Ethanol enhances naloxone sensitization and disrupts morphine discrimination - Comparison to dizocilpine and pentobarbital: Explanation of enhancing acute and attenuating chronic effects

1. Ethanol affects ligand-gated ion channels as a positive modulator of gam ma-aminobutyric acid (GABA(A)) receptor function and an N-methyl-D-aspartat e (NMDA) antagonist. NMDA antagonists attenuate chronic drug effects. Accor dingly, we found that ethanol decreased morphine dependence and locomotor s ensitization. We now test whether ethanol alters sensitization to the disru pting effects of naloxone on schedule-controlled responding after morphine administration or affects the acute stimulus effects of morphine. 2. Groups of rats, trained to lever-press for food, were co-administered et hanol (1 g/kg; IP), the NMDA antagonist dizocilpine (DZ; 0.05 mg/kg; IP), t he GABA(A) agonist pentobarbital (PB; 3 mg/kg IP), or vehicle with morphine (5 mg/kg SC). Separate groups received naloxone (0.1-1 mg/kg SC) 4-hrs lat er, prior to food sessions (FR15; 30 min) on three consecutive days. Ethano l enhanced the suppressive effects of higher naloxone doses on all three da ys. DZ and PB altered this behavior differentially by day and naloxone dose . 3. Next, we examined the effects of ethanol, DZ, PB, and naloxone (0.3 mg/k g; SC) on morphine discrimination. Rats, trained to discriminate morphine ( 3.2 mg/kg SC) from saline in a two-lever, food-reinforced procedure, were t ested with morphine (0, 1-5.6 mg/kg) after vehicle and drug administrations . Naloxone blocked dose-related responding to morphine, demonstrating pharm acological specificity, and altered response rates. Both ethanol and DZ, bu t not PB, disrupted morphine-appropriate responding. 4. The paradox that ethanol and DZ attenuate chronic morphine effects while enhancing acute effects may reflect a temporal pattern of primary mu opiat e receptor function followed by secondary NRIDA-mediated processes induced by morphine administration.