Context-drug-associations and reinstatement of drug-seeking behavior in male rats: Adolescent and adult time-dependent effects.

RATIONALE: Drug use during adolescence results in a life-long risk to develop substance-use disorders. Adolescent rats are sensitive to different drug-associated cues, compared to adults; however, the contribution of adolescent-formed context-drug-associations to elicit relapse-like behavior is underexplored. OBJECTIVES: The present study compared the effect of adolescent vs adult-formed context-drug associations to elicit time-dependent increases in cocaine-seeking behavior. This objective was accomplished using an abbreviated (ABRV) operant cocaine self-administration (Coc-SA), Extinction (EXT) paradigm, with cocaine-seeking tests occurring 1 day after training (T1, early relapse) or following 15 days of abstinence (T15, late relapse). METHODS: Adolescent and adult rats received ABRV Coc-SA in a distinct context (2 hr, 2x/day over 5 days) then EXT in a second context (2 hr, 2x/day over 4 days). Adolescent or adult cocaine-exposed rats were then tested (2 hr, non-rewarded) in either the previous EXT or Coc-paired contexts during early or late relapse. RESULTS & CONCLUSIONS: As previously reported, both adolescent and adult cocaine-exposed rats displayed similar magnitudes of cocaine intake and lever presses during Coc-SA, EXT, and early relapse. Independent analysis of adolescent and adult groups revealed differences in lever responding, specifically rats with cocaine exposure during adolescence showed time-dependent increases in lever responding during late relapse. These data suggest that cocaine-context associations formed during adolescence can elicit craving during adulthood and that these age-specific differences in contextual sensitivity may not be immediately observed at early relapse periods.

Cocaine reward and reinstatement in adolescent versus adult rodents.

Adolescence is a critical juncture when initiation of drug use intersects with profound developmental changes in the brain. Adolescent drug use increases the risk to develop substance use disorders (SUDs) later in life, but the mechanisms that confer this vulnerability are not understood. SUDs are defined by cycles of use, abstinence, and relapse. Intense craving during drug-free periods is often triggered by cues and environmental contexts associated with previous use. In contrast to our understanding of stimuli that elicit craving and relapse in adults, the behavioral processes that occur during periods of abstinence and relapse in adolescents are poorly understood. The current mini-review will summarize findings from preclinical rodent studies that used cocaine conditioned place preference and operant cocaine self-administration to examine subsequent effects on reward, relapse and incubation of craving.

Influence of reconsolidation in maintenance of cocaine-associated contextual memories formed during adolescence or adulthood.

Adolescents are at increased risk to develop substance use disorders and suffer from relapse throughout life. Targeted weakening of drug-associated memories has been shown to reduce relapse-like behavior in adult rats, however this process has been understudied in adolescents. We aimed to examine whether adolescent-formed, cocaine-associated memories could be manipulated via reconsolidation mechanisms. To accomplish this objective, we used an abbreviated operant cocaine self-administration paradigm (ABRV Coc-SA). Adult and adolescent rats received jugular catheterization surgery followed by ABRV Coc-SA in a distinct context for 2 h, 2×/day over 5 days. Extinction training (EXT) occurred in a second context for 2 h, 2×/day over 4 days. To retrieve cocaine-context memories, rats were exposed to the cocaine-paired context for 15 min, followed by subcutaneous injection of vehicle or the protein synthesis inhibitor cycloheximide (2.5 mg/kg). Two additional EXT sessions were conducted before a 2 h reinstatement test in the cocaine-paired context to assess cocaine-seeking behavior. We find that both adult and adolescent cocaine-exposed rats show similar levels of cocaine-seeking behavior regardless of post-reactivation treatment. Our results suggest that systemic treatment with the protein synthesis inhibitor cycloheximide does not impair reconsolidation of cocaine-context memories and subsequent relapse during adulthood or adolescence.