Effects of nicotine on mesolimbocortical dopaminergic neurotransmission : a pharmacological study in the rat

Sammanfattning: Tobacco-smoking represents a form of drug addiction to nicotine (NlC) and the reinforcing and dependence-producing properties of NIC depend largely on central dopamine (DA) neurons, located in the ventral tegmental area (VTA) and projecting mainly to the nucleus accumbens (NAc; mesolimbic DA system) and the medial prefrontal cortex (PFC; mesocortical DA system). Generally, the mesolimbic DA system plays a pivotal role in the reinforcing effects of natural rewards as well as of drugs of abuse. Thus, in the present study the mode of action of NIC on these two central DA systems was further explored in the rat. Microdialysis of extracellular DA was carried out in freely moving animals. Dopamine output was also monitored with differential normal pulse voltammetry (DNPV) in anesthetized animals. Neuronal activity of VTA DA cells was registered by means of single cell recordings in vivo. Moreover, measurements of locomotor activity in an open field were performed as well as assessments of expression of immediate early genes, e.g. c-fos, in several brain regions by means of immunohistochemical detection of their protein products, i.e. Fos-like immunoreactivity (FLI). By means of local infusions of the nicotinic receptor (nAChR) antagonist mecamylamine (MEC), systemic nicotine-induced DA release in the NAc was found to be mainly executed within the VTA. Systemic NIC also increased DA release in the PFC and this effect was enhanced during subchronic NIC treatment, whereas NIC-induced accumbal DA release was unaltered by the same treatment. In addition, a selective DA D,-mediated increase in FLI was observed both in the PFC and in the shell region of the NAc, a subdivision of the NAc intimately coupled to the PFC, during chronic NIC administration. By means of DNPV, NIC was found to preferentially stimulate DA release in the shell of the NAc, both in acute and chronic experiments. Moreover, behavioral sensitization to NIC-induced locomotor stimulation was observed in chronic experiments both with systemic and intra-VTA application of NIC. The latter treatment also increased FLI in the NAc. In addition, systemic NIC preferentially increased VTA DA neuronal burst activity, i.e. an effect similar to the physiological reward response of these cells, starting at a lower dose in NIC-pretreated than in drug-naive animals. The effects of systemic NIC on mesolimbic DA neurotransmission, including neurochemical alterations in postsynaptic regions, as well as on DA-related behavior, seem thus to be essentially mediated via stimulation of nAChRs located within the VTA. The observed pattern of response of central DA systems to chronic NIC administration appears rather unique among dependence-producing drugs, and its subjective benefits may accordingly be related to augmented DA activity in the PFC, and include, for example, focused attention and cognitive enhancement, at least under certain conditions. A preferential facilitation of prefrontal DA output seems to be a common denominator for several atypical antipsychotic drugs which, similarly to chronic NIC, have been shown to augment burst firing in VTA DA neurons as well as DA release and c-fos expression preferentially in the shell of the NAc and in the PFC. The data underline the notion, that the extremely high prevalence of cigarette smoking in schizophrenia may indeed represent a form of attempted self-medication.