Subject-regulated dosing alters morphine self-administration behavior and morphine-stimulated [35S]GTPgammaS binding.

Abstract

Repeated intake of opioids is associated with dose escalation and alterations in signal transduction at the G-protein-coupled receptor level. The current study utilized two experiments to identify factors in rats that influence consumption rates such as daily intake of self-administered morphine and receptor desensitization. In Experiment 1, rats self-administered either 0.30, 1.00, or 3.00 mg/kg/infusion morphine sulfate (morphine) during 7 daily 4-h sessions. For Experiment 2, rats were assigned to groups that self-administered either 1) self-regulated escalating doses of morphine, 2) a fixed dose of morphine, or 3) saline during 18-h sessions for 7 days to determine if dose control would increase consumption without significantly decreasing response rate. We then assessed morphine-stimulated [(35)S]GTPgammaS binding in the amygdala and thalamus from these three groups in Experiment 2. Results from Experiment 1 demonstrated that 0.30 mg/kg/morphine did not support stable self-administration. For Experiment 2, the self-escalation group self-administered more morphine than the fixed-dose group, yet maintained similar response rates. Additionally, self-escalation rats demonstrated decreased morphine-stimulated [(35)S]GTPgammaS binding in membranes prepared from amygdalar and thalamic nuclei compared to the fixed-dose and control groups. Our results suggest that session length inversely affects consumption rates for fixed doses of morphine. Self-regulated dosing of morphine is also associated with rapid escalation of daily consumption and no significant alterations in consumption rates. These results suggest subject-regulated dosing is a useful approach for modeling dose escalation associated with opioid dependence.