Enhanced alcohol-seeking behavior by nicotine in the posterior ventral tegmental area of female alcohol-preferring (P) rats: modulation by serotonin-3 and nicotinic cholinergic receptors

Abstract

Rationale: Alcohol and nicotine co-use can reciprocally promote self-administration and drug-craving/drug-seeking behaviors. To date, the neurocircuitry in which nicotine influences ethanol (EtOH) seeking has not been elucidated. Clinical and preclinical research has suggested that the activation of the mesolimbic dopamine system is involved in the promotion of drug seeking. Alcohol, nicotine, and serotonin-3 (5-HT3) receptors interact within the posterior ventral tegmental area (pVTA) to regulate drug reward. Recently, our laboratory has reported that systemic administration of nicotine can promote context-induced EtOH seeking.

Objectives: The goals of the current study were to (1) determine if microinjections of pharmacologically relevant levels of nicotine into the pVTA would enhance EtOH seeking, (2) determine if coadministration of nicotinic cholinergic receptor antagonist (nACh) or 5-HT3 receptor antagonists would block the ability of nicotine microinjected into the pVTA to promote EtOH seeking, and (3) determine if 5-HT3 receptors in the pVTA can modulate EtOH seeking.

Results: Nicotine (100 and 200 μM) microinjected into the pVTA enhanced EtOH seeking. Coinfusion with 200 μM mecamylamine (nACh antagonist) or 100 and 200 μM zacopride (5-HT3 receptor antagonist) blocked the observed nicotine enhancement of EtOH seeking. The data also indicated that microinjection of 1 μM CPBG (5-HT3 receptor agonist) promotes context-induced EtOH seeking; conversely, microinjection of 100 and 200 μM zacopride alone reduced context-induced EtOH seeking.

Conclusions: Overall, the results show that nicotine-enhanced EtOH-seeking behavior is modulated by 5-HT3 and nACh receptors within the pVTA and that the 5-HT3 receptor system within pVTA may be a potential pharmacological target to inhibit EtOH-seeking behaviors.

Fig. 1

Representative dual placements for the microinfusions of aCSF, nicotine, zacopride, or CPBG into pVTA of P rats are shown. Filled circles represent placements of injection sites within the pVTA (defined as −5.4 to −6.0 mm bregma)

Fig. 2

Mean (±SEM) responses per session on the lever previously associated with the delivery of EtOH (a) or water (b) by P rats (n=6–7/group) microinjected with aCSF or 50, 100, or 200 µM nicotine into the pVTA. Asterisk (*) indicates that rats that administered aCSF or 50, 100, or 200 µM nicotine responded significantly (p<0.05) more on the EtOH lever during the first PSR session compared to extinction baseline levels. Double pound (##) indicates that 100 or 200 µM nicotine increased responding on the EtOH lever during the first PSR session compared to the aCSF and 50 µM nicotine (p<0.05)

Fig. 3

Mean (±SEM) responses per session on the lever previously associated with the delivery of EtOH (a) or water (b) by P rats (n= 1–6/group), with placements in the anterior VTA and red nucleus, microinjected with aCSF or 50, 100, or 200 µM nicotine. No significant differences were detected

Fig. 4

Mean (±SEM) responses per session on the lever previously associated with the delivery of EtOH (a) or water (b) by P rats (n=6–7/group) microinjected with aCSF or 100 µM nicotine, 100 µM nicotine+ 100 µM mecamylamine (a nonselective nicotinic receptor antagonist), or 100 µM nicotine+µM mecamylamine into the pVTA. Asterisk (*) indicates that rats that administered aCSF, 100 µM nicotine, or 100 µM nicotine+100 µM mecamylamine responded significantly (p<0.05) more on the EtOH lever during the first PSR session compared to extinction baseline levels. Double pound (##) indicates that 100 µM nicotine or 100 µM nicotine+100 µM mecamylamine increased responding on the EtOH lever during the first PSR session compared to the aCSF, whereas 100 µM nicotine+200 µM mecamylamine decreased responding on the EtOH lever during the first PSR session compared to 100 µM nicotine or 100 µM nicotine+100 µM mecamylamine (p<0.05)

Fig. 5

Mean (±SEM) responses per session on the lever previously associated with the delivery of EtOH (a) or water (b) by P rats (n=5–7/group) microinjected with aCSF, 100 µM nicotine, 100 µM nicotine+ 100 µM zacopride (a 5-HT₃ receptor antagonist), or 100 µM nicotine+ 200 µM zacopride into the pVTA. Asterisk (*) indicates that rats that administered aCSF or 100 µM nicotine responded significantly (p<0.05) more on the EtOH lever during the first PSR session compared to extinction baseline levels. Double pound (##) indicates that 100 µM nicotine+100 µM zacopride, or 100 µM nicotine+200 µM zacopride decreased responding on the EtOH lever during the first PSR session compared to the aCSF or 100 µM nicotine (p<0.05)

Fig. 6

Mean (±SEM) responses per session on the lever previously associated with the delivery of EtOH (a) or water (b) by P rats (n=5–8/group) microinjected with aCSF, or 100 or 200 µM zacopride (a 5-HT₃ receptor antagonist) into the pVTA. Asterisk (*) indicates that rats that administered aCSF responded significantly (p<0.01) more on the EtOH lever during the first PSR session compared to extinction baseline levels. Double pound (##) indicates that 100 or 200 µM zacopride significantly decreased responding on the EtOH lever during the first PSR session compared to aCSF (p<0.01)

Fig. 7

Mean (±SEM) responses per session on the lever previously associated with the delivery of EtOH (a) or water (b) by P rats (n=4–5/group) microinjected with aCSF, or 1 or 10 µM CPBG (a 5-HT₃ receptor agonist) into the pVTA. Asterisk (*) indicates that rats that administered aCSF or 1 µM CPBG responded significantly (p<0.05) more on the EtOH lever during the first PSR session compared to extinction baseline levels. Double pound (##) indicates that 1 µM CPBG increased responding on the EtOH lever, and 10 µM CPBG decreased responding on the EtOH lever during the first PSR session compared to the aCSF (p<0.01)