Dedrosomatic And Terminal Sites Of Nicotines Action

The experiments considered above provide evidence that nicotine can act directly at the terminals of mesocorticolimbic and nigrostriatal neurons to release nicotine, ostensibly by acting upon nicotinic receptors on the presynaptic nerve terminal.

FIGURE 3.1 Concentration-response relationship of nicotine in synaptosomes from striatum, nucleus accumbens, frontal cortex, and amygdala. Tissue, prepared and perfused as described, was challenged with 30 second pulses of L-nicotine at the concentrations indicated. The resulting increase in the baseline release (extrapolated from the period preceding the pulse) is presented as the percent increase over baseline at each concentration.

FIGURE 3.1 Concentration-response relationship of nicotine in synaptosomes from striatum, nucleus accumbens, frontal cortex, and amygdala. Tissue, prepared and perfused as described, was challenged with 30 second pulses of L-nicotine at the concentrations indicated. The resulting increase in the baseline release (extrapolated from the period preceding the pulse) is presented as the percent increase over baseline at each concentration.

Audioradiographic studies of Clarke using [3H]nicotine demonstrated that high affinity nicotinic receptors are present on dopaminergic terminals in these brain areas (Clarke et al., 1985; Clarke and Pert, 1985). These studies also showed that nicotinic receptors were on the soma of these neurons in the VTA and the SN. The experiments of Lichtensteiger and coworkers (1976, 1982) found that the local application of nicotine to the SN produced an increase in firing of dopaminergic neurons and an increase in DA metabolite levels in the striatum. This provided evidence that the elevation in DA levels in the striatum might be the result of its action on somatodendritic receptors rather than those at the terminal. Similarly, microdialysis studies by Yoshida et al. (1993) have demonstrated that the local administration of nicotine into the VTA results in an increase in DA levels in the NAc. The finding that the application of tetrodotoxin abolishes the increase in nicotine-stimulated DA release in intact preparations of the NAc (Benwell et al., 1993) and striatum (Marshall et al., 1996) indicates that neuroconduction is required, thus providing further evidence that nicotine's interaction with receptors at the somatodendritic area of mesolimbic and nigrostriatal neurons is responsible for the effects of systemically administered nicotine.

The most convincing evidence for a dendrosomatic site of action for nicotine-stimulated DA release has come from the experiments of Nisell et al. (1994a, 1994b) in which the nicotinic antagonist, mecamylamine, was infused into either the NAc or VTA. These studies showed that the nAChRs in the VTA are primarily responsible for the stimulation of DA release in the NAc. This was further demonstrated by the experiments of Corrigall et al. (1994) showing that nicotine self-administration is blocked by the administration of nicotinic antagonists in the VTA but not in the NAc. Further microdialysis studies by Nisell and coworkers have demonstrated that the release of DA occurs primarily in the shell of the NAc compared to the core (Nisell et al., 1997). Interestingly, it has recently been shown that sensitization to nicotine's locomotor effect following chronic administration is accompanied by a decreased release of DA in the shell of the Nac, but an increase in DA release in the core (Cadoni and DiChiara, 2000).

From these studies it could be concluded that nAChR located on the dendrites and cell bodies of dopaminergic neurons in the VTA and SN are the receptors which preferentially give rise to nicotine-stimulated increase in DA levels at the nerve endings of the NAc and striatum, and that these dendrosomatic nAChRs are primarily responsible for the rewarding effects of nicotine. The nAChR in the SN appear to receive their major cholinergic input from neurons projecting from the peduncu-lopontine tegmental nucleus (Clarke et al., 1987; Beninato and Spencer, 1987; Blaha and Winn, 1993), whereas the cholinergic input to the VTA emanates primarily from the laterodorsal tegmental nucleus (Blaha et al., 1996) — an area important in nicotine self-administration (Lanca et al., 2000). While there are clearly presynaptic nAChRs located on the terminals of the nigrostriatal and mesocorticolimbic neurons which can mediate the release of DA in response to local nicotine administration, as discussed previously, the functional significance of these receptors with regards to the systemic- or self-administration of nicotine is unknown, nor is whether these receptors receive cholinergic input by which they might serve a modulatory role on dopaminergic neurotransmission at the synapse (Vizi and Lendvai, 1999).

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