The Mesocorticolimbic DA System Pharmacological Neuroadaptation to Nicotine Exposure

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The mesocorticolimbic DA system has been the object of intense research in the field of drug addiction because:

1. It is a relevant component of the reward system (16).

2. It is involved in stimulus-reward learning and in the incentive motivational effects of drugs (19,20).

3. When exposed to chronic treatment with addictive drugs, it is the site of neuroadaptive changes, such as sensitization or dysregulation associated with negative emotional states (19,21,68,69).

Midbrain DA neurons contain mRNA for all the principal nAChR subunits (70). However, it is not clear if all of them form functional receptors. High-affinity binding for 125I-D-bungarotoxin and 3H-nicotine suggests that D7 and Q2-containing nAChR proteins, respectively, are actually expressed. Antibodies against D4 have been recently used to confirm the presence of this subunit as translated protein, strongly supporting the presence of a functioning D4D2 nAChR (71).

Pharmacological doses of nicotine are known to stimulate DA neurons of the VTA preferentially (72,73) vs those of the substantia nigra (74), and most likely by a direct action. Pioneering studies by Fuxe and collaborators using the Falk-Hillarp and related techniques showed that exposure to nicotine or smoked tobacco increases the rate of disappearance of fluorescent DA from mesolimbic DA terminals in rats (75,76). These data suggest that nicotine enhances the impulse flow and release of DA in nucleus accumbens. Neurochemical experiments using in vivo microdialysis show that acute nicotine induces DA release in the terminal fields of midbrain DA neurons, in particular in the shell of the nucleus accumbens (77,78,79). Nicotine effects in the nucleus accumbens are antagonized by mecamylamine microinjected into the VTA, but not into the nucleus accumbens (80). This result suggests that, in vivo, nAChRs located in the VTA region are of relevance in controlling DA overflow. Interestingly, acute nicotine at doses of 50-100 <xg/kg also increases the spontaneous burst firing of extracellu-larly recorded DA VTA neurons, most likely via NMDA receptor-dependent activation (81), and burst firing of VTA neurons has been associated with DA release (82). The mechanisms seem to be dependent on nAChR containing D4 or D3, but not D7 (72).

Repeated daily exposures to systemic nicotine result in sensitization of its stimulatory effects on DA overflow in the nucleus accumbens and prefrontal cortex (78) in a manner that recalls the effects of chronic exposures to cocaine or amphetamine (68). On the other hand, sensitized responses to acute systemic challenges with nicotine are antagonized by mecamylamine, and can be induced by local microinjection into the VTA (78). These results point to a key role of nAChR located in the VTA region to induce sensitization to nicotine effects following chronic nicotine treatments. Interest ingly, when nicotine is constantly infused using subcutaneous osmotic minipumps, and not injected, it results in desensitization and tolerance of nicotine effects on DA release (83,84). Recent data indicates that repeated nicotine administration (0.4-0.5 mg/kg) can result in sensitization of DA release in the core of the nucleus accumbens and DA release tolerance in the shell (85), but not in the medial prefrontal cortex (84,85), suggesting a complexity due to differences in neuroanatomical compartments. All in all, these data suggest that repeated passive exposure to nicotine can enhance DA neurotransmission in the mesocorticolimbic DA system. However, to date, there is no evidence that this effect is also produced in rats trained to nicotine self-administration, casting doubt about the relevance of DA release sensitization for the reinforcing effects of nicotine.

In contrast to the central role of VTA neurons in the sensitization of DA release to nicotine, recent microdialysis experiments performed by locally perfusing nicotine into the terminal fields of midbrain DA neurons showed a dose-dependent increase of mecamylamine-sensitive DA release produced by acute nicotine. Chronic nicotine treatment further enhances DA release in response to nicotine when locally infused via microdialysis probes into the nucleus accumbens, striatum, and prefrontal cortex in rat (86). Experiments performed in vitro on synaptosomes confirm that DA is released via □4D2 and D3Q2 nAChR-dependent Na+~ and Ca2+-sensitive channel-operated mechanisms (87,88). Interestingly, when DA release was studied in striatal slices ex mortem in rats injected daily with nicotine, enhancement of nicotine-induced DA overflow response was measured (89), whereas desensitization was seen in synaptosomes obtained from rats continuously infused with nicotine (66,88). Therefore, nAChR expressed at the synaptic terminals of midbrain DA neurons is likely to contribute to the development of mesocorticolimbic DA system sensitization to nicotine effects only under specific conditions.

3.4.1. Effects of Nicotine on the DA Systems Mediated by U7-Containing AChR

Attenuation of systemic nicotine- and food-induced DA overflow in the nucleus accumbens was also produced by microinjections of the D7-subunit-selective antagonist methyllycaconetine (MLA) into the VTA (90). These D7-dependent effects are most likely mediated by presynaptic nAChR located on glutamatergic neurons projecting to the VTA (91). Electrophysiological experiments on brain slices containing VTA DA neurons of rats previously continuously infused with nicotine for several days show desensitization of D7-dependent currents, suggesting that chronic nicotine attenuates □7-mediated synaptic transmission (73). However, in vivo studies indicate that MLA was unable to block the discriminative properties of nicotine in rats (92) nor was nicotine self-administration, suggesting that D7 is not involved in the discriminative effects of nicotine, most likely mediated by hippocampal or prefrontal cortex rather than the DA systems (90).

3.4.2. Effects of Chronic Nicotine on Thyrosine Hydroxylase (TH) in Mesolimbic DA Neurons

In vivo acute nicotine stimulates the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthetic pathway of DA, in DAergic terminals of the nucleus accumbens, whereas tolerance to this effect is observed following repeated nicotine administration (93). Conversely, acute nicotine does not change the levels of TH immunoreactivity in the VTA and substantia nigra, whereas increases are observed following repeated nicotine administration (94). No data are available on the effects of chronic nicotine self-administration on TH levels and activity.

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