Are all the positive reinforcing effects of nicotine mediated only by meso-corticolimbic DA? Some discrepancies in the experiments cited above, and evidence of neuroadaptation in other neurotransmitter systems, may open some alternatives. Two examples follow.
1. A cDNA microarray experiment reveals effects on biochemical pathways whose changes have not been related to DA effects (e.g., EGRF) (113).
2. In rats, cocaine self-administration completely downregulates c-fos expression in the nucleus accumbens, whereas nicotine does not, suggesting a D1 receptor-independent mechanism for activating transcription of c-fos (108,110).
In fact, here, as in the anterior cingulate cortex, nicotine may act directly either on postsynaptic nAChR located in cortical or accumbens interneurons, or in pre-synaptic nAChR located on nordadrenaline, glutamate, or GABAergic terminals, exerting important modulatory roles.
Below we list some other examples of possible involvement as substrate for the addictive properties of nicotine, organized along the major neurotransmitter systems (see also ref. 33).
3.7.1. Noradrenaline (NE)
Nicotine stimulates the in vitro release of NE from slices or synaptosomes from hippocampus and cerebral cortex via D3- or D4-containing nAChR (114,115). In rats, acute nicotine administration increases TH mRNA in the locus coeruleus, whereas chronic nicotine administration increases TH levels in the locus coeruleus and telen-cephalic terminal fields (cerebral cortex, hippocampus, etc.) (94). Acute nicotine also increases NE release in the hippocampus as measured by microdialysis (116). This release is antagonized by injections of mecamylamine into the locus coeruleus, but not into the hippocampus (117), while intrahippocampal D-BG or MLA antagonizes the NE release (118). These data suggest somatic mediation of NE release by D4Q2 nAChR located near the locus coeruleus, and distal mediation of NE release by presynaptic D7 nAChR in hippocampus. Finally, chronic nicotine exposure enhances the nicotine-induced NE release (117). Hippocampus has been involved in mediating some discriminative effects of nicotine (119), supporting a potential role of NE in this component of drug self-administration. In addition, NE substrates can be involved in mediating the antismoking effects of bupropion, a mild DA- and NE-uptake blocker (98,120). However, no NE antagonist or selective NE neurochemical lesions are known to affect nicotine self-administration in rats.
Serotonin has been suggested to participate to the control of motivated consummaroty behavior (121), and evidence indicates some involvement in cocaine self-administration, in particular via 5-HT1B receptors (122). However, a role for serotonin in mediating the reinforcing effects of nicotine seems to be excluded by the lack of effects of several serotonergic drugs in affecting nicotine self-administration (123,124,125). These results are at variance with other preclinical observations showing motivational effects of 5-HT3 antagonists, for example in the rat place preference paradigm (126).
These results were not confirmed in human smokers (125). In addition, when smokers were treated with antidepressant seroronin-uptake inhibitors such as fluoxetine, no therapeutic effects were shown (127). There is a general agreement that antidepres-sants are effective only in the subpopulation in which depression and smoking are co-morbidities. Moreover, data on the effects of chronic nicotine on the molecular expression patterns of serotonin-related enzymes or receptor in CNS are missing, leaving the picture rather incomplete.
Glutamate is probably the most common excitatory neurotransmitter of the brain, and glutamatergic neurons are integral part of the reward system (16,33). Several electrophysiological effects of nicotine are mediated by a direct effect on glutamatergic neurons. For example, in anesthetized rats, nicotine increases the firing of locus coer-uleus dose-dependently (128) via a glutamate-dependent mechanism. More interesting, nicotine stimulates presynaptic D7 nicotinic receptors within the VTA localized on glutamatergic afferents from the medial prefrontal cortex, producing an increase in glutamate concentrations that stimulates the NMDA receptors expressed by DA-containing neurons in the VTA (91). According to Svensson and collaborators, the resulting enhanced burst firing of VTA neurons would enhance DA release in the nerve terminal regions. In this view, glutamate-containing neurons are instrumental for the building of sensitized DA functions that underlies the condition of nicotine dependence.
Glutamate has been involved as one of the mediators of sensitization to nicotine. Co-administration of the NMDA receptor antagonist MK801 or D-CPPene during the nicotine pretreatment phase attenuates the development of locomotor and intra-accumbens DA release sensitisation (78,129), suggesting a potential role in determining nicotine dependence.
The effects of glutamatergic drugs on nicotine self-administration have been rarely addressed (14,33). So far, there is no evidence of direct effects of systemically administered glutamate antagonists.
Chronic nicotine increases increases ^-endorphin in the hypothalamus (130), and Met-enkephaline in the striatum and nucleus accumbens only 24 h after last nicotine administration, and returns to basal level 7 d afterward (131,132). This time-dependency partially explains the lack of effects reported in other studies (e.g., ref. 133). Increase of Pro-dynorphin following chronic nicotine was reported in nucleus accumbens (133). The role of opiates in nicotine dependence is not fully understood. Naloxone does not affect intravenous nicotine self-administration in rats (91), nor does it modify DA release in nucleus accumbens in rats chronically infused with nicotine (85). However, naloxone precipitates a withdrawal syndrome in rats chronically infused with nicotine (95), and reduces cigarette consumption in smokers (134), suggesting a motivational role as part of the central stress system (21). Initial reports of craving reduction in smokers with naloxone (135) were not confirmed in other studies with naloxone or naltrexone (134,136). In rats, Corrigal and collaborators reported that the Qreceptor agonist DAMGO, injected into the VTA, shows modest effects on intravenous nicotine self-administration (137). Overall, these data indicate a minor involvement of opiate peptides in the positive reinforcing aspects of nicotine dependence.
3.7.5. Gamma Aminobutyric Acid (GABA)
GABAergic neurotransmission is a recognized component of the reward pathway (16). Administration of a single dose of nicotine increases GABA release from the nerve terminals and synaptosomes of several brain structures, including the VTA-sub-stantia nigra and hippocampus (138,139), via D2-containing nAChR (140). In VTA-substantia nigra, nicotine effects depend on viable presynaptic D1 neurotransmission, suggesting a presynaptic modulatory effect on the feedback loop from striatum-nucleus accumbens to VTA (138). Corrigal and collaborators showed that intra-VTA microinjections of baclofen, a GABAb receptor agonist, attenuates intravenous nicotine self-administration in rats (137), supporting a direct role of GABAergic neurotrasmission in the reinforcing properties of nicotine. The antimotivational role of GABAB receptor agonism is also supported by the baclofen-induced complete blockade of Dhydroxybu-tyric acid self-administration in mice (141). However, clinical data in 24-h-abstinent smokers administered 20 mg of baclofen showed no effects on number of cigarettes smoked or craving score during the following 3-h fee-smoking period (142). Mild sedative-like effects (increased "relaxing"), and changes in the sensory perception of smoked cigarettes (increased "harsh" and decrease "liking") were also reported, suggesting a role for facilitation of smoking cessation. Recent evidence suggests that this role is shared by another pro-GABAergic drug, □ vinyl-GABA (Vigabatrin; 143). Administration of 75-150 mg/kg of Dvinyl-GABA to rats completely antagonizes the nicotine-induced DA release in nucleus accumbens and the development of nicotine-induced conditioned place preference. Presently, nicotine-GABA interactions are a topic for intense research, and a likely target for future antismoking therapy (144).
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