tyrosyl-1-2-3-4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine and Disease-Models--Animal

The delta opioid receptor (DOR) agonist DPDPE decreases ethanol (EtOH) consumption when injected into the ventral tegmental area (VTA). We previously showed that DPDPE inhibition of GABAA receptor-mediated inhibitory postsynaptic currents (GABAAR IPSCs) is associated with reduced EtOH consumption. To determine whether self-administration of EtOH is required to change VTA DOR function, we compared the effects of passively administered (gavaged) and self-administered (two-bottle choice) EtOH. Because rats showed variability in DOR regulation of drinking and inhibition of GABAAR IPSCs, we examined whether these changes can be predicted before EtOH exposure by behavioral measures of anxiety or intoxication. Functional DORs were seen with both gavaged and self-administered EtOH, although the magnitude of DPDPE-induced inhibition correlated with behavioral measures only when EtOH was self-administered. Specifically, DPDPE-induced inhibition correlated with predrinking measures of open arm time in the plus maze (n = 19, R = .69, p = .001), with change in maximum fall latency on the rotarod (n = 17, R = .89, p = .000001), and with blood corticosterone (n = 17, R = .66, p = .004) in drinking animals. This DOR-mediated inhibition persisted for at least 14 days after EtOH access was terminated. Together, these findings indicate that anxious animals and those with the greatest EtOH-induced motor impairment have the most robust DPDPE-induced inhibition of GABAAR IPSCs in VTA neurons. These data also extend our understanding of the possible therapeutic value of the DOR for treatment of alcoholism by showing that its relevant synaptic action persists during abstinence.

Topics: Analgesics, Opioid; Animals; Anxiety; Central Nervous System Depressants; Conditioning, Operant; Disease Models, Animal; Enkephalin, D-Penicillamine (2,5)-; Ethanol; Hydrocortisone; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Male; Maze Learning; Microinjections; Motor Activity; Narcotic Antagonists; Oligopeptides; Patch-Clamp Techniques; Rats; Rats, Inbred Lew; Receptors, Opioid, delta; Rotarod Performance Test; Self Administration; Statistics as Topic; Tetrahydroisoquinolines; Ventral Tegmental Area