Peri-adolescent bupropion treatment alters adult operant responding and is associated with reduced ΔFosB and thin spine density in the nucleus accumbens in rats

Exposure to pharmacological agents can disrupt brain development, producing maladaptive neurobehavioural output. The reward system is established over a protracted developmental time period which allows for age-specific vulnerabilities to external influence. Bupropion (BUP) inhibits dopamine (DA) and norepinephrine (NE) transporters, indirectly increasing synaptic availability of DA and NE. In the current work, short- and long-term effects of BUP treatment during sensitive periods of postnatal development in rats were evaluated to assess reward-related neurobehavioural outcomes. Male and female Long-Evans rats were administered 10 or 20 mg/kg BUP or saline subcutaneously for one week during preadolescence (p18-24) or peri-adolescence (p34-40). Ambulatory activity was assessed during drug treatment and 25 days after treatment. Reward-related outcomes were assessed during a 10-day period starting 2 weeks after the final drug treatment and included operant training, extinction, and progressive ratio tests. Exposure to BUP during preadolescence had minimal effects. Exposure during peri-adolescence resulted in pronounced on-drug psychomotor responses and off-drug stimulus discrimination deficits (i.e., increased incorrect lever pressing) during extinction and progressive ratio tests. Reduced density of thin spines and ΔFosB-labelling in the nucleus accumbens were also observed in the peri-adolescent BUP-treated groups. The behavioural and neural outcomes suggest that BUP treatment disrupted the development of the reward system in an age- and dose-specific manner resulting in impaired stability of response-reward associations in adulthood.