1.
Ethanol affects
ligand-gated ion channels as a positive modulator of
gamma-aminobutyric acid (
GABA(A)) receptor function and an
N-methyl-D-aspartate (
NMDA) antagonist.
NMDA antagonists attenuate chronic
drug effects. Accordingly, we found that
ethanol decreased
morphine dependence and locomotor sensitization. We now test whether
ethanol alters sensitization to the disrupting 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
ethanol (1 g/kg; i.p.), the
NMDA antagonist
dizocilpine (DZ; 0.05 mg/kg; i.p.), the
GABA(A) agonist
pentobarbital (PB; 3 mg/kg i.p.), or vehicle with
morphine (5 mg/kg s.c.). Separate groups received
naloxone (0.1-1 mg/kg s.c.) 4-hrs later, prior to food sessions (FR15; 30 min) on three consecutive days.
Ethanol enhanced the suppressive effects of higher
naloxone doses on all three days. 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/kg; s.c.) on
morphine discrimination. Rats, trained to discriminate
morphine (3.2 mg/kg s.c.) from saline in a two-lever, food-reinforced procedure, were tested with
morphine (0, 1-5.6 mg/kg) after vehicle and
drug administrations.
Naloxone blocked dose-related responding to
morphine, demonstrating pharmacological specificity, and altered response rates. Both
ethanol and DZ, but 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
opiate receptor function followed by secondary
NMDA-mediated processes induced by
morphine administration.