Neurotensin agonists: possible drugs for treatment of psychostimulant abuse
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).
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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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Cited by (28)
Gene-environment interactions in a rat model of depression. Maternal separation affects neurotensin in selected brain regions
2016, NeuropeptidesCitation Excerpt :Neurotensin is a tridecapeptide originally isolated from the bovine hypothalamus with a wide range of behavioral and physiological effects, including hypotension, analgesia, sedation, hypothermia and reward (Caceda et al., 2006; Ferraro et al., 2016; Nemeroff, 1980). While there is extensive literature on neurotensin in schizophrenia, psychosis and addiction (Binder et al., 2001; Kinkead and Nemeroff, 2002; Liu and Borgland, 2015; Richelson et al., 2003; Sarhan et al., 1997), there is a paucity of papers dealing with affective disorders and no publications regarding neurotensin in animal models of depression. However, neurotensin interacts with the dopaminergic system which is intricately related to reward and, by extension, anhedonia.
The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex
2010, Brain ResearchCitation Excerpt :NT was directly injected into brain of NT (Petrie et al., 2005), while in this and all our other studies, NT69L was given outside the brain. We have discussed previously that conclusions about the effects of an NT receptor agonist given outside the brain cannot be predicted from studies in which an NT receptor agonist is injected into discrete areas of the brain (Richelson et al., 2003). Perhaps most interesting are our results showing for the first time that an NT receptor agonist robustly increased extracellular concentrations of glycine in the mPFC.
Mesolimbic dopamine and cortico-accumbens glutamate afferents as major targets for the regulation of the ventral striato-pallidal GABA pathways by neurotensin peptides
2007, Brain Research ReviewsCitation Excerpt :The mesolimbic and mesocortical DA pathways are highly implicated in the pathogenesis of schizophrenia and in the psychomotor stimulant and reinforcing effects of drugs, such as d-amphetamine and cocaine. Because of the well known interactions between NT and the mesolimbic and mesocortical DA systems, NT signalling appears to be one of the specific neurochemical mechanisms for the rewarding activity of cocaine and other drugs of abuse (McBride et al., 1999; Richelson et al., 2003; Fredrickson et al., 2005; Lopak and Erb, 2005) and have also been implicated in the pathogenesis of schizophrenia and in the mechanism of action of antipsychotic drugs (Kinkead and Nemeroff, 2002, 2006; Dobner et al., 2003; St-Gelais et al., 2004; Dobner, 2005; Caceda et al., 2006; Boules et al., 2005; 2007; Geisler and Zahm, 2006). Since the potential involvement of NT in schizophrenia and psychostimulant actions has been recently reviewed, here the functional paradox of neuroleptic action versus psychostimulant effects of NT will be discussed.
NTS1 neurotensin receptor
2007, xPharm: The Comprehensive Pharmacology Reference