Nicotine modulates alcohol-seeking and relapse by alcohol-preferring (P) rats in a time-dependent manner

Abstract

Background: Alcohol is frequently co-abused with smoking. In humans, nicotine use can increase alcohol craving and consumption. The objectives of the current study were to assess the acute effects of nicotine on alcohol seeking and relapse at 2 different time points.

Methods: Adult female alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% ethanol (EtOH) (v/v) and water on a concurrent fixed-ratio 5-fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1-hour sessions. Following 10 weeks of daily 1-hour sessions, rats underwent 7 extinction sessions, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without EtOH or water being present for 4 sessions (Pavlovian Spontaneous Recovery [PSR]). Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (relapse). Nicotine (0, 0.1, 0.3, or 1.0 mg/kg) was injected subcutaneously immediately or 4 hours prior to PSR or relapse testing.

Results: Injections of nicotine immediately prior to testing reduced (5 to 10 responses PSR; 50 to 60 responses relapse), whereas injections of nicotine 4 hours prior to testing increased (up to 150 responses for PSR; up to 400 responses for relapse with 1.0 mg/kg dose) responses on the EtOH lever during PSR and relapse tests.

Conclusions: The results of this study demonstrate that acute effects of nicotine on EtOH-seeking and relapse behaviors may be time dependent, with the immediate effects being a result of nicotine possibly acting as a substitute for EtOH, whereas with a delay of 4 hours, priming effects of nicotine alterations in nicotinic receptors, and/or the effects of nicotine's metabolites (i.e., cotinine and nornicotine) may enhance the expression of EtOH-seeking and relapse behaviors.

Fig. 1

Mean (± S.E.M.) responses per session on the lever previously associated with the delivery of EtOH in P rats given saline (n = 4–5/time point) or 0.1, 0.3, or 1.0 mg/kg nicotine (n = 6–10/dose/time point) subcutaneously immediately or 4-hr prior to the first PSR session. Upper Panel: asterisk (*) indicates that rats administered saline responded significantly (p < 0.05) more on the EtOH lever during the first PSR session compared to extinction baseline levels, whereas rats administered 0.1, 0.3, or 1.0 mg/kg nicotine immediately prior to the first PSR session responded significantly less than extinction baseline. Pound (#) indicates that all doses of nicotine reduced EtOH responding during the first PSR session compared to the saline group (p<0.05). Lower Panel: asterisk (*) indicates that rats administered saline, 0.1, 0.3, or 1.0 mg/kg nicotine 4-hr prior to the first session responded significantly (p < 0.05) more on the EtOH lever during the first PSR session compared to extinction baseline levels. Pound symbol (#) indicates that 1.0 mg/kg nicotine increased EtOH responding during the first PSR session compared to all other groups (p < 0.05).

Fig. 2

Mean (± S.E.M.) responses per 10-min blocks on the lever previously associated with the delivery of EtOH in P rats given saline (n = 4–5/time point), or 0.1, 0.3, or 1.0 mg/kg nicotine (n = 6–10/dose/time point) immediately or 4-hr prior to only the first PSR session. Upper Panel: asterisk (*) indicates that rats administered 0.1 mg/kg nicotine immediately prior to the test session responded significantly (p < 0.05) less on the EtOH lever during 0–20-min of PSR testing compared to saline. Middle Panel: asterisk (*) indicates that rats administered 0.3 mg/kg nicotine immediately prior to first the PSR session responded significantly (p < 0.05) less on the EtOH lever during 0–20-min of PSR testing compared to saline and rats administered 0.3 mg/kg nicotine 4-hr prior testing. Rats administered 0.3 mg/kg nicotine 4-hr prior to PSR testing displayed an increase in EtOH lever responses during the 50–60 period. Lower Panel: asterisk (*) indicates that rats administered 1.0 mg/kg nicotine immediately prior to test session responded significantly (p < 0.05) less on the EtOH lever during 0–20-min of PSR testing compared to saline and rats administered 1.0 mg/kg nicotine 4-hr prior testing. Rats administered 1.0 mg/kg nicotine 4-hr prior to PSR testing displayed an increase in EtOH responses during the 40–60 period.

Fig. 3

Mean (± S.E.M.) responses per session on the lever previously associated with the delivery of water in P rats given saline (n = 4–5/time point), or 0.1, 0.3, or 1.0 mg/kg nicotine (n = 6–10/dose/time point) subcutaneously immediately or 4-hr prior to the first PSR session. Upper Panel: asterisk (*) indicates that rats administered 0.3 mg/kg nicotine responded significantly (p < 0.05) less on the water lever during the first PSR session compared to extinction baseline levels. There were no significant water responding differences when animals were administered saline or 0.1 or 1.0 mg/kg of nicotine immediately prior to the first PSR session. Lower Panel: asterisk (*) indicates that rats administered saline or 0.1 mg/kg nicotine 4-hr prior to the first session responded significantly (p < 0.05) more on the water lever during the first PSR session compared to extinction baseline levels. There were no significant water responding differences when animals were administered 0.3 or 1.0 mg/kg nicotine 4-hr prior to the first PSR session.

Fig. 4

Mean (± S.E.M.) responses per session on the EtOH lever by P rats given saline (n = 4–5/time point), or 0.1, 0.3, or 1.0 mg/kg nicotine (n = 7–9/group/time point) immediately or 4-hr prior to only the first relapse session. Upper Panel: asterisk (*) indicates that rats administered 0.1, 0.3, or 1.0 mg/kg nicotine immediately prior to the first relapse session responded significantly (p < 0.05) less than baseline, and rats given saline had higher responding than baseline. Pound symbol (#) indicates that all doses of nicotine reduced EtOH responding during the first relapse session compared to the saline group (p<0.05). Lower Panel: asterisk (*) indicates that rats administered saline or 0.1, 0.3, or 1.0 mg/kg nicotine 4-hr prior to the first relapse session responded significantly (p < 0.05) more on the EtOH lever compared to baseline levels. Pound symbol (#) indicates that 0.3 and 1.0 mg/kg nicotine increased EtOH responding significantly more than the saline group (p < 0.05).

Fig. 5

Mean (± S.E.M.) responses per 10-min blocks on the EtOH lever by P rats given saline (n = 4–5/time point), or 0.1, 0.3, or 1.0 mg/kg nicotine (n = 7–9/group/time point) immediately or 4-hr prior to the first relapse session. Upper Panel: asterisk (*) indicates that rats administered saline or 0.1 mg/kg 4-hr prior to test session responded significantly (p < 0.05) more on the EtOH lever during initial 0–20-min and final 10-min of relapse testing compared to rats injected with 0.1 mg/kg nicotine immediately prior to the test session. Middle Panel: asterisk (*) indicates that rats administered 0.3 mg/kg nicotine immediately responded significantly (p < 0.05) less on the EtOH lever during 0–20-min of relapse testing compared to saline, and rats administered 0.3 mg/kg nicotine 4-hr prior to relapse testing displayed an increase in EtOH responding during the 3^rd and 6^th 10-min block compared to saline. Lower Panel: asterisk (*) indicates that rats administered 1.0 mg/kg nicotine immediately responded significantly (p < 0.05) less on the EtOH lever during 0–20-min of relapse testing compared to saline, and rats administered 1.0 mg/kg nicotine 4-hr prior to relapse testing displayed an increase in EtOH lever responses during 1^st, 2^nd, and 6^th 10-min block compared to saline.

Fig. 6

Mean (± S.E.M.) responses per session on the water lever by P rats given saline (n = 4–5/time point), or 0.1, 0.3, or 1.0 mg/kg nicotine (n = 7–9/group/time point) immediately or 4-hr prior to only the first relapse session. Upper Panel: There were no significant differences in water responding when the rats were administered saline or 0.1, 0.3, or 1.0 mg/kg nicotine immediately prior to the first relapse. Lower Panel: asterisk (*) indicates that rats administered saline or 0.1 mg/kg of nicotine 4-hr prior to the first relapse session responded significantly (p < 0.05) more on the water lever compared to baseline levels. There were no significant differences water responding when rats were administered 0.3 or 1.0 mg/kg nicotine 4-hr prior to the first relapse test.