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Sensitization of the Mesoaccumbens Dopamine Response to Nicotine

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Abstract

This article reviews the evidence that pretreatment with nicotine causes a regionally selective sensitization of its stimulatory effects on a pathway, the mesoaccumbens dopamine (DA) system, which has been implicated in the locomotor stimulant response to nicotine and its ability to reinforce self-administration. The sensitization evoked by daily injections of nicotine is associated with a regionally selective downregulation of the control of mesoaccumbens DA neurons by inhibitory autoreceptors and depends upon co-stimulation of NMDA glutamatergic receptors. It is suggested that the sensitization is related to enhanced burst firing of mesoaccumbens neurons, which results in an enhancement of DA release into the extracellular space between the cells where it acts upon putative extrasynaptic dopamine receptors. The studies with NMDA receptor antagonists revealed a dissociation between the expression of sensitized mesoaccumbens DA and locomotor responses to nicotine. It is proposed, therefore, that the sensitized mesoaccumbens DA responses to nicotine may be implicated in psychopharmacological responses to drug concerned more closely with nicotine dependence.

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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      Similar to other drugs of abuse, nicotine activates the mesolimbic pathway by increasing cell firing of dopaminergic neurons in the VTA via nicotinic receptors (McGehee et al., 1995). Nicotine microinfusions into the VTA which resulted in sensitization of dopamine release (Balfour et al., 1998), also reduced NFL (by 34%, p < 0.05), NFM (by 42%, p < 0.01), and NFH levels (by 38%, p < 0.05) in the VTA but not in the substantia nigra in rats (Bunnemann et al., 2000; Sbarbati et al., 2002) without altering neuron numbers. The similar reductions of NF proteins in the VTA by the chronic treatment of different drugs of abuse with reinforcing properties suggest that common mechanisms underlie these addictive states.

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