TRATTAMENTO CRONICO ED ASTINENZA DA NICOTINA: EFFETTI IN VIVO SULL'ESPRESSIONE DEI RECETTORI COLINERGICI NICOTINICI E GLUTAMMATERGICI NEL SNC DI RODITORI

Like many other drugs of abuse, nicotine has two effects that contribute to its additive properties: its reinforcing or rewarding properties, and the aversive abstinence syndrome that develops when it is precipitously withdrawn. These effects are due to neural adaptations that change whole cell physiology and behavior and are mainly due to nicotine’s interactions with neural nicotinic acetylcholine receptors. Mice with different a4 and b2 subunit expression (wild-type, heterozygotes and null-mutant for each gene) where chronically treated with one of four doses of nicotine (0, 0.25, 1 or 4 mg/kg/h), than the mice treated with higher dose were exposed to 1, 4 or 14 days of withdrawal. Chronic nicotine treatment increases the density of nicotinic acetylcholine receptor (nAChR) binding sites both in wild-type and heterozygotes. These increases are most pronounced for the a4b2* nAChR subtype. The extent of the increase is dependent on the dose of nicotine administered and is saturable. Furthermore, the magnitude of the increase varies among brain regions. In the cortex nicotine also increases the expression of the a4b2 subtype with the (a4)2(b2)3 stoichiometry. a4 and b2 KO mice have little detectable nicotinic receptors that contain the a3b4 subunits and these receptors were unaffected by chronic nicotine treatment. We also analysed the expression of glutamatergic receptor subunits at the end of nicotine treatment (4mg/kg/h) and after 1, 4 or 14 days of withdrawal in two areas of mesocorticolimbic dopaminergic system: the Striatum and the Ventral Tegmental Area (VTA) . We found that after chronic treatment, in VTA synaptosomes there is a selective upregulation of GluA2/3 AMPA receptors whereas during withdrawal there is a significative increase in AMPA GluA1 receptors and NMDA receptors containing GluN1 and GluN2A subunits. In striatal synaptosomes after nicotine treatment there is a significant decrease of GluA2/3 AMPA receptors that is maintained during the 14 days nicotine withdrawal. At 4 days withdrawal there is a transient decrease in GluA1 AMPA and GluN1 and GluN2A containing NMDA receptors Our data suggest that ionotropic glutamate receptors are up regulated in the VTA early during nicotine withdrawal whereas they are down regulated in the striatum. These findings suggest that chronic nicotine selectively changes the levels of ionotropic glutamate receptor subunits in a brain region-specific manner.