Voluntary alcohol intake alters the motivation to seek intravenous oxycodone and neuronal activation during the reinstatement of oxycodone and sucrose seeking.

Opioid-alcohol polysubstance use is prevalent and worsens treatment outcomes. Here we assessed whether co-consumption of oxycodone and alcohol influence the intake of one another, demand for oxycodone, and the neurocircuitry underlying cue-primed reinstatement of oxycodone-seeking. Male and female rats underwent oxycodone intravenous self-administration (IVSA) with homecage access to alcohol (20% v/v) and/or water immediately after the IVSA session. Next, economic demand for intravenous oxycodone was assessed while access to alcohol and/or water continued. Control rats self-administered sucrose followed by access to alcohol and/or water. Rats underwent a cue-primed reinstatement test and brains were processed for c-fos mRNA expression. While both sexes decreased oxycodone intake if they had access to alcohol, and decreased alcohol intake if they had access to oxycodone, only female oxycodone + alcohol rats exhibited decreased demand elasticity and increased cue-primed reinstatement. Alcohol consumption increased the number of basolateral and central amygdala neurons activated during sucrose and oxycodone reinstatement and the number of ventral and dorsal striatum neurons engaged by sucrose reinstatement. Nucleus accumbens shell dopamine 1 receptor expressing neurons displayed activation patterns consistent with oxycodone reinstatement. Thus, alcohol alters the motivation to seek oxycodone in a sex-dependent manner and the neural circuitry engaged by cue-primed reinstatement of sucrose and oxycodone-seeking.

Voluntary alcohol intake alters the motivation to seek intravenous oxycodone and neuronal activation during the reinstatement of oxycodone and sucrose seeking.

Opioid-alcohol polysubstance use is prevalent and worsens treatment outcomes. Here we assessed whether co-consumption of oxycodone and alcohol would influence intake of one another, demand for oxycodone, and the neurocircuitry underlying cue-primed reinstatement of oxycodone-seeking. Male and female rats underwent oxycodone intravenous self-administration (IVSA) with access to either alcohol (20% v/v) and water or only water immediately after the IVSA session. Next, economic demand for intravenous oxycodone was assessed while access to alcohol and/or water continued. Control rats self-administered sucrose followed by access to alcohol and/or water. Rats underwent extinction training and brains were processed for c-fos mRNA expression immediately following a cue-primed reinstatement test. While both sexes decreased oxycodone intake if they had access to alcohol, and decreased alcohol intake if they had access to oxycodone, female oxycodone+alcohol rats exhibited decreased demand elasticity for intravenous oxycodone and increased cue-primed reinstatement while male rats did not. Spontaneous withdrawal signs were correlated with oxycodone intake while alcohol intake was correlated with anxiety-like behavior. Alcohol consumption increased the number of basolateral and central amygdala neurons activated during sucrose and oxycodone reinstatement and the number of ventral and dorsal striatum neurons engaged by sucrose reinstatement. Nucleus accumbens shell dopamine 1 receptor containing neurons displayed activation patterns consistent with oxycodone reinstatement. Thus, alcohol alters the motivation to seek oxycodone in a sex-dependent manner and alters the neural circuitry engaged by cue-primed reinstatement of sucrose and oxycodone-seeking.

Individual differences in cocaine seeking during voluntary abstinence predicts cocaine relapse and the circuitry mediating relapse.

RATIONALE: There are no FDA-approved treatments to facilitate recovery from cocaine use disorder. Contingency management offers non-drug reinforcers to encourage abstinence and is effective at reducing drug seeking during treatment, but once discontinued, relapse rates increase. OBJECTIVES: We sought to establish a choice-based rodent model of voluntary abstinence (VA) from cocaine to test the ability of ceftriaxone, an antibiotic consistently shown to prevent relapse to cocaine seeking in rodents, to attenuate relapse after discontinuation of VA, and to investigate relapse-induced neuronal activation via c-Fos expression. METHODS: Male Sprague-Dawley rats self-administered sucrose pellets for 5 days and intravenous cocaine for 12 days. Rats then underwent 14 days of voluntary or forced abstinence. VA sessions entailed the opportunity to choose between sucrose and cocaine delivery in discrete trials (20 trials/day). Ceftriaxone (or vehicle) was administered during the last 7 days of abstinence. During a relapse test, only the cocaine-paired lever was available and presses on the lever delivered cocaine-paired cues. RESULTS: There were more presses on the sucrose lever during VA, but cocaine intake did not decline to zero. Ceftriaxone had no effect on cocaine intake during VA. Neither ceftriaxone nor VA reduced cocaine seeking during the relapse test, and cocaine intake during VA positively correlated with cocaine seeking during the test in vehicle-treated animals. Relapse-induced c-Fos expression was found to be greater in the ventral orbitofrontal cortex following VA. CONCLUSIONS: Sucrose availability leads to a decrease in, but not cessation of, cocaine seeking and a differential engagement of the circuitry underlying relapse.