Elsevier

Brain Research

Volume 665, Issue 2, 5 December 1994, Pages 237-244
Brain Research

Endogenous neurotensin antagonizes methamphetamine-enhanced dopaminergic activity

https://doi.org/10.1016/0006-8993(94)91343-9Get rights and content

Abstract

Neurotensin (NT) has been proposed to be an endogenous neuroleptic based on observations that i.c.v. administration of this peptide antagonizes dopamine-mediated behavior. Because NT influences dopamine activity, this peptide may contribute to the pathogenesis of psychotic disorders such as schizophrenia; however, the precise physiological effects of NT remain speculative. In order to elucidate the function of endogenous NT, a selective NT antiserum (NTAS) was administered i.c.v. through a push-pull cannula in unanesthetized, freely moving rats in combination with dopamine activation caused by methamphetamine (METH). Locomotor and rearing activities induced by a low dose of METH (0.5 mg/kg) were substantially enhanced (4–5-fold) in rats receiving NTAS compared to control animals receiving METH alone. Similarly raised antiserum to vasoactive intestinal polypeptide (VIP) did not alter METH-induced effects. To determine a possible mechanism for these observations, perfusate delivered into the cerebral ventricular space was collected by push-pull cannulae and assayed for dopamine release. METH-induced dopamine release was enhanced 4–5-fold by co-administration of NTAS but not VIP antiserum. To verify these observations, and to identify the site of dopamine release, this experiment was repeated utilizing microdialysis and the recently described NT antagonist, SR-48692. Results from this experiment were similar to those found using NTAS. Like NTAS, co-administration of the NT antagonist enhanced the behavioral responses to a low dose of METH. These studies with SR-48692 also revealed that blockade of NT receptors increased METH-induced release of dopamine from the nucleus accumbens. These findings are the first to demonstrate directly that endogenous NT antagonizes stimulated dopamine pathways and its inactivation substantially enhances METH-induced DA release and related behaviors.

Reference (33)

  • SchmidtC.J. et al.

    In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoaminergic systems in the rat brain

    Biochem. Pharmacol.

    (1987)
  • SinghN.A. et al.

    Role of N-methyl-d-aspartate receptors in dopamine D1-, but not2-, mediated changes in striatal and accumbens neurotensin systems

    Brain Res.

    (1992)
  • TanganelliS. et al.

    Facilitation of GABA release by neurotensin is associated with a reduction of dopamine release in rat nucleus accumbens

    Neuroscience

    (1994)
  • AndersonF.L. et al.

    Vasoactive intestinal polypeptide in canine hearts: effect of total cardiac denervation

    Am. J. Physiol.

    (1992)
  • BodnarR.J. et al.

    The effects of centrally administered antisera to neurotensin and related peptides upon nociception and related behaviors

  • CadorM. et al.

    Behavioral analysis of the effect of neurotensin injected into the ventral mesencephalon on the investigatory and spontaneous motor behavior in the rat

    Psychopharmacology

    (1985)
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