Sex differences in opioid reinforcement under a fentanyl vs. food choice procedure in rats

AbstractBackgroundOpioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied and the role of sex is largely unknown.MethodsMale (n=10) and female (n=9) rats responded under a fentanyl-vs.-food “choice” procedure during daily 2h sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12h sessions. After two weeks of this self-administration regimen, the nucleus accumbens (NAc) and ventral tegmental area (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-vs.-food choice were determined.ResultsPrior to opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited a similar increase in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with transcriptional hyperfunction in the NAc and VTA of opioid-withdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males, but failed to further decrease fentanyl choice in females.ConclusionsThese results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.

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Extinguishing cocaine-associated discriminative stimuli attenuates cocaine vs food choice in male rhesus monkeys

10.1101/753699 ◽

2019 ◽

Author(s):

Matthew L Banks ◽

Blake A. Hutsell ◽

S Stevens Negus

Keyword(s):

Food Choice ◽

Rhesus Monkeys ◽

Fixed Ratio ◽

Concurrent Schedule ◽

Food Delivery ◽

Self Administration ◽

Discriminative Stimuli ◽

Choice Procedure ◽

Choice Procedures ◽

Male Rhesus

ABSTRACTBackgroundIn drug addiction, relapse can be triggered by cues that function as discriminative stimuli to signal contingencies of drug availability and promote drug-taking behavior. Extinction procedures can weaken the association between drug-associated cues and drug use and may reduce the probability of relapse. This study evaluated effects of a regimen of extinction training on cocaine self-administration maintained in rhesus monkeys under a cocaine-vs.-food choice procedure that has been used previously to evaluate effectiveness of other candidate treatments for cocaine abuse.MethodsBehavior was initially maintained under a concurrent schedule of food delivery (1-g food pellets; fixed-ratio 100 schedule) and cocaine injections (0-0.1 mg/kg/injection; fixed-ratio 10 schedule) during daily 2-h choice sessions in male rhesus monkeys (n=4). Subsequently, choice sessions were supplemented by daily 20-h extinction sessions for 14 consecutive days. During extinction sessions, cocaine-associated discriminative stimuli were presented, but responding did not produce cocaine injections. Cocaine continued to be available during choice sessions.ResultsPrior to extinction, cocaine maintained a dose-dependent increase in cocaine vs. food choice. Responding during extinction sessions declined to low levels by the fifth day. Exposure to extinction sessions produced a more gradual but significant decline in cocaine choice and a complementary increase in food choice during choice sessions.ConclusionsThese preclinical results support the effectiveness of extinguishing cocaine-associated discriminative stimuli as a non-pharmacological treatment strategy for reducing cocaine choice. Moreover, these results also support the construct validity of preclinical drug vs. food choice procedures as a tool for candidate treatment evaluation for cocaine addiction.

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