Behavioral and neurochemical effects of cocaine and diphenhydramine combinations in rhesus monkeys

Diphenhydramine (DPH) is an over-the-counter medication used in the treatment of allergic symptoms. While DPH abuse is infrequent, recent preclinical evidence suggests that DPH and cocaine combinations may have enhanced reinforcing properties. The aims were to assess the reinforcing effectiveness of cocaine and DPH alone or in combination under a second-order schedule of reinforcement and to examine the neurochemical basis of this interaction using in vivo microdialysis in awake rhesus monkeys. Cocaine (0.03-0.3 mg/kg per injection), DPH (0.3-3.0 mg/kg per injection), or a combination was available under a second-order schedule of intravenous drug reinforcement (n = 3). In microdialysis studies, noncontingent cocaine (0.1-1.0 mg/kg, iv), DPH (1.7 and 3.0 mg/kg, iv), or a combination was administered and changes in extracellular dopamine levels in the caudate nucleus were examined (n = 3-5). Cocaine and DPH dose-dependently maintained operant responding. Dose combinations of 1.0 or 1.7 mg/kg per injection DPH and 0.03 mg/kg per injection cocaine maintained greater rates of operant responding than 0.03 mg/kg per injection cocaine alone in the second component of the behavioral session. In microdialysis studies, cocaine dose-dependently increased extracellular dopamine levels, but no dose of DPH tested significantly increased dopamine levels above baseline. Moreover, combining DPH with cocaine did not enhance cocaine-induced dopamine increases. The results support previous evidence of enhanced reinforcement with cocaine and DPH combinations and extend this finding to operant behavior maintained under a second-order schedule. However, the reinforcing effects of DPH alone or in combination with cocaine do not appear to be mediated via changes in dopamine overflow.