Effort-related motivational effects of methylphenidate: Reversal of the low-effort bias induced by tetrabenazine and enhancement of progressive ratio responding in male and female rats.

Dopamine (DA) regulates behavioral activation and effort-related aspects of motivation. Blockade of DA storage by tetrabenazine (TBZ) induces depressive symptoms in humans, including fatigue and apathy. TBZ shifts choice behavior in rodents from high-effort to low-effort options, which can be used to model motivational symptoms observed in psychiatric disorders. The catecholamine transport inhibitor methylphenidate (MPH) reverses the effort-related effects of TBZ in male rats, but this effect needs to be investigated in females. The current study examined the effects of MPH on effort-based choice in male and female rats. Animals were tested on the fixed ratio 5 (FR5)/chow feeding choice task. Because of sex differences in the effects of TBZ, 1.0 mg/kg was used in males, while 2.0 mg/kg was used in females. In both sexes, TBZ shifted choice from lever pressing to chow intake. Co-administration of MPH reversed the effort-related effects of TBZ in males at all doses tested (0.5-4.0 mg/kg IP), whereas only 1.0 and 2.0 mg/kg MPH reversed the effects of TBZ in females. Rats also were tested on a progressive ratio (PROG) schedule and a PROG/chow feeding choice task to assess the effects of MPH administered alone (0.5-4.0 mg/kg IP). MPH increased high-effort PROG responding on both tasks in males, whereas females showed no significant increase in lever pressing across the dose range tested. Investigating sex differences in the pharmacology and neurochemistry of effort-based choice enhances our understanding of sex as a factor in motivational dysfunctions, and may foster the development of treatments for effort-related psychiatric symptoms.