Elsevier

Life Sciences

Volume 73, Issue 6, 27 June 2003, Pages 679-690
Life Sciences

Neurotensin agonists: possible drugs for treatment of psychostimulant abuse

https://doi.org/10.1016/S0024-3205(03)00388-6Get rights and content

Abstract

Although many neuropeptides have been implicated in the pathophysiology of psychostimulant abuse, the tridecapeptide neurotensin holds a prominent position in this field due to the compelling literature on this peptide and psychostimulants. These data strongly support the hypothesis that a neurotensin agonist will be clinically useful to treat the abuse of psychostimulants, including nicotine. This paper reviews the evidence for a role for neurotensin in stimulant abuse and for a neurotensin agonist for its treatment.

Introduction

Neurotensin (NT) is an endogenous tridecapeptide discovered nearly three decades ago Carraway and Leeman, 1973, Tyler-McMahon et al., 2000a, Tyler-McMahon et al., 2000b. It derives its name from the facts that it was found in brain and that it causes hypotension in animals, when it is injected peripherally. The amino acid sequence is pyroGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH. Most, if not all, of the activity mediated by NT(1–13) is seen with the shorter fragment, NT(8–13). The accumulated evidence has shown that neurotensin behaves as a neurotransmitter or neuromodulator in the central nervous system (CNS) and that there are striking interactions between NT via its receptors (NTR) and central dopaminergic systems Tyler-McMahon et al., 2000a, Tyler-McMahon et al., 2000b to antagonize functionally dopamine in the mesolimbic system Nemeroff et al., 1983, Ford and Marsden, 1990, while increasing dopaminergic transmission in the nigrostriatal system (Drumheller et al., 1990).

Section snippets

Neurotensin and its receptors

Neurotensin mediates its effects through its receptors Le et al., 1996, Vincent et al., 1999, first identified by radioligand binding techniques Kitabgi et al., 1977, Uhl and Snyder, 1977. The first neurotensin receptor (NTR) was molecularly cloned from rat brain (Tanaka et al., 1990), from a human colonic carcinoma cell line (Vita et al., 1993), and from human brain by our group (Watson et al., 1993). This receptor has been called NTR-1. The second neurotensin receptor (NTR-2), which in

Neurotensin and neuroleptics

Interest in neurotensin over the years stems largely from its remarkable similarities, when it is injected into brains of animals, to systemically administered antipsychotic drugs. Thus, centrally administered neurotensin behaves in certain paradigms like an atypical neuroleptic drug, such as clozapine (Jolicoeur et al., 1993). Like antipsychotic drugs, centrally administered neurotensin causes hypothermia (Bissette et al., 1976). Unlike antipsychotic drugs, centrally administered neurotensin

Neurotensin and psychostimulants

The psychomotor stimulant and reinforcing effects of drugs, such as D-amphetamine and cocaine, have long been linked to dopamine systems in brain. The mesocorticolimbic dopamine system, to which NT co-localizes (Studler et al., 1988), appears to be the specific anatomical site for the rewarding activity of cocaine Roberts et al., 1977, Roberts et al., 1980 and other drugs (McBride et al., 1999), including nicotine (DiChiara, 2000). NT has modulating effects on these neurons and many studies

Neurotensin agonists

Despite considerable effort by industry and academia over about two decades, non-peptide neurotensin agonists for NTR-1 have been elusive. While peptide agonists of NTR-1 have nanomolar and sub-nanomolar affinities for the receptor, the partially-nonpeptide and nonpeptide compounds that we have developed over the years have affinities in the micro molar range Cusack et al., 1993, Dodd et al., 1994, Hong et al., 1997a, Hong et al., 1997b. On the other hand, we have had considerable success

Should a neurotensin receptor agonist or a neurotensin receptor antagonist be used to treat psychostimulant abuse?

From the discussions above, the question arises whether a neurotensin receptor agonist or a neurotensin antagonist should be used to treat psychostimulant abuse. The answer is clear, to the extent that animal models are predictive of human addiction. Abusers of psychostimulants are likely already in a sensitized state. Since the neurotensin receptor antagonist has little effect on the stimulating effects of the psychostimulant once the subject is in the sensitized state, while the neurotensin

Acknowledgements

This work was supported by the Mayo Foundation for Medical Education and Research and the Forrest C. Lattner Foundation, Inc.

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