Effects of Drug-Ethanol Combinations on Ethanol Self-Administration, Motor Coordination, and Cognition in C57BL/6J Mice

Abstract

Thirty-six male (n = 18) and female (n = 18) C57BL/6J mice were trained to operantly self-administer (SA) 10% ethanol in 5% sucrose (ETOH; N = 24, n = 12 male and 12 female) or 5% sucrose alone (SUCR; N = 12, 6 male and 6 female) under an FR-10 schedule of reinforcement where a nose poke into either a left or right hole was reinforced. Following criterion SA of ≥25 reinforcers per 20-min session for 3 consecutive days, mice received i.p. drug injections of d-amphetamine (AMP; 0.25–1.0 mg/kg), methylphenidate (MPH; 1.5–3.0 mg/kg), caffeine (CAF; 10.0–20.0 mg/kg), nicotine (NIC; 0.3–0.6 mg/kg), and alprazolam (ALZ; 0.75–1.5 mg/kg) 5- to 30-min prior to 10-min SA sessions using a counterbalanced within-subjects design. Mice acquired ETOH SA within 45 days and SUCR SA within 23 days. Average blood ethanol concentrations on ETOH SA Day 73 was 78.4 ± 33.6 mg/dL. AMP significantly decreased ETOH SA at doses that decreased response rates but did not affect motor coordination. Tolerance developed to the motor-impairing effects of ETOH SA, although low doses of stimulant drugs tended to minimize, and ALZ significantly increased, motor impairment caused by ETOH SA alone. Self-administered doses of ETOH impaired 23-hr novel object recognition, which was exacerbated by the high dose of ALZ, but not affected by stimulant drugs. These results suggest that humans may coabuse psycho-stimulants and benzodiazepine drugs with alcohol due to their ability to enhance the reinforcing properties of alcohol, and not likely for cognitive-enhancing effects.