Effects of voluntary oral THC on oxycodone seeking and protein kinase signaling in rat nucleus accumbens and prefrontal cortex

Katherine E. Driver, MS
University of Florida

Co-authors: Katherine Driver¹, Barry Setlow¹, Lori Knackstedt¹, Marek Schwendt^1
1University of Florida

Background: Despite a poor understanding of the risks and benefits of opioid-cannabinoid interactions, opioid use disorder (OUD) is currently considered a qualifying condition for the use of medical marijuana in several US states. There is some clinical evidence suggesting that co-use of cannabinoids can reduce rates of opioid use and severity of withdrawal. However, these reductions in behavior may be at the cost of elevated anxiety and/or depression in OUD patients. Thus, well-controlled, translational animal models are necessary to investigate the neural and behavioral consequences of cannabinoid-opioid co-use.

Objectives: Here, we investigated the effects of daily oral ∆9- tetrahydrocannabinol (THC) consumption on behavioral economic demand for intravenously (IV) self-administered oxycodone in adult and adolescent male and female Sprague Dawley rats, and subsequently assessed protein kinase signaling associated with CB1 cannabinoid and mu opioid receptor activity in brain regions implicated in opioid-seeking behavior.

Methods: Rats were trained to self-administer IV oxycodone or sucrose pellets on an FR3 schedule of reinforcement. After reaching stable intake, rats underwent economic demand procedures in which FR requirements to earn a single reinforcer increased in quarter-log unit increments every second day until 0 reinforcers were earned. Throughout demand curve testing, rats also consumed gelatin containing either THC (1.0 mg/kg) or vehicle, immediately following each operant session (and 22 hr prior to the next session). After several doses of daily THC, somatic signs of withdrawal and anxiety-like behavior were assessed at 22 hr withdrawal. Upon completing the demand curve (0 rewards earned at FR), self-administration was re-established, followed by 14 days of home-cage abstinence and a cue-primed test of oxycodone/sucrose seeking. Immunoblotting was used to assess (phospho)protein levels in relevant brain regions.

Results: THC increased demand elasticity (i.e., reduced seeking) for oxycodone but not sucrose, in adult but not adolescent rats. Total expression and phosphorylation activity of the kinases AKT and PKA were not affected by either oxycodone experience or THC within the adult cohort, with adolescent data pending. There were no effects of THC on withdrawal or anxiety-like behavior in either age group.

Conclusions: Our data suggest that, in male and female Sprague Dawley rats that initiated oxycodone use during adulthood, THC consumption leads to increased demand elasticity for oxycodone IV self-administration and reduced oxycodone seeking. In rats that initiated oxycodone IVSA in adolescence, however, THC had no effects on oxycodone seeking. Further research into neural mechanisms mediating age-dependent THC effects is needed.