Research reportNicotine-induced behavioral sensitization is associated with extracellular dopamine release and expression of c-Fos in the striatum and nucleus accumbens of the rat
Introduction
Evidence suggests that nicotine, an alkaloid agonist of nicotinic acetylcholine receptors (nAChRs), has neurochemical as well as behavioral properties common to other psychostimulants such as cocaine and amphetamine [6], [40]. Repeated injections of the psychostimulants, including nicotine, can produce behavioral sensitization, as evidenced by an enhanced locomotor response to a subsequent injection of the drug [10], [23], [42]. Since behavioral sensitization has been implicated in the development of drug addiction [42], [43], and in drug-induced psychosis [41], [42], [46], there has been a great deal of interest in elucidating the neural mechanisms underlying behavioral sensitization.
Considerable evidence suggests that the behavioral and reinforcing effects of nicotine may be mediated by central dopaminergic systems, especially the mesolimbic system from the ventral tegmental area (VTA) to the nucleus accumbens [18]. It has been shown that nicotine can act on nAChRs localized both on dopaminergic cell bodies in the VTA and on their nerve terminals in the nucleus accumbens [5], [11], [14], [28], [31]. Nicotine increases dopamine (DA) release in the nucleus accumbens [4], [21], [29], [33], and systemic injections of nicotine increase the firing rate of dopaminergic neurons [32]. Lesions of the mesolimbic dopaminergic system abolish both locomotor activation and the reinforcing effects of nicotine [9], [12]. These findings suggest that the activation of DA transmission in the mesolimbic systems plays a critical role in the stimulant and reinforcing effects of nicotine.
Many studies have also focused on the role of the mesolimbic system as a mediator of the behavioral sensitization produced by chronic injections of psychostimulants, and it has been demonstrated that the development of psychostimulant-induced behavioral sensitization might be associated with alterations of neurotransmission in the mesolimbic DA pathways [20], [24], [54]. However, the experimental results obtained from the mesolimbic DA systems as to the mediator of the long-term behavioral effects of nicotine have not been consistent. Whereas several studies showed that repeated injections of nicotine that produced behavioral sensitization resulted in an increase of extracellular DA release in the nucleus accumbens [3], [50], others reported that no significant changes were observed after chronic nicotine administration [13], [34].
Several studies have also demonstrated that sensitization to the locomotor-stimulating effects of psychostimulants may be mediated through an action on the nigrostriatal dopaminergic system, which projects from the substantia nigra to the striatum, one of the interconnected nuclei implicated in the expression of behavioral sensitization ([39], for a review). Relatively little, however, is known about the role of the nigrostriatal DA system in the long-term behavioral effects produced by repeated injections of nicotine.
Recently, it has been shown that many neurons respond to excitation of a sufficient magnitude and duration by expressing the proto-oncogene c-fos [16], [19], [44], and immunocytochemical detection of the Fos protein has been used to map the neural circuitry affected by a variety of behavioral and pharmacological treatments [16], [19], [48], [55]. Several studies have demonstrated that injections of nicotine produced the expression of c-Fos in dopaminergic target areas such as nucleus accumbens, striatum, and prefrontal cortex [26], [30], [36]. Since many studies suggest that alterations in the DA terminal areas may be critical in the long-term effects of nicotine [29], it is likely that the behavioral sensitization to nicotine may reflect alterations in extracellular DA release or postsynaptic gene expression.
In order to investigate the relation of nicotine-induced behavioral sensitization with alterations of DA transmission in the mesolimbic and the nigrostriatal systems, we examined and measured extracellular DA release after local injections of nicotine directly into the striatum or the nucleus accumbens was animals given repeated nicotine treatments using an in vivo microdialysis technique. Furthermore, the functioning of the striatum and nucleus accumbens were examined using c-Fos immunocytochemistry in order to investigate the effect of repeated injections of nicotine on the postsynaptic neural activity associated with nicotine-induced behavioral sensitization. Parts of this study have been presented in abstract form [47].
Section snippets
Subjects
Subjects were 81 male Sprague–Dawley rats, weighing 280–320 g at the start of the experiment. Rats were kept on a 12-h light, 12-h dark cycle in individual home cages with food and water available ad libitum.
Measurements of locomotor activity
Locomotor activity was measured in a round infrared photocell cage measuring 40 cm diameter with 45 cm high walls. Four infrared beams were positioned 3.5 cm above the floor in order to detect horizontal movements. The walls and floor were made of clear Plexiglas and were painted black.
Histological analysis
Examination of stained sections revealed that all dialysis probes were located within the nucleus accumbens and the striatum at the level of the anterior commissure within the rostro-caudal coordinate approximately +1.20 mm [38], as shown in Fig. 4C, similar to those illustrated in a previous publication [27].
Locomotor activity
When animals given repeated nicotine treatments were challenged with systemic nicotine 3 days later, behavioral responses were significantly increased, compared with those of control or
Discussion
The results of the present study demonstrate that repeated daily injections of nicotine markedly increased the locomotor response to a subsequent systemic challenge with nicotine. The present results also clearly demonstrate that local infusion of nicotine into the nucleus accumbens or the striatum resulted in a dose-dependent increase of dopamine output, which was potentiated in animals given repeated nicotine treatments. Furthermore, it was shown that repeated nicotine pretreatment using an
Acknowledgements
The authors would like to thank SungJae Oh and SunHye Choi for their excellent technical support, and Nijole Grazulis for her valuable comments on the manuscript. These studies were supported in part by grants from the Ministry of Health and Welfare (HNP-99-O-01-0005) and Korea Research Foundation (KRF-99-041-F-00205 and BK21 project), Korea.
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