Timing of amphetamine exposure in relation to puberty onset determines its effects on anhedonia, exploratory behavior, and dopamine D₁ receptor expression in young adulthood

Non-medical use of amphetamine (AMPH) among adolescents is prevalent, which is problematic given the potential consequences of developmental drug exposure on brain function and behavior. Previously we found in adult male rats that AMPH exposure starting before puberty induces a persistent decrease in dopamine D₁ receptor (D₁R) function in the medial prefrontal cortex (mPFC). Here we investigated if this dysfunction was associated with changes in D₁R expression in the mPFC and nucleus accumbens (NAc). We also determined if starting drug exposure well before or near the onset of puberty would influence AMPH-induced changes in D₁R expression and behavior. Male and female Sprague–Dawley rats were treated once every other day (10 injections total) with saline or 3 mg/kg AMPH (i.p.) from either postnatal day (P) 27 to 45 (pre-puberty groups; Pre-P) or P37 to 55 (peri-puberty groups; Peri-P). After 1, 7 and 21 days of withdrawal, sucrose preference tests were performed to assess anhedonia. Exploratory behavior was studied in an open-field arena and on an elevated plus maze (EPM). Rats were then sacrificed for Western blot analysis of D₁R expression. We found that AMPH withdrawal induced decreases in sucrose preference that persisted in rats with Peri-P onset treatment. Pre-P onset AMPH exposure led to increased open-arm exploration in the EPM test, as well as a decreased D₁R level in the mPFC but not NAc. Our results demonstrated that AMPH exposure starting at different developmental stages resulted in distinct neurobehavioral abnormalities, suggesting an important role of exposure timing in drug-induced plasticity.