File(s) not publicly available
Nicotinic effects on midbrain dopamine neurons : a dual mechanism of action
The neurons of the mesocorticolimbic dopamine system are located in the ventral tegmental area (VTA) in the mesencephalon and send their projections to forebrain structures, such as the prefrontal cortex, the amygdala and the nucleus accumbens. The dopamine system is important in regulating mood and motivation as well as cognitive function and appear to be primarily involved in drug dependence, since most drugs abused by man stimulate this system. Nicotine stimulates dopamine neurons both by increasing their single spike activity and burst activity. Burst activity is characterized by action potentials fired rapidly in short episodes with longer intervals in between and is particularly effective in releasing dopamine in the terminal areas and increasing the postsynatic activation of the protoonco gene c-fos. Nicotine-induced dopamine release in the nucleus accumbens seems to be more or less exclusively dependent on the neuronal activation elicited via stimulation of nicotinic acetylcholine receptors (nAChRs) in the VTA. Burst firing of dopamine neurons is controlled by excitatory amino acids (EAAs) acting at NMDA receptors in the VTA. In many parts of brain, nicotine, instead of exciting neurons directly, as first thought, has been shown to act preferentially indirectly, i.e. by facilitating the release of EAAs. Recent evidence also suggests that nAChRs of the [alpha]7* subtype may be involved in presynaptic facilitation of EAA release. Therefore, the specific aim of the present project has been to analyze the role of EAAs in the stimulatory effects of nicotine on the mesocorticolimbic dopamine system and, in particular, the role of [alpha]7* nAChRs in this regard.
Using microdialysis we found that the effect of nicotine (0.5 mg/kg s.c. free base) on dopamine release in the nucleus accumbens was attenuated by concomitant infusion in the VTA of the NMDA receptor antagonist AP-5, but not the AMPA/kainate receptor antagonist CNQX Nicotine also increased the levels of EAAs in the VTA an effect that was prevented by concomitant infusion of the 0 selective nAChR antagonist methyllycaconitine (MLA). Local infusion of MLA in the VTA also blocked nicotine-induced dopamine release in the nucleus accumbens. These data indicate that nicotine may act presynaptically at [alpha]7* nAChRs to stimulate the release of EAAs. Presynaptic [alpha]7* nAChRs may reside on [alpha]7* originating in the prefrontal cortex, since they provide an important source of glutamatergic [alpha]7* for dopamine neurons in the VTA. Therefore, excitotoxic lesions were made in the prefrontal cortex and autoradiography binding with nAChR ligands was performed on sections of the VTA. [alpha]-bungarotoxin binding, which represents binding to 0 nAChRs, was reduced by 30% in lesioned animals compared to controls, providing anatomical support for our notion. The postsynaptic consequences in the nucleus accumbens and medial prefrontal cortex of the corresponding pharmacological manipulations within the VTA was measured with Fos-immunohistochemistry. Nicotine increased Fos-expression in the nucleus accumbens and the medial prefrontal cortex. nAChR and NMDA receptor blockade in the VTA by mecamylamine or AP-5 prevented the effect of systemic nicotine on Fosexpression in the nucleus accumbens but not in the medial prefrontal cortex. MLA (6.0 mg/kg i.p.) antagonized the effect of nicotine on Fos expression both in the nucleus accumbens and the prefrontal cortex. MLA also inhibited nicotine-induced burst firing in dopamine neurons without affecting nicotine's effect on firing rate. In contrast the [alpha]4[beta]2 selective antagonist dihydro-[beta]-erythroidine [DH[beta]E, 1.0 mg/kg s.c.) prevented nicotine's effect on firing rate but did nor antagonize the nicotine-induced increase in burst firing. Accordingly, DH[beta]E did not affect the nicotine-induced Fos-expression in the nucleus accumbens and the prefrontal cortex. Also, we found that a 0 agonist (AR-R-17779) increased burst firing in dopamine neurons without affecting single spike activity, whereas an [alpha]4[beta]2 agonist (A-85380) increased single spike firing without affecting burst activity. These data suggest that [alpha]7* nAChRs are primarily involved in the burst firing enhancing effects of nicotine, whereas [alpha]4[beta]2 nAChRs appear to be primarily responsible for the nicotine-induced increase in single spike firing.
Consequently, nicotine may activate dopamine neurons by two separate but convergent mechanisms. These mechanisms are both likely to contribute to different aspects of nicotine dependence. Selective ligands for nAChRs subtypes may be less dependence producing and might, therefore be used therapeutically since nicotine exerts several potentially beneficial effects on a number of CNS functions.
List of scientific papers
I. Schilström B, Nomikos GG, Nisell M, Hertel P, Svensson TH (1998). "N-methyl-D-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens" Neuroscience 82(3): 781-789
https://pubmed.ncbi.nlm.nih.gov/98144529
II. Schilström B, Svensson HM, Svensson TH, Nomikos GG (1998). "Nicotine and food induced dopamine release in the nucleus accumbens of the rat: putative role of alpha7 nicotinic receptors in the ventral tegmental area" Neuroscience 85(4): 1005-1009
https://pubmed.ncbi.nlm.nih.gov/98345266
III. Schilström B, De Villiers S, Malmerfelt A, Svensson TH, Nomikos GG (2000). "Nicotine-induced Fos expression in the nucleus accumbens and the medial prefrontal cortex of the rat: role of nicotinic and NMDA receptors in the ventral tegmental area." Synapse 36(4): 314-321
https://pubmed.ncbi.nlm.nih.gov/20280167
IV. Schilström B, Fagerquist MV, Zhang X, Hertel P, Panagis G, Nomikos GG, Svensson TH (2000). "Putative role of presynaptic alpha7 nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area" Synapse (In Print)
V. Schilström B, Rawal N, Mameli-Engvall M, Nomikos GG, Svensson TH (2000). "Dual effects of nicotine on dopamine neurons mediated by different nicotinic receptor subtypes" (Manuscript)
History
Defence date
2000-09-29Department
- Department of Physiology and Pharmacology
Publication year
2000Thesis type
- Doctoral thesis
ISBN-10
91-628-4309-5Number of supporting papers
5Language
- eng