Pertussis toxin attenuates intracranial morphine self-administration.

Mu and delta opioid receptor subtypes are thought to mediate the reinforcing actions of opioids. Since these opioid receptors use pertussis toxin (PTX)-sensitive inhibitory G-proteins for signal transduction, we determined whether PTX would block the opioid reinforcement signals produced by intrahippocampal or intraventral tegmental area (VTA) injections of morphine in rats. Hippocampal PTX pretreatment prevented the acquisition of intrahippocampal morphine self-administration. Similarly, in rats previously trained to self-administer morphine in the VTA, PTX injections in the VTA abolished morphine self-administration behavior, while sparing behavior reinforced by food pellets. This result suggested that the toxin did not interfere generally with motor capacity but rather acted selectively to block morphine reinforcement. Inactivated PTX did not reduce VTA morphine self-administration, thus demonstrating that PTX blockade of opioid reinforcement is primarily due to enzymatic inactivation of inhibitory G-proteins. All these findings are consistent with the hypothesis that inhibitory G-proteins in the hippocampus and VTA mediate the reinforcing effects of opioid drugs.