Suppression of Ethanol Responding by Centrally Administered CTOP and Naltrindole in AA and Wistar Rats


Reprint requests: Petri Hyytiä, PhD, Department of Mental Health and Alcohol Research, National Public Health Institute, POB 719, 00101 Helsinki, Finland; Fax: 358-9-133-2781; E-mail:


Background: Both μ- and δ-opioid receptors have been implicated in the reinforcing actions of ethanol. However, selective opioid receptor antagonists have not altered ethanol intake in all rodent strains consistently, which suggests that genotype may modulate their suppressive effects. Therefore, we tested the effects of the selective μ-antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2(CTOP) and the selective δ-antagonist naltrindole in both high-drinking AA (Alko, Alcohol) and heterogeneous Wistar rats.

Methods: AA and Wistar rats were trained to respond for ethanol (10% w/v) in a two-lever operant condition by using a saccharin fading procedure. After stable baseline responding was established, rats were implanted stereotaxically either with a guide cannula above the lateral ventricle or with bilateral cannulas above the nucleus accumbens, basolateral amygdala, or ventral tegmental area. After postoperative recovery, AA and Wistar animals were tested after intracerebroventricular microinjections of either CTOP (0–3 μg) or naltrindole (0–30 μg) or subcutaneous injections of naloxone (0–1 g/kg), which was used as a reference antagonist. Effects of intracerebral microinjections of CTOP and naltrindole (both 0–500 ng) were tested only in Wistar rats.

Results: Subcutaneous naloxone and intracerebroventricular CTOP and naltrindole suppressed ethanol self-administration in a similar manner in AA and Wistar rats. Cumulative response patterns indicated that naloxone and naltrindole had no effect on the initiation of responding but suppressed it later during the session, whereas CTOP also affected initiation. In Wistar rats, naltrindole microinjections into both the nucleus accumbens and basolateral amygdala decreased ethanol responding, whereas CTOP was effective only in the amygdala. Injections of these antagonists into the ventral tegmental area had little effect on ethanol intake.

Conclusions: The results confirm previous results which showed that both μ- and δ-opioid receptors are involved in the regulation of ethanol self-administration and indicate that genetic differences between AA and Wistar rats produced by selection do not modify the effects of opioid antagonists. The nucleus accumbens and the basolateral amygdala may be important central sites for the mediation of their suppressive effects.