Locomotor Stimulation and Mesocortical Dopamine Release Following Chronic Nicotine Treatment in the Rat

Chronic nicotine (NIC) pretreatment has been shown to enhance NICinduced locomotor stimulation, an effect that seems critically dependent on activation of brain dopamine (DA) systems. In the present study the effects of chronic, intermittent NIC treatment were examined in the rat to establish whether such behavioral sensitization is associated with specific, regional changes in brain dopaminergic activity. Male rats received daily injections in their home cage with either saline (SAL) or NIC (0.5 mgkg, s.c.) for 12 days. Twenty-four hours later, the locomotor activity of the animals subjected to NIC challenge as well as the functional responsiveness of the mesolimbocortical dopaminergic system were assessed. To this end, microdialysis experiments were performed in awake animals, measuring extracellular concentrations of DA and its metabolites in the prefrontal cortex (PFC) and the nucleus accumbens (NAC). Extracellular single cell recordings from DA neurons in the ventral tegmental area (VTA) were also performed in anesthetized animals. NIC (0.5 mgkg, s.c.) increased all measured parameters of locomotor activity, with the exception of rearing, in SAL-pretreated animals; these effects were substantially enhanced after pretreatment with NIC. Nicotine (0.5 mgkg, s.c.) increased DA release in both the PFC and the NAC in SAL-treated animals. Nicotine pretreatment significantly enhanced this effect in the PFC, whereas it did not affect the response in the NAC. Low doses of intravenously administered NIC dose-dependently increased burst activity, starting at 12 pgkg in the SAL pretreated animals and at 6 pgkg in the NIC-pretreated animals, and also dose-dependently increased firing rate in SAL as well as NIC-pretreated animals, although starting at a higher dose level, i.e., 25 pgkg. These results demonstrate that behavioral sensitization after chronic NIC treatment is accompanied by an enhanced dopamine release specifically within the PFC. This phenomenon may be highly significant for the dependence-producing effects of NIC, particularly in association with major psychiatric disorder, such as schizophrenia. o 1996 Wiley-Liss, Inc. INTRODUCTION lism of DA is increased mainly in mesolimbic, as compared to nigrostriatal, DA neurons after systemic NIC administration (Andersson et al., 1981; Grenhoff and Several lines of experimental evidence indicate that stimulation of brain dopamine (DA) systems is of major Svensson, 1988). Furthermore, NIC administration has significance for the reinforcing and dependence producbeen shown to increase neuronal DA release in vitro ing properties of nicotine W C ; see Clarke, 1990; Corri(Giorguieff-Chesselet et 1979; ~~~i~~ et 1988; gall, 1991; Grenhoff and Svensson, 1989; ~vensson et Rowell et d., 1987), as well as in vivo, utilizing microdial., 1990). Accordingly, nicotinic receptors seem to be located both on cell bodies and terminals of mesolimbic and nigrostriatal DA neurons (Clarke and Pert, 1985; Schwartz et al., 1984) and synthesis, as well as metaboReceived April 28, 1995; accepted in revised form August 7, 1995