An acetaldehyde-sequestering agent inhibits appetitive reinforcement and behavioral stimulation induced by ethanol in preweanling rats

Abstract

Ethanol's motivational consequences have been related to the actions of acetaldehyde, a metabolic product of ethanol oxidation. The present study assessed the role of acetaldehyde in the motivational effects of ethanol on preweanling rats. In Experiment 1 pups (postnatal days 13-14, PD 13-14) were given systemic administration of D-penicillamine (DP, a drug that sequesters acetaldehyde: 0, 25, 50 or 75 mg/kg) before pairings of 1.0 g/kg ethanol and a rough surface (sandpaper, conditioned stimulus, CS). At test, pups given sandpaper-ethanol pairings exhibited greater preference for the CS than unpaired controls, but this preference was not expressed by pups given DP. Pre-training administration of 25 or 50 mg/kg DP completely blocked the expression of ethanol-mediated appetitive conditioning. D-penicillamine did not alter blood ethanol levels. Subsequent experiments revealed that ethanol-induced activation was blocked by central (intra-cisterna magna injections, volume: 1 μl, dose: 0 or 75 μg) but not systemic treatment with DP (0, 25, 50 or 75 mg/kg; ip). These results indicate that: (a) preweanling rats are sensitive to the reinforcing effect of ethanol, and (b) that this effect is associated with the motor activating effect of the drug. These effects seem to be mediated by the first metabolite of ethanol, acetaldehyde.

Figure 1

Ethanol-induced motivational learning. Time spent on sandpaper (conditioned stimulus, CS, top panel) and its corresponding percentage of preference (bottom panel) as a function of conditioning procedures [sandpaper paired or unpaired with intragastric administration of 1.0 g/kg ethanol] and treatment with d-penicillamine, an acetaldehyde-sequestering agent (0, 25, 75 or 75 mg/kg, ip), prior to conditioning. Each group illustrated in the figure had 12 animals. Asterisks (*) indicate significant differences between the paired-0.0 mg/kg DP group and the remaining groups (p < 0.05). Number signs (#) indicate significant differences between an ethanol-treated group and its corresponding vehicle-treated control (p < 0.05).Vertical bars represent the standard error of the means (S.E.M.).

Figure 2

Ethanol-induced motor activity after systemic d-penicillamine. Locomotor activity (distance traveled, cms) during ethanol post-administration time 5–9, 10–14 and 15–19 minutes (evaluations bins 1, 2 and 3; respectively) in 13-day old male and female rats. The animals were given d-penicillamine (0, 25, 75 or 75 mg/kg, ip) 25 min prior to the administration of ethanol (1.25 g/kg, intragastric) or its vehicle. Animals in the untreated group (n = 11) were assessed for locomotor activity but did not receive intubations or injections. Each of the eight groups treated with ethanol and d-penicillamine had 12 animals. The statistical analysis (ANOVA) revealed independent significant main effects of ethanol treatment, d-penicillamine treatment and bin of evaluation, F_1,98 = 5.62, p < 0.05; F_3,99 = 5.32, p < 0.005 and F_2,196 = 19.53, p < 0.001. The vertical bars indicate the SEM.

Figure 3

Ethanol-induced motor activity after central d-penicillamine. Locomotor activity (distance traveled, cms) during ethanol post-administration time 5–9 minutes in 13-day old male and female rats. The animals were given intra-cisterna magna injections of d-penicillamine (volume: 1 μl, dose: 0 or 75 μg; vehicle: saline) 10 min before the administration of ethanol (1.25 g/kg, intragastric) or its vehicle. Animals in the untreated group (n=12) had neither d-penicillamine nor ethanol treatment. Yet, they were assessed for motor activity similarly to the other groups. Each of the four groups treated with ethanol and d-penicillamine had 12–15 animals. The asterisk (*) indicates significant differences between the ethanol-0.0 mg/kg DP group and the remaining groups (p < 0.05). The vertical bars indicate the SEM.