alpha 3 beta 4 nicotinic acetylcholine receptors in the medial habenula modulate the mesolimbic dopaminergic response to acute nicotine in vivo

作者：McCallum Sarah E^*; Cowe Matthew A; Lewis Samuel W; Glick Stanley D

来源：Neuropharmacology, 2012, 63(3): 434-440.

DOI：10.1016/j.neuropharm.2012.04.015

• Nicotine
• Dopamine
• Microdialysis
• 18-Methoxycoronaridine
• Nicotinic receptor
• Rat
• Medial habenula

Habenulo-interpeduncular nicotinic receptors, particularly those containing alpha 3, beta 4 and alpha 5 subunits, have recently been implicated in the reinforcing effects of nicotine. Our laboratory has shown that injection of alpha 3 beta 4 nicotinic receptor antagonists into the medial habenula (MHb) decreases self-administration of multiple abused drugs, including nicotine (Glick et al., 2006, 2008; 2011). However, it is unclear whether blockade of MHb nicotinic receptors has a direct effect on mesolimbic dopamine. Here, we performed in vivo microdialysis in female rats. Microdialysis probes were implanted into the nucleus accumbens (NAcc) and alpha 3 beta 4 nicotinic receptor antagonists (18-methoxycoronaridine; 18-MC or alpha-conotoxin AuIB; AuIB), were injected into the ipsilateral MHb, just prior to systemic nicotine (0.4 mg/kg, s.c.). Dialysate samples were collected before and after drug administration and levels of extracellular dopamine and its metabolites were measured using HPLC. Acute nicotine administration increased levels of extracellular dopamine and its metabolites in the NAcc. Pre-treatment with intra-habenular AuIB or 18-MC prevented nicotine-induced increases in accumbal dopamine. Neither drug had an effect on nicotine-induced increases in dopamine metabolites, suggesting that alpha 3 beta 4 receptors do not play a role in dopamine metabolism. The effect of intra-habenular blockade of alpha 3 beta 4 receptors on NAcc dopamine was selective for acute nicotine: neither AuIB nor 18-MC prevented increases in NAcc dopamine stimulated by acute D-amphetamine or morphine. These results suggest the mesolimbic response to acute nicotine, but not to acute administration of other drugs of abuse, is directly modulated by alpha 3 beta 4 nicotinic receptors in the MHb, and emphasize a critical role for habenular nicotinic receptors in nicotine%26apos;s reinforcing effects.

• 出版日期2012-9