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Neurotensin agonists: possible drugs for treatment of psychostimulant abuse
Life Sciences 73 (2003) 679 – 690 www.elsevier.com/locate/lifescie
Neurotensin agonists: possible drugs for treatment of psychostimulant abuse Elliott Richelson *, Mona Boules, Paul Fredrickson Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
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. D 2003 Elsevier Science Inc. All rights reserved.
Introduction Neurotensin (NT) is an endogenous tridecapeptide discovered nearly three decades ago (Carraway and Leeman, 1973; Tyler-McMahon et al., 2000a,b). 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,b) 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).
* Corresponding author. Tel.: +1-904-953-2439; fax: +1-904-953-2482. E-mail address: [email protected] (E. Richelson). 0024-3205/03/$ - see front matter D 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0024-3205(03)00388-6
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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 binding assays is sensitive to the antihistamine levocabastine, has been molecularly cloned from mouse (Mazella et al., 1996), rat (Chalon et al., 1996), and human (Vita et al., 1997). Both NTR-1 and NTR-2 are 7transmembrane spanning, G-protein coupled receptors. The third neurotensin ‘‘receptor,’’ is presently a binding site, since no functional response is known to occur upon binding of NT. Therefore, strictly speaking, it is not a receptor. It is also a transmembrane protein, but spans the membrane only once and is identical to the protein called ‘‘sortilin’’ (Mazella et al., 1998). Activation of NTR-1 and NTR-2 results in an increase in intracellular inositol phosphates and Ca++. In brain, NTR-1 is much more highly localized than is NTR-2, which is more homogeneously distributed. All brain structures containing NTR-1 mRNA also contain NTR-2 mRNA, with only the substantia nigra having high levels of both messengers (Walker et al., 1998). On the other hand, while there are high levels of binding sites for NTR-1 in rat substantia nigra (Boudin et al., 1996), there are relatively low levels of binding sites for NTR-2 in this structure (Schotte et al., 1986; Kitabgi et al., 1987; Asselin et al., 2001). NTR-2 receptors in rat brain are thought to be predominantly associated with glial cells (Schotte et al., 1988). After binding to its receptor in brain, NT undergoes retrograde transport, culminating in the induction of the gene for tyrosine 3-hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines (Castel et al., 1989, 1990, 1992, 1993; Burgevin et al., 1992; Beaudet et al., 1994). Thus, within 4 h of injection of radiolabeled-NT into the striatum, cells in the substantia nigra are labeled and mRNA for tyrosine 3-hydroxylase is increased. This up-regulation of TH by NT has recently been shown to occur within hours in a human neuroblastoma cell line in culture (Najimi et al., 2001). Additionally, NT binding to its receptors may allosterically decrease the affinity of dopamine for its receptors (DiazCabiale et al., 2002). An advance in the study of neurotensin and its receptors came with the synthesis of a novel, nonpeptide neurotensin receptor antagonist, SR48692 (2-[1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxytphenyl) pyrazol-3-yl) carbonylamin]) (Gully et al., 1993). This compound has affinity for NTR-1 (Gully et al., 1993) and NTR-2 (Chalon et al., 1996). However, in vivo SR48692 does not block all the effects of neurotensin, suggesting that more subtypes of receptors exist for this peptide (Le et al., 1996). More, recently, another antagonist, SR142948A, with a broader spectrum of activity in vivo against NT was introduced (Gully et al., 1997). Interestingly, although in vivo the antagonists have no intrinsic activities (Gully et al., 1997) in vitro at NTR-2 these antagonists activate the receptor, while agonists at NTR-1 antagonize NTR-2 (Vita et al., 1998). Roles for the three molecularly-cloned NTRs in brain are far from being fully elucidated. However, it is very likely that in rats and in mice NTR-1 activation mediates antinociception, hypothermia, hypotension, and sedation (Tyler et al., 1999a,b; Pettibone et al., 2002). Although NTR-1 also likely mediates neurotensin’s effects on dopaminergic neurons (e.g., increased DA synthesis and release), studies to define the subtypes involved have not been done. Thus far, no definitive roles for either NTR2 or NTR-3 have been found.
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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 has potent analgesic effects not involving opioid receptors (Clineschmidt and McGuffin, 1977). In fact, neurotensin is more potent than morphine on a molar basis, when tested as an analgesic by injection into rodent brain (Nemeroff et al., 1979; Al-Rodhan et al., 1991). A role for neurotensin in neuropsychiatric disease has been hypothesized for over two decades (Nemeroff, 1980). More recently, in an autoradiographic study, there was a 40% reduction in neurotensin receptors in the entorhinal cortex of schizophrenics compared to controls (Wolf et al., 1995). These results were confirmed and extended (Lahti et al., 1998). In a large group of drug-free schizophrenics, those with the lowest CSF neurotensin concentrations had significantly higher levels of pretreatment psychopathology (Sharma et al., 1997). Improvements in overall psychopathology and, in particular, negative symptoms, correlated with increases in CSF neurotensin concentrations during treatment. It has long been know that neuroleptics elevate brain levels of neurotensin-immunoreactive (NT-IR) material (Govoni et al., 1980). However, those neuroleptics that are more likely to cause extrapyramidal side effects (typical neuroleptics) are more likely to induce expression of neurotensin in the extrapyramidal system, in addition to the limbic system (Merchant et al., 1992; Merchant and Dorsa, 1993). On the other hand, drugs that are less likely to cause these motor side effects (atypical neuroleptics), are more likely to induce expression of neurotensin only in the limbic system, the area thought to be the site of their therapeutic effects. These results have led researchers to suggest that both the therapeutic effects and the extrapyramidal side effects of neuroleptics are mediated through the release of neurotensin. Based on studies by our group (Cusack et al., 2000a,b), we think that at least in the extrapyramidal system, the increased synthesis and release of neurotensin is a compensatory mechanism caused by the blockade of dopamine receptors. More specifically, we have found that one of our brain-penetrating analogs of NT(8 – 13) {called ‘‘NT69L’’ or [N-methyl-Arg8,L-Lys9,L-neoTrp11,tert-Leu12]NT(8–13)} can prevent or block the catalepsy induced by haloperidol (Cusack et al., 2000a,b). Catalepsy or muscle rigidity in rodents is a measure of a drug’s propensity to cause extrapyramidal side effects (e.g, drug-induced parkinsonism) in patients (Munkvad et al., 1968). The NT(8–13) analog by itself does not cause catalepsy. Furthermore, in knock-out mice that lack NT, haloperidol still causes catalepsy (Dobner et al., 2001), indicating that NT does not mediate the cataleptic effects of DA receptor blockers.
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, 1980) and other drugs (McBride et al., 1999), including nicotine
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(DiChiara, 2000). NT has modulating effects on these neurons and many studies link neurotensin with the behavioral effects of CNS stimulants (Ervin et al., 1981; Robledo et al., 1993). Psychomotor stimulants up-regulate levels of NT-IR material (Cain et al., 1993; Gygi et al., 1994; Wagstaff et al., 1996) and levels of the neurotensin precursor mRNA in rat nucleus accumbens and striatum (Castel et al., 1994; Merchant et al., 1994; Betancur et al., 1997; Adams et al., 2001). These increases, which may be compensatory changes, appear to be mediated by dopamine receptors and NMDA receptors, since the effects in both regions can be completely blocked with a dopamine D2 receptor antagonist (Wagstaff et al., 1996) or an NMDA receptor antagonist (Hanson et al., 1995). Additionally, chronic cocaine treatment of rats modifies NT binding sites in brain (Pilotte et al., 1991). Some behavioral effects of NT injected into brain have similarities to those of psychomotor stimulants given outside the brain. Specifically, NT injected into the ventral tegmental area (VTA), the origins of the dopamine system associated with mediating the reinforcing actions of drugs (reward behavior), causes hyperactivity (Kalivas, 1994) and dopamine release in the nucleus accumbens (Kalivas and Duffy, 1990a,b). On the other hand, NT injection into the nucleus accumbens reduces the responses to psychostimulants (Ervin et al., 1981; Robledo et al., 1993). Also, NT has rewarding effects in rats (Glimcher et al., 1984), which will self-infuse this peptide into the VTA (Glimcher et al., 1987). However, the rewarding effects of brain self-stimulation in rats are suppressed by intracerebroventricular injection of NT (Bauco and Rompre, 2001). Neurotensin may play a role in the initiation of sensitization to psychostimulants (Horger et al., 1994; Rompre and Perron, 2000; Panayi et al., 2002). This sensitization is an enhanced locomotor response to the stimulant after repeated administrations of the drug. Behavioral sensitization to psychostimulants is a complex process thought to involve mesocorticolimbic dopamine neurons, with influences from glutamate, GABA, n-opioid and other neurotransmitter systems that produce long-term changes in neurotransmission (Pierce and Kalivas, 1997; Hahn et al., 2000). Additionally, this process, which is thought to play a role in the development of addiction to psychostimulants, is divided into initiation and expression. Initiation is the sequence of events leading to sensitization and expression is the enduring behavioral changes with sensitization. Both initiation of and expression of sensitization are thought to involve separate neurochemical processes that are temporally distinct (Pierce and Kalivas, 1997). The studies suggesting that endogenous neurotensin is involved in sensitization to psychostimulants involved the use of the NT receptor antagonist SR48692 and cocaine (Horger et al., 1994) or Damphetamine (Rompre and Perron, 2000; Panayi et al., 2002). Although there is one report that SR48692 (1 mg/kg) acutely blocks the vertical, but not the horizontal, activity induced by cocaine (15 mg/kg) (Betancur et al., 1998), in most studies this antagonist has no effects acutely on activity induced by either cocaine (Horger et al., 1994) or D-amphetamine (Rompre and Perron, 2000; Panayi et al., 2002). However, SR48692 has been shown either to delay the development of sensitization to cocaine (Horger et al., 1994) or to block the development of sensitization to D-amphetamine (Rompre and Perron, 2000; Panayi et al., 2002). On the other hand, we have shown that the neurotensin receptor agonist NT69L blocks the acute locomotor effects of cocaine (Fig. 2A) and D-amphetamine (Fig. 2B) (Boules et al., 2001a,b). In addition, NT69L blocked the acute locomotor effects of nicotine (Fig. 2C), as well as, both the initiation and expression of sensitization to this stimulant (Fredrickson et al., 2003). As with its effects on nicotine sensitization, NT69L will very likely block the initiation and expression of sensitization to other psychostimulants, such as cocaine and D-amphetamine. How then could both a neurotensin receptor agonist and a neurotensin receptor antagonist have the same effects on sensitization
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to psychostimulants? This is a question that requires further research. However, we can speculate and offer some hypotheses. It is clear that the effects of the neurotensin receptor antagonist require repeated treatments over days to have its effects on sensitization. It is also clear that relatively high dosages of the antagonist are required for the effect to occur. Thus, there is likely an adaptive process that must occur for the antagonist to block sensitization. Classically, chronic blockade of a receptor can lead to upregulation and supersensitivity of that receptor. For example, chronic blockade of dopamine D2 receptors by so-called typical neuroleptics, such as haloperidol, can cause the involuntary movement disorder called tardive dyskinesia. This motor side effect of neuroleptics is thought to be due to supersensitivity of dopamine receptors. Likewise, chronic blockade of neurotensin receptors would have the functional effect of making neurotensin a more efficacious agonist at its receptor. An alternative hypothesis is also based on classical pharmacology. Through a feedback mechanism as a result of chronic blockade of its receptors, there could be an increase in the synthesis and release of neurotensin. This is also seen with blockade of dopamine receptors. By this feedback mechanism, chronic blockade of neurotensin receptors can result again in an increased activation of neurotensin receptors. However, in the continued presence of an antagonist, such compensatory mechanisms would be masked, as is often the case with typical neuroleptics and dopamine receptor supersensitivity. In this case, upon withdrawal of the dopamine antagonist, the dyskinesias become clinically apparent. These hypotheses make particular sense, because the experimental paradigms in which the neurotensin antagonist blocked supersensitivity to psychostimulants or delayed its onset, required preexposure to the antagonist followed by a period of time, when the antagonist was withdrawn (Horger et al., 1994; Rompre and Perron, 2000; Panayi et al., 2002). Thus, for example, pre-exposure to the neurotensin receptor antagonist SR48692 followed by a 7-day drug-free period, but not co-treatment with this antagonist delays the development of cocaine sensitization (Horger et al., 1994). As with repeated injections of cocaine, repeated injections of neurotensin into the ventral tegmental area (VTA) augments the motor-stimulating effects of this peptide (Kalivas and Taylor, 1985). Thus, 1 Ag of neurotensin injected daily into the VTA causes an increase in activity that peaks after 4 daily injections. There is also an increase in dopamine release in the nucleus accumbens with repeated NT injections (Kalivas and Duffy, 1990a,b), as well as with repeated cocaine injections (Kalivas and Duffy, 1990a,b). On the other hand, we have found that the neurotensin receptor agonist, NT69L, given intraperitoneally at 1 mg/kg for 5 daily injections continued to block the hyperactivity caused by cocaine, while having no effects on basal locomotor activity (Boules et al., unpublished observations). Additionally, NT69L had some initial depressant effects on locomotor activity that diminished within 30
Fig. 1. Structure of neo-tryptophan in relation to tryptophan and tyrosine.
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min. Such results clearly indicate that globally activating brain receptors for neurotensin can produce results different from localized activation of neurotensin receptors in brain.
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
Fig. 2. Blockade by NT69L (1 mg/kg) of locomotor activity induced by (A) cocaine, (B) D-amphetamine, and (C) nicotine in rats. Male Sprague-Dawley rats weighing 200 – 250 g were housed in a temperature-controlled room with free access to food and water under artificial 12 h light/dark cycle. All tests were conducted during the light cycle. All procedures were approved by the Mayo Foundation Institutional Animal Use and Care Committee. Rats were placed in a Plexiglass Opto-Varimax Minor motility chamber (Columbus Instruments, Columbus, OH) for 1 h for acclimation. Baseline activity was recorded for 30 min for each rat. The rats were then injected with either NT69L (1 mg/kg) or an equivalent volume (100 Al) of saline and placed in the chamber for 30 min, after which the animals received an intraperitoneal (i.p.) injection of (A) cocaine (40 mg/kg i.p.), (B) Damphetamine (5 mg/kg i.p.), or (C) nicotine (0.35 mg/kg subcutaneously) or saline. Activity was then measured and reported as indicated in the figures. For statistical analyses, either one-way ANOVA (for A and B) or the Rank Sum Test (C) was used. ‘‘*’’ indicates level of significance as follows: (A) P < 0.003 for ‘‘NT69/cocaine’’ compared to ‘‘sal/cocaine;’’ (B) P < 0.008 for ‘‘NT69/D-amp’’ compared to ‘‘sal/D-amp;’’ and (C) P < 0.006 for ‘‘NT69/nic’’ or ‘‘sal/sal’’ compared to ‘‘sal/nic.’’
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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,b). On the other hand, we have had considerable success developing peptide analogs of the 8–13 fragment of neurotensin that bind to both NTR-1 and NTR-2 (Cusack et al., 1995, 1996, 2000a,b; Pang et al., 1996; Tyler et al., 1998, 1999a,b; Boules et al., 2000; TylerMcMahon et al., 2000a,b). From these studies, we have defined the binding site for NT(8–13) as the third outer loop of NTR-1. In addition, we have developed brain-penetrating analogs that bind with higher affinity to the human than to the rat NTR-1, largely as a result of the incorporation into these peptides of our novel amino acid, neo-Trp (Fig. 1) (Fauq et al., 1998). This amino acid is a regioisomer of tryptophan. Much of our animal studies has focused on NT69L, described above. This compound is presently in pre-clinical toxicology studies, so that we can test it in humans. However, in laboratory animals (rats and mice) after intraperitoneal injection, this peptide causes profound hypothermia, antinociception (Tyler-McMahon et al., 2000a,b), blockade of the catalepsy caused by haloperidol, blockade of the climbing behavior caused by high dose apomorphine (Cusack et al., 2000a,b), blockade of the locomotor hyperactivity caused by the psychostimulants cocaine (Fig. 2A), D-amphetamine (Fig. 2B) (Boules et al., 2001a,b), and nicotine (Fig. 2C), and blockade of the initiation and expression of sensitization to nicotine (Fredrickson et al., 2003). Additionally, in an animal model of Parkinson’s disease, namely, rats lesioned unilaterally in the nigrostriatal pathway by the neurotoxin 6-hydroxydopamine, NT69L blocks the rotation caused by both D-amphetamine and apomorphine (Boules et al., 2001a,b). There is a differential tolerance to the effects of NT69L after intraperitoneal injection. Specifically, tolerance developed after a single dose of NT69L to its effects on body temperature, nociception, and haloperidol-induced catalepsy. For all other effects of NT69L listed above, tolerance developed slowly, if at all. For example, after 5 daily injections of NT69L (1 mg/kg), it continued to block the effects of cocaine (40 mg/kg i.p.) in rats without evidence of tolerance. These results are to be contrasted with those of others (Hertel et al., 2002) who suggested that after twice daily injections of NT69L for 6 days, tolerance could develop to a very low dosage of NT69L (0.157 mg/kg) that was without acute effects on blocking the hyperactivity caused by Damphetamine.
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 agonist can block expression of the sensitized state, it is the neurotensin receptor agonist that should be used for treatment of psychostimulant abuse. In addition, although agonists of neurotransmitter receptors often induce tachyphylaxis, which is manifested as tolerance, such potential for tolerance does not preclude the clinical use of a drug.
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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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Neurotensin agonists: possible drugs for treatment of psychostimulant abuse Elliott Richelson *, Mona Boules, Paul Fredrickson Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
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. D 2003 Elsevier Science Inc. All rights reserved.
Introduction Neurotensin (NT) is an endogenous tridecapeptide discovered nearly three decades ago (Carraway and Leeman, 1973; Tyler-McMahon et al., 2000a,b). 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,b) 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).
* Corresponding author. Tel.: +1-904-953-2439; fax: +1-904-953-2482. E-mail address: [email protected] (E. Richelson). 0024-3205/03/$ - see front matter D 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0024-3205(03)00388-6
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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 binding assays is sensitive to the antihistamine levocabastine, has been molecularly cloned from mouse (Mazella et al., 1996), rat (Chalon et al., 1996), and human (Vita et al., 1997). Both NTR-1 and NTR-2 are 7transmembrane spanning, G-protein coupled receptors. The third neurotensin ‘‘receptor,’’ is presently a binding site, since no functional response is known to occur upon binding of NT. Therefore, strictly speaking, it is not a receptor. It is also a transmembrane protein, but spans the membrane only once and is identical to the protein called ‘‘sortilin’’ (Mazella et al., 1998). Activation of NTR-1 and NTR-2 results in an increase in intracellular inositol phosphates and Ca++. In brain, NTR-1 is much more highly localized than is NTR-2, which is more homogeneously distributed. All brain structures containing NTR-1 mRNA also contain NTR-2 mRNA, with only the substantia nigra having high levels of both messengers (Walker et al., 1998). On the other hand, while there are high levels of binding sites for NTR-1 in rat substantia nigra (Boudin et al., 1996), there are relatively low levels of binding sites for NTR-2 in this structure (Schotte et al., 1986; Kitabgi et al., 1987; Asselin et al., 2001). NTR-2 receptors in rat brain are thought to be predominantly associated with glial cells (Schotte et al., 1988). After binding to its receptor in brain, NT undergoes retrograde transport, culminating in the induction of the gene for tyrosine 3-hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines (Castel et al., 1989, 1990, 1992, 1993; Burgevin et al., 1992; Beaudet et al., 1994). Thus, within 4 h of injection of radiolabeled-NT into the striatum, cells in the substantia nigra are labeled and mRNA for tyrosine 3-hydroxylase is increased. This up-regulation of TH by NT has recently been shown to occur within hours in a human neuroblastoma cell line in culture (Najimi et al., 2001). Additionally, NT binding to its receptors may allosterically decrease the affinity of dopamine for its receptors (DiazCabiale et al., 2002). An advance in the study of neurotensin and its receptors came with the synthesis of a novel, nonpeptide neurotensin receptor antagonist, SR48692 (2-[1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxytphenyl) pyrazol-3-yl) carbonylamin]) (Gully et al., 1993). This compound has affinity for NTR-1 (Gully et al., 1993) and NTR-2 (Chalon et al., 1996). However, in vivo SR48692 does not block all the effects of neurotensin, suggesting that more subtypes of receptors exist for this peptide (Le et al., 1996). More, recently, another antagonist, SR142948A, with a broader spectrum of activity in vivo against NT was introduced (Gully et al., 1997). Interestingly, although in vivo the antagonists have no intrinsic activities (Gully et al., 1997) in vitro at NTR-2 these antagonists activate the receptor, while agonists at NTR-1 antagonize NTR-2 (Vita et al., 1998). Roles for the three molecularly-cloned NTRs in brain are far from being fully elucidated. However, it is very likely that in rats and in mice NTR-1 activation mediates antinociception, hypothermia, hypotension, and sedation (Tyler et al., 1999a,b; Pettibone et al., 2002). Although NTR-1 also likely mediates neurotensin’s effects on dopaminergic neurons (e.g., increased DA synthesis and release), studies to define the subtypes involved have not been done. Thus far, no definitive roles for either NTR2 or NTR-3 have been found.
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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 has potent analgesic effects not involving opioid receptors (Clineschmidt and McGuffin, 1977). In fact, neurotensin is more potent than morphine on a molar basis, when tested as an analgesic by injection into rodent brain (Nemeroff et al., 1979; Al-Rodhan et al., 1991). A role for neurotensin in neuropsychiatric disease has been hypothesized for over two decades (Nemeroff, 1980). More recently, in an autoradiographic study, there was a 40% reduction in neurotensin receptors in the entorhinal cortex of schizophrenics compared to controls (Wolf et al., 1995). These results were confirmed and extended (Lahti et al., 1998). In a large group of drug-free schizophrenics, those with the lowest CSF neurotensin concentrations had significantly higher levels of pretreatment psychopathology (Sharma et al., 1997). Improvements in overall psychopathology and, in particular, negative symptoms, correlated with increases in CSF neurotensin concentrations during treatment. It has long been know that neuroleptics elevate brain levels of neurotensin-immunoreactive (NT-IR) material (Govoni et al., 1980). However, those neuroleptics that are more likely to cause extrapyramidal side effects (typical neuroleptics) are more likely to induce expression of neurotensin in the extrapyramidal system, in addition to the limbic system (Merchant et al., 1992; Merchant and Dorsa, 1993). On the other hand, drugs that are less likely to cause these motor side effects (atypical neuroleptics), are more likely to induce expression of neurotensin only in the limbic system, the area thought to be the site of their therapeutic effects. These results have led researchers to suggest that both the therapeutic effects and the extrapyramidal side effects of neuroleptics are mediated through the release of neurotensin. Based on studies by our group (Cusack et al., 2000a,b), we think that at least in the extrapyramidal system, the increased synthesis and release of neurotensin is a compensatory mechanism caused by the blockade of dopamine receptors. More specifically, we have found that one of our brain-penetrating analogs of NT(8 – 13) {called ‘‘NT69L’’ or [N-methyl-Arg8,L-Lys9,L-neoTrp11,tert-Leu12]NT(8–13)} can prevent or block the catalepsy induced by haloperidol (Cusack et al., 2000a,b). Catalepsy or muscle rigidity in rodents is a measure of a drug’s propensity to cause extrapyramidal side effects (e.g, drug-induced parkinsonism) in patients (Munkvad et al., 1968). The NT(8–13) analog by itself does not cause catalepsy. Furthermore, in knock-out mice that lack NT, haloperidol still causes catalepsy (Dobner et al., 2001), indicating that NT does not mediate the cataleptic effects of DA receptor blockers.
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, 1980) and other drugs (McBride et al., 1999), including nicotine
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(DiChiara, 2000). NT has modulating effects on these neurons and many studies link neurotensin with the behavioral effects of CNS stimulants (Ervin et al., 1981; Robledo et al., 1993). Psychomotor stimulants up-regulate levels of NT-IR material (Cain et al., 1993; Gygi et al., 1994; Wagstaff et al., 1996) and levels of the neurotensin precursor mRNA in rat nucleus accumbens and striatum (Castel et al., 1994; Merchant et al., 1994; Betancur et al., 1997; Adams et al., 2001). These increases, which may be compensatory changes, appear to be mediated by dopamine receptors and NMDA receptors, since the effects in both regions can be completely blocked with a dopamine D2 receptor antagonist (Wagstaff et al., 1996) or an NMDA receptor antagonist (Hanson et al., 1995). Additionally, chronic cocaine treatment of rats modifies NT binding sites in brain (Pilotte et al., 1991). Some behavioral effects of NT injected into brain have similarities to those of psychomotor stimulants given outside the brain. Specifically, NT injected into the ventral tegmental area (VTA), the origins of the dopamine system associated with mediating the reinforcing actions of drugs (reward behavior), causes hyperactivity (Kalivas, 1994) and dopamine release in the nucleus accumbens (Kalivas and Duffy, 1990a,b). On the other hand, NT injection into the nucleus accumbens reduces the responses to psychostimulants (Ervin et al., 1981; Robledo et al., 1993). Also, NT has rewarding effects in rats (Glimcher et al., 1984), which will self-infuse this peptide into the VTA (Glimcher et al., 1987). However, the rewarding effects of brain self-stimulation in rats are suppressed by intracerebroventricular injection of NT (Bauco and Rompre, 2001). Neurotensin may play a role in the initiation of sensitization to psychostimulants (Horger et al., 1994; Rompre and Perron, 2000; Panayi et al., 2002). This sensitization is an enhanced locomotor response to the stimulant after repeated administrations of the drug. Behavioral sensitization to psychostimulants is a complex process thought to involve mesocorticolimbic dopamine neurons, with influences from glutamate, GABA, n-opioid and other neurotransmitter systems that produce long-term changes in neurotransmission (Pierce and Kalivas, 1997; Hahn et al., 2000). Additionally, this process, which is thought to play a role in the development of addiction to psychostimulants, is divided into initiation and expression. Initiation is the sequence of events leading to sensitization and expression is the enduring behavioral changes with sensitization. Both initiation of and expression of sensitization are thought to involve separate neurochemical processes that are temporally distinct (Pierce and Kalivas, 1997). The studies suggesting that endogenous neurotensin is involved in sensitization to psychostimulants involved the use of the NT receptor antagonist SR48692 and cocaine (Horger et al., 1994) or Damphetamine (Rompre and Perron, 2000; Panayi et al., 2002). Although there is one report that SR48692 (1 mg/kg) acutely blocks the vertical, but not the horizontal, activity induced by cocaine (15 mg/kg) (Betancur et al., 1998), in most studies this antagonist has no effects acutely on activity induced by either cocaine (Horger et al., 1994) or D-amphetamine (Rompre and Perron, 2000; Panayi et al., 2002). However, SR48692 has been shown either to delay the development of sensitization to cocaine (Horger et al., 1994) or to block the development of sensitization to D-amphetamine (Rompre and Perron, 2000; Panayi et al., 2002). On the other hand, we have shown that the neurotensin receptor agonist NT69L blocks the acute locomotor effects of cocaine (Fig. 2A) and D-amphetamine (Fig. 2B) (Boules et al., 2001a,b). In addition, NT69L blocked the acute locomotor effects of nicotine (Fig. 2C), as well as, both the initiation and expression of sensitization to this stimulant (Fredrickson et al., 2003). As with its effects on nicotine sensitization, NT69L will very likely block the initiation and expression of sensitization to other psychostimulants, such as cocaine and D-amphetamine. How then could both a neurotensin receptor agonist and a neurotensin receptor antagonist have the same effects on sensitization
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to psychostimulants? This is a question that requires further research. However, we can speculate and offer some hypotheses. It is clear that the effects of the neurotensin receptor antagonist require repeated treatments over days to have its effects on sensitization. It is also clear that relatively high dosages of the antagonist are required for the effect to occur. Thus, there is likely an adaptive process that must occur for the antagonist to block sensitization. Classically, chronic blockade of a receptor can lead to upregulation and supersensitivity of that receptor. For example, chronic blockade of dopamine D2 receptors by so-called typical neuroleptics, such as haloperidol, can cause the involuntary movement disorder called tardive dyskinesia. This motor side effect of neuroleptics is thought to be due to supersensitivity of dopamine receptors. Likewise, chronic blockade of neurotensin receptors would have the functional effect of making neurotensin a more efficacious agonist at its receptor. An alternative hypothesis is also based on classical pharmacology. Through a feedback mechanism as a result of chronic blockade of its receptors, there could be an increase in the synthesis and release of neurotensin. This is also seen with blockade of dopamine receptors. By this feedback mechanism, chronic blockade of neurotensin receptors can result again in an increased activation of neurotensin receptors. However, in the continued presence of an antagonist, such compensatory mechanisms would be masked, as is often the case with typical neuroleptics and dopamine receptor supersensitivity. In this case, upon withdrawal of the dopamine antagonist, the dyskinesias become clinically apparent. These hypotheses make particular sense, because the experimental paradigms in which the neurotensin antagonist blocked supersensitivity to psychostimulants or delayed its onset, required preexposure to the antagonist followed by a period of time, when the antagonist was withdrawn (Horger et al., 1994; Rompre and Perron, 2000; Panayi et al., 2002). Thus, for example, pre-exposure to the neurotensin receptor antagonist SR48692 followed by a 7-day drug-free period, but not co-treatment with this antagonist delays the development of cocaine sensitization (Horger et al., 1994). As with repeated injections of cocaine, repeated injections of neurotensin into the ventral tegmental area (VTA) augments the motor-stimulating effects of this peptide (Kalivas and Taylor, 1985). Thus, 1 Ag of neurotensin injected daily into the VTA causes an increase in activity that peaks after 4 daily injections. There is also an increase in dopamine release in the nucleus accumbens with repeated NT injections (Kalivas and Duffy, 1990a,b), as well as with repeated cocaine injections (Kalivas and Duffy, 1990a,b). On the other hand, we have found that the neurotensin receptor agonist, NT69L, given intraperitoneally at 1 mg/kg for 5 daily injections continued to block the hyperactivity caused by cocaine, while having no effects on basal locomotor activity (Boules et al., unpublished observations). Additionally, NT69L had some initial depressant effects on locomotor activity that diminished within 30
Fig. 1. Structure of neo-tryptophan in relation to tryptophan and tyrosine.
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min. Such results clearly indicate that globally activating brain receptors for neurotensin can produce results different from localized activation of neurotensin receptors in brain.
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
Fig. 2. Blockade by NT69L (1 mg/kg) of locomotor activity induced by (A) cocaine, (B) D-amphetamine, and (C) nicotine in rats. Male Sprague-Dawley rats weighing 200 – 250 g were housed in a temperature-controlled room with free access to food and water under artificial 12 h light/dark cycle. All tests were conducted during the light cycle. All procedures were approved by the Mayo Foundation Institutional Animal Use and Care Committee. Rats were placed in a Plexiglass Opto-Varimax Minor motility chamber (Columbus Instruments, Columbus, OH) for 1 h for acclimation. Baseline activity was recorded for 30 min for each rat. The rats were then injected with either NT69L (1 mg/kg) or an equivalent volume (100 Al) of saline and placed in the chamber for 30 min, after which the animals received an intraperitoneal (i.p.) injection of (A) cocaine (40 mg/kg i.p.), (B) Damphetamine (5 mg/kg i.p.), or (C) nicotine (0.35 mg/kg subcutaneously) or saline. Activity was then measured and reported as indicated in the figures. For statistical analyses, either one-way ANOVA (for A and B) or the Rank Sum Test (C) was used. ‘‘*’’ indicates level of significance as follows: (A) P < 0.003 for ‘‘NT69/cocaine’’ compared to ‘‘sal/cocaine;’’ (B) P < 0.008 for ‘‘NT69/D-amp’’ compared to ‘‘sal/D-amp;’’ and (C) P < 0.006 for ‘‘NT69/nic’’ or ‘‘sal/sal’’ compared to ‘‘sal/nic.’’
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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,b). On the other hand, we have had considerable success developing peptide analogs of the 8–13 fragment of neurotensin that bind to both NTR-1 and NTR-2 (Cusack et al., 1995, 1996, 2000a,b; Pang et al., 1996; Tyler et al., 1998, 1999a,b; Boules et al., 2000; TylerMcMahon et al., 2000a,b). From these studies, we have defined the binding site for NT(8–13) as the third outer loop of NTR-1. In addition, we have developed brain-penetrating analogs that bind with higher affinity to the human than to the rat NTR-1, largely as a result of the incorporation into these peptides of our novel amino acid, neo-Trp (Fig. 1) (Fauq et al., 1998). This amino acid is a regioisomer of tryptophan. Much of our animal studies has focused on NT69L, described above. This compound is presently in pre-clinical toxicology studies, so that we can test it in humans. However, in laboratory animals (rats and mice) after intraperitoneal injection, this peptide causes profound hypothermia, antinociception (Tyler-McMahon et al., 2000a,b), blockade of the catalepsy caused by haloperidol, blockade of the climbing behavior caused by high dose apomorphine (Cusack et al., 2000a,b), blockade of the locomotor hyperactivity caused by the psychostimulants cocaine (Fig. 2A), D-amphetamine (Fig. 2B) (Boules et al., 2001a,b), and nicotine (Fig. 2C), and blockade of the initiation and expression of sensitization to nicotine (Fredrickson et al., 2003). Additionally, in an animal model of Parkinson’s disease, namely, rats lesioned unilaterally in the nigrostriatal pathway by the neurotoxin 6-hydroxydopamine, NT69L blocks the rotation caused by both D-amphetamine and apomorphine (Boules et al., 2001a,b). There is a differential tolerance to the effects of NT69L after intraperitoneal injection. Specifically, tolerance developed after a single dose of NT69L to its effects on body temperature, nociception, and haloperidol-induced catalepsy. For all other effects of NT69L listed above, tolerance developed slowly, if at all. For example, after 5 daily injections of NT69L (1 mg/kg), it continued to block the effects of cocaine (40 mg/kg i.p.) in rats without evidence of tolerance. These results are to be contrasted with those of others (Hertel et al., 2002) who suggested that after twice daily injections of NT69L for 6 days, tolerance could develop to a very low dosage of NT69L (0.157 mg/kg) that was without acute effects on blocking the hyperactivity caused by Damphetamine.
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 agonist can block expression of the sensitized state, it is the neurotensin receptor agonist that should be used for treatment of psychostimulant abuse. In addition, although agonists of neurotransmitter receptors often induce tachyphylaxis, which is manifested as tolerance, such potential for tolerance does not preclude the clinical use of a drug.
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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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