Opioid receptors and the discriminative stimulus effects of ethanol in squirrel monkeys: Mu and delta opioid receptor mechanisms

Abstract

Mu and delta opioid receptors modulate the reinforcing effects of ethanol, however, their role in the subjective effects of ethanol is not well understood. This study evaluated the contribution of mu and delta opioid receptors to the subjective effects of ethanol using drug discrimination procedures. Monkeys were trained to discriminate ethanol from saline under a schedule of food delivery. In tests, ethanol engendered increases in drug-lever responding, reaching a maximum of >80%. The mu opioid receptor agonists fentanyl and buprenorphine and the delta opioid receptor agonists SNC 80 and SNC 162 did not substitute for the discriminative stimulus effects of ethanol. As pretreatments, the full agonists fentanyl and SNC 80 enhanced the effects of low doses of ethanol and fentanyl attenuated the effects of the ethanol training dose. Although the possibility of pharmacological antagonism of the effects of ethanol cannot be ruled out, a more likely alternative is that the diminished effects of ethanol were due to perceptual masking of the ethanol stimulus. In contrast, the partial agonists buprenorphine and SNC 162 did not alter ethanol's effects. Finally, the discriminative stimulus effects of ethanol were attenuated following administration of presumably mu-selective doses of the antagonist naltrexone, but not after administration of the delta opioid receptor antagonist naltrindole. The ability of naltrexone to block the discriminative stimulus effects of ethanol likely reflects its capacity to attenuate ethanol-induced increases in endogenous opioids, in particular beta-endorphin, because attenuation of the ethanol stimulus was not accompanied by significant suppression of response rate.

Figure 1

Percentage of ethanol-lever responding (left) and response rate (right) engendered by ethanol in squirrel monkeys trained to discriminate ethanol from vehicle. Points above “V” show the effects of saline administered in the first component followed by cumulative doses of ethanol. Data are means (± S.E.M.) in four subjects.

Figure 2

Percentage of ethanol-lever responding (top) and response rate (bottom) engendered by the mu opioid receptor agonists fentanyl and buprenorphine, and the delta opioid receptor agonists SNC 80 and SNC 162 in squirrel monkeys trained to discriminate ethanol from vehicle. Horizontal dashed lines represent mean (± S.E.M.) response rates after vehicle administration. Data are means (± S.E.M.) in four subjects. *Note that P<0.05, Bonferroni t-test.

Figure 3

Percentage of ethanol-lever responding (top) and response rate (bottom) engendered by ethanol after vehicle pretreatment (filled circles) and after pretreatment with the mu opioid receptor agonists fentanyl (left, open triangles) and buprenorphine (right, open triangles) in squirrel monkeys trained to discriminate ethanol from saline. Data are means (± S.E.M.) in four subjects. *Note that P<0.05, Bonferroni t-test.

Figure 4

Percentage of ethanol-lever responding (top) and response rate (bottom) engendered by ethanol after vehicle pretreatment (filled circles) and after pretreatment with the delta opioid receptor agonists SNC 80 (left, open triangles) and SNC 162 (right, open triangles) in squirrel monkeys trained to discriminate ethanol from saline. Data are means (± S.E.M.) in four subjects. *Note that P<0.05, Bonferroni t-test.

Figure 5

Percentage of ethanol-lever responding (top) and response rate (bottom) engendered by ethanol, alone and after pretreatment with either A) naltrexone or B) naltrindole in squirrel monkeys trained to discriminate ethanol from vehicle. Data are means (± S.E.M.) in four subjects. *Note that P<0.05, Bonferroni t-test.