Subject-regulated dosing alters morphine self-administration behavior and morphine-stimulated [35S]GTPgammaS binding.
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.
Kruzich
P J
PJ
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York 10021, USA. kruzichp@ohsu.edu
Chen
A C H
AC
Unterwald
E M
EM
Kreek
M J
MJ
D000679:Amygdala / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000494:pharmacology*; D009021:Morphine Dependence; D009294:Narcotics / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D012646:Self Administration; D013788:Thalamus / Q000378:metabolism; D013997:Time Factors
D009294:Narcotics; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine