first comprehensive investigation of the effect of NT on endogenous DA release evoked by low levels of electrical stimulation in single, thin slices of striatum and nucleus accumbens. Since NT may be an endogenous neuroleptic and since neuroleptics increase the release of DA via blockage of presynaptic D-2 DA receptors, we hypothesize that NT will increase the release of DA, under conditions in which neuroleptic increase release. Furthermore, we will determine whether NT produces its effect on endogenous DA release (1) directly via NT receptors on dopaminergic nerve terminals, or (2) via an indirect effect involving NT receptors on non-dopaminergic neurons, or (3) via an interaction with D-2 DA autoreceptors. Subsequently, we will determine if the relationship between the neurotensinergic and dopaminergic systems is altered after chronic in vivo administration of neuroleptics. Our recent development of a unique, highly sensitive HPLC methodology to measure endogenous DA and its major metabolite enables us to carry out the proposed experiments. Interactions between NT and DA may be relevant to the pathogenesis of schizophrenia, a disorder traditionally attributed to hyperactivity of central dopaminergic systems. Furthermore, results of these studies may be instrumental in the development of new antipsycotic agents, which, in contrast to neuroleptic, lack untoward extrapyramidal side-effects.
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