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

Abstract: Tobacco-smoking represents a form of drug addiction to nicotine (NlC) and thereinforcing and dependence-producing properties of NIC depend largely on centraldopamine (DA) neurons, located in the ventral tegmental area (VTA) and projectingmainly to the nucleus accumbens (NAc; mesolimbic DA system) and the medial prefrontalcortex (PFC; mesocortical DA system). Generally, the mesolimbic DA system plays apivotal role in the reinforcing effects of natural rewards as well as of drugs ofabuse. Thus, in the present study the mode of action of NIC on these two centralDA systems was further explored in the rat. Microdialysis of extracellular DA was carried out in freely moving animals. Dopamineoutput was also monitored with differential normal pulse voltammetry (DNPV) in anesthetizedanimals. Neuronal activity of VTA DA cells was registered by means of single cellrecordings in vivo. Moreover, measurements of locomotor activity in an open fieldwere 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 theirprotein 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 executedwithin the VTA. Systemic NIC also increased DA release in the PFC and this effectwas enhanced during subchronic NIC treatment, whereas NIC-induced accumbal DA releasewas unaltered by the same treatment. In addition, a selective DA D,-mediated increasein FLI was observed both in the PFC and in the shell region of the NAc, a subdivisionof the NAc intimately coupled to the PFC, during chronic NIC administration. By meansof DNPV, NIC was found to preferentially stimulate DA release in the shell of theNAc, both in acute and chronic experiments. Moreover, behavioral sensitization toNIC-induced locomotor stimulation was observed in chronic experiments both with systemicand intra-VTA application of NIC. The latter treatment also increased FLI in theNAc. In addition, systemic NIC preferentially increased VTA DA neuronal burst activity,i.e. an effect similar to the physiological reward response of these cells, startingat a lower dose in NIC-pretreated than in drug-naive animals. The effects of systemic NIC on mesolimbic DA neurotransmission, including neurochemicalalterations in postsynaptic regions, as well as on DA-related behavior, seem thusto be essentially mediated via stimulation of nAChRs located within the VTA. Theobserved pattern of response of central DA systems to chronic NIC administrationappears rather unique among dependence-producing drugs, and its subjective benefitsmay accordingly be related to augmented DA activity in the PFC, and include, forexample, focused attention and cognitive enhancement, at least under certain conditions.A preferential facilitation of prefrontal DA output seems to be a common denominatorfor several atypical antipsychotic drugs which, similarly to chronic NIC, have beenshown to augment burst firing in VTA DA neurons as well as DA release and c-fos expressionpreferentially 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 indeedrepresent a forrn of attempted self-medication. Key words: nicotine, dopamine, ventral tegmental area, accumbens, prefrontal cortex,c-fos, drug-dependence, sensitization, mecamylamine, D, receptors, SCH 23390 ISBN 91-628-2825-8 1998 Magnus Nisell