Interactions of Modafinil or Methylphenidate with the Reinforcing and Neurochemical Effects of Cocaine

Abstract

Modafinil (MOD) and methylphenidate (MPH) are FDA‐approved wakefulness‐promoting agents, and MPH is also approved as a medication to treat attention deficit disorders. College students, who misuse MOD and MPH as “smart drugs” to increase cognitive performance, are also likely a population at high risk for abuse of illicit stimulants, such as cocaine (COC). Since MOD and MPH like COC target the dopamine (DA) transporter, and their interactions have not yet been fully described, it is critical to determine the effects of MOD on the reinforcing effects of COC. In the present study MOD (0.1‐10 mg/kg iv) failed to maintain self‐administration (SA) behavior above vehicle levels in rats trained with COC (0.1‐1 mg/kg iv), whereas MPH SA was maintained above vehicle levels at doses comparable to those for COC SA (0.1‐1 mg/kg iv). However, both MOD (10‐32 mg/kg ip) and MPH (1‐10 mg/kg ip) pre‐treatments dose‐dependently potentiated COC SA, shifting the dose‐response curve to the left. COC, at doses that maintain SA, also produced dose‐related stimulation of DA levels in the nucleus accumbens shell, a brain area involved in drug reinforcement. While MPH enhanced this cocaine‐dependent increase in DA, MOD had no significant effects. In summary, MOD had an unusual stimulant profile compared to COC and MPH. The results suggest MOD may enhance reinforcing effects when combined with sub‐threshold doses of COC. Further the results indicate a basis for clinical use of MOD as an agonist substitution therapy for stimulant abuse, as it shares many pharmacological effects of COC, but appears to have low abuse liability of its own.Support: NIDA/IRP