ArticlesSensitization of the Mesoaccumbens Dopamine Response to Nicotine
Section snippets
The role of central nicotinic receptors
Nicotine exerts its effects in the brain by stimulating neuronal nicotinic receptors [55]. The mesoaccumbens DA responses to nicotine are mediated by these receptors because both the acute and sensitized responses to the drug are attenuated by systemic injections of the nicotinic antagonist, mecamylamine, which crosses the blood–brain barrier, but not by the quaternary antagonist, hexamethonium, which penetrates less readily into the brain 11, 30. This conclusion is supported by results that
Regional specificity of the response to nicotine
Electrophysiological studies suggest that the DA neurons that innervate the nucleus accumbens are more sensitive to nicotine that those that innervate the caudate/putamen [35]. Dialysis studies also suggest that nicotine exerts a greater effect on DA overflow in the accumbens than the caudate/putamen [30], and that the projections to the accumbens respond to lower doses of nicotine than those that are required to stimulate the neurons that innervate the caudate/putamen [10]. The expression of
The mechanisms underlying the development of sensitized mesoaccumbens dopamine responses to nicotine
The studies outlined in the sections above imply that systemic nicotine exerts its effects on mesoaccumbens DA neurons by stimulating nicotinic receptors located on the somatodendritic membranes of the cells. Therefore, to test the hypothesis that pretreatment with the drug caused sensitization of the responses mediated by these receptors, the effects of intra-VTA injections of nicotine on DA overflow in the nucleus accumbens were examined. The results of these experiments showed that
Studies with nomifensine
Much of the DA released from nerve terminals in the brain is thought to be cleared from the synaptic cleft by rapid reuptake into the nerve terminal cytoplasm by transporters located within the terminal membrane. The probes used to investigate the effects of drugs on neurotransmitter release are located in the interstitial space between cells. Thus, they do not measure neurotransmitter release directly into the synaptic cleft but overflow into the extracellular space sampled by the probe. A
Electrophysiological correlates of sensitization
The data clearly suggest that the expression of sensitized mesoaccumbens DA responses to nicotine involve the co-stimulation of NMDA receptors. Glutamate-secreting pathways are thought to innervate both the nucleus accumbens and the VTA, and it is possible, therefore, that increased glutamate secretion could influence DA release at the level of the nerve terminals or the electrophysiological responses to nicotine elicited by its effects on DA-secreting cells in the VTA. This issue remains to be
Putative psychopharmacological significance of sensitized dopamine responses to nicotine
Clarke and colleagues [19]have reported that the locomotor stimulant properties of nicotine are abolished if the mesoaccumbens DA system is lesioned by injecting 6-hydroxydopamine bilaterally into the nucleus accumbens. These and other observations led Clarke [16]to suggest that the locomotor stimulant properties of the drug are mediated by its stimulatory effects on the DA projections to the accumbens. This conclusion is consistent with the results of subsequent studies that have both
Acknowledgements
The studies in the author’s laboratory were supported by project grants from the VERUM Foundation and the Wellcome Trust. M. A.-A. was supported by a studentship from the British Pharmacological Society. The raclopride uesed in the studies was a generous gift from Astra Pharmaceuticals Ltd.
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