Topiramate selectively attenuates nicotine‐induced increases in monoamine release

It is widely held that the reinforcing and dependence-producing properties of nicotine rely on activation of the mesocorticolimbic dopamine (DA) system. This notion is primarily derived from demonstrations that lesions of ventral tegmental area (VTA) DA neurons projecting to the nucleus accumbens (NAcc) can reduce both locomotor activation and the reinforcing effects of nicotine (Clarke et al., 1988; Corrigall et al., 1992). However, it appears that pharmacologically targeting isolated DA receptors is not sufficient to reduce symptoms associated with nicotine dependence (Di Chiara, 2000; Kameda et al., 2000). Recent studies suggest that N-methyl-D-aspartate (NMDA) glutamate receptor activation within the VTA may be required for nicotine to stimulate DA release in the NAcc (LeikolaPelho and Jackson, 1992; Nisell et al., 1994; Shim et al., 2001), consistent with demonstrations that microinfusion of ionotropic glutamate receptor antagonists reduces nicotine-induced increases in neurochemical and locomotor activity (Schilstrom et al., 1998; Svensson et al., 1998). It has been proposed that this effect is mimicked by noradrenergic neurons, such that nicotine-induced increases in norepinephrine (NE) activity, associated with its cognition-enhancing effects, is mediated by glutamatergic transmission (Chen and Engberg, 1989; Erhardt et al., 2000). Alternatively, it has been proposed that augmented NAcc DA activity is the result of a disinhibited system, where increasing the activity of GABAergic interneurons modulates rewardrelated neurochemical and behavioral changes induced by nicotine (Corrigall et al., 2000; Dewey et al., 1999; Kawahara et al., 1999). Consistent with this, studies in our laboratory (Dewey et al., 1999; Schiffer et al., 2000) and others (Bevins et al., 2001) have demonstrated that pretreatment with g-vinyl GABA (GVG), which blocks GABA degredation, modulates nicotine-induced increases in DA and craving for nicotine in animal models. It follows that if both decreasing excitatory activity with glutamatergic antagonists and increasing inhibitory activity with GABA agonists can reduce nicotineinduced increases in DA, a drug which possesses both mechanisms might also suppress nicotine-induced increases in neurotransmitter activity. Topiramate (Topomaxt) was developed as an anticonvulsant and is well tolerated in humans, with some evidence of relieving symptoms associated with bipolar disorder and obesity (Gordon and Price, 1999; Teter et al., 2000). Topiramate reduces EAA activity by antagonizing ionotropic alpha-amino-3-hydroxy-5-metyloisoxazolo-4-propionate (AMPA)/kainate glutamate receptors (Gibbs et al., 2000; Skradski and White, 2000). Further, considerable evidence indicates topiramate increases brain GABA levels (Petroff et al., 1999, 2001; White et al., 1997), possibly by activating a novel site on the GABAA receptor complex (Czuczwar and Patsalos, 2001). In the present study, we used in vivo microdialysis to explore the effects of acute pretreatment with topiramate (25 mg/kg or 50 mg/kg) on increases in mesolimbic extracellular DA, NE, and serotonin (5-HT) activity following a subcutaneous dose of nicotine (0.4 mg/kg). Further, we present the effects of topiramate (75 mg/kg) on nicotine-induced DA release in animals pretreated with nicotine for 14 days. Details of microdialysis methods can be found in Dewey et al. (1999). Briefly, 2 days prior to the microdialysis experiments, siliconized guide cannulae were implanted targeting the NAcc ( A 5 1 1.5 mm, L 5 2 1.0 mm, V 5 2 5.6 mm). Pretreated animals received their last dose of nicotine on the day before the surgery, 2 days prior to the microdialysis study. Dialysate samples were assayed for monoamine content by