1. Introduction
Cigarette smoking has been conceptualized as a gateway to use and abuse of illicit drugs such as cocaine [
1]. Whether this is causal or represents availability and cultural attitudes is as yet unproven [
2]. However, animal models provide growing evidence for a “priming effect” of nicotine on reward circuitry. This priming effect may increase the risk for cocaine abuse and dependence [
3,
4].
Animal models of psychostimulant abuse include behavioral sensitization, conditioned place preference, drug discrimination, and self-administration [
5]. Nicotine pretreatment enhances cocaine self-administration in adolescent [
6,
7,
8] and in adult [
9] rats. Nicotine also increases cocaine’s discriminative stimulus and reinforcing effects in rhesus monkeys [
10]. In another recent study [
4], locomotor sensitization was increased by 98%, conditioned place preference by 78%, and cocaine-induced reduction in long-term potentiation was increased by 24% when nicotine was given prior to, and then concurrent with cocaine. Reversing the order of drug administration had no effect. Therefore, nicotine primed the response to cocaine, but cocaine did not have a similar effect on nicotine-induced behaviors or synaptic plasticity.
These animal studies suggest, although do not prove, that tobacco users are at increased risk for cocaine dependence, and that continued use of nicotine may be a negative prognostic factor for abstinence from cocaine. Furthermore, these studies point toward a need for therapies that target both nicotine and cocaine dependence. For the past decade, our laboratory has studied the effects of neurotensin (NT) analogs on neuropsychiatric diseases including psychostimulant abuse. One of our analogs, NT69L, an analog of NT(8-13), blocks the initiation and expression of nicotine-induced locomotor sensitization [
11], and attenuates nicotine self-administration in rats [
12].
NT is a neuropeptide that is closely associated with, and modulates DA [
13], ACh, glutamate, and GABA neurotransmission involved in addiction and reward pathways. Local administration of NT in the prefrontal cortex (PFC) increases extracellular levels of ACh and GABA [
14]. In support of these data are results with the NT agonist NT69L [
15] which was developed in our laboratory. NT has also been reported to enhance GABAergic activity in rat hippocampus [
16] and to reduce glutamatergic neurotransmission in dorsolateral striatum [
17]. However, NT must be administered centrally to have an effect because it is easily degraded by peptidases. Our laboratory has developed a number of NT agonists that can be administered systemically and maintain the central effects of NT. The most studied of these agonists is NT69L which binds with equal affinity to the two well characterized NT receptors (NTS1 and NTS2).
Our work with the NT agonist NT69L shows that it blocks nicotine-induced sensitization [
11,
18] and nicotine self-administration [
12]. While the role of NT is strongly implicated in nicotine addiction, its role in cocaine addiction is controversial. Administration of cocaine increases NT immunoreactivity in the dorsal striatum, substantia nigra and globus pallidus [
19], increases NT mRNA in the rostral striatum [
20] and increases NT gene expression in the ventrolateral striatum [
21]. The use of NT gene knockout mice showed that NT is not involved in cocaine mediated behavior except under certain conditions where the absence of endogenous NT causes a slight prolongation of the effects of cocaine [
22]. The use of either NT agonists or antagonists to treat cocaine locomotor activity and locomotor sensitization gave mixed results. Administration of the NT antagonist SR48692 did not alter cocaine-induced locomotor activity [
23,
24] except when administered chronically and in high doses [
24]. Others reported partial reversal of the expression of locomotor sensitization with SR48692 [
25] or a delay in the development of cocaine sensitization when the SR compound is given prior to but not in conjunction with cocaine [
26]. There is also mixed data with the use of NT agonists. Systemic administration of the nonselective NT agonist NT69L [
27] or central administration of NT [
24] attenuate cocaine-induced locomotor activity. However, central administration of NT(8-13) did not alter cocaine-induced locomotor activity or cocaine sensitization [
28]. Biochemically, NT [
24] and NT69L [
29] interact with dopamine, the neurotransmitter that promotes the motivational process for both nicotine and cocaine.
The primary goal of the present study was to examine the effect of the neurotensin receptor agonist, NT69L, on nicotine-induced potentiation of cocaine locomotor sensitization.
4. Discussion
Locomotor sensitization is a robust and readily assayed effect of psychostimulants. It measures the animal’s gradually increasing behavioral and motivational response to a fixed drug dose, assayed as an increase in locomotor activity [
4] (for review, Robinson and Berridge, [
31]). Locomotor sensitization has been shown in rodents to be associated with augmented drug reward and increased vulnerability to relapse [
31].
Locomotor sensitization is separated into two components: induction and expression. Induction of sensitization is the progressive increase in locomotor activity during drug treatment, while the expression of sensitization is demonstrated following challenge with cocaine after a drug-free period [
32]. Our results show that the rats developed locomotor sensitization after repeated injections of nicotine, as we previously showed [
11]. Additionally, and similar to previous studies [
7,
8,
33,
34], both induction and expression of locomotor sensitization were observed in the present study after four daily injections of cocaine and cocaine challenge. Our group has reported that NT69L blocks the initiation and expression of nicotine sensitization [
11], as well as nicotine self-administration [
12].
In the present study NT69L attenuated the expression of cocaine sensitization. Sub-chronic injection of nicotine enhanced cocaine-induced sensitization, results that are consistent with the “gateway” effect of nicotine on cocaine abuse [
4]. Prior studies showed cross-sensitization of nicotine and cocaine-induced locomotion [
35,
36]. In a study of adolescent rats designed to model smoking behaviors of human adolescents, injections of low dose nicotine (0.06 mg/kg) did not produce behavioral sensitization. However, low dose nicotine did enable locomotor sensitization to cocaine that was not seen in control animals [
8]. The difference in the results between our study and that of the McQuown group might be due to: (1) difference in the rat species used; (2) age difference in animals (adolescent
versus adults); (3) dose and route of administration of nicotine; and (4) dose and route of administration of cocaine. The effect of NT69L on cocaine sensitization in the nicotine treated group indicates its possible therapeutic effect even with the enhanced locomotor sensitization induced by nicotine.
Cocaine dependence results from drug-induced neural adaptations in mesocorticolimbic dopamine pathways and associated glutamatergic circuitry [
37]. Induction of sensitization requires activation of dopaminergic and glutamatergic neurotransmission in the ventral tegmental area [
38,
39] and glutamatergic input from the prefrontal cortex [
40,
41]. Expression of sensitization is primarily attributed to neurochemical changes in the nucleus accumbens [
42] leading to cocaine-induced increase in dopamine and glutamate release in the nucleus accumbens [
34,
43,
44].
Our previous studies [
29] show that pretreatment with NT69L attenuates the acute nicotine evoked increases in dopamine in the nucleus accumbens shell and reverses the increase in dopamine levels in the nucleus accumbens core. NT69L also modulates tyrosine hydroxylase, dopamine D1 and D2 receptor mRNA levels in the striatum, prefrontal cortex, and ventral tegmental area in rats that self-infused nicotine [
12]. In addition to modulating dopaminergic neurotransmission, NT69L modulates the glutamatergic neurotransmission that is involved in the addiction of cocaine and other drugs such as alcohol ([
45]; Boules
et al., unpublished data).
NT69L’s attenuation of some of the biochemical effects of acute and chronic nicotine is consistent with this peptide's attenuation of nicotine-induced behavioral effects. Findings by Levine
et al. [
4] suggest that nicotine replacement therapy given to cocaine addicts for smoking cessation may undermine efforts to treat cocaine addiction. Novel therapies, such as neurotensin analogs, therefore, warrant additional study.