Effects of caffeine and its metabolite paraxanthine on intracranial self-stimulation in male rats.

Caffeine is the most widely used psychostimulant in the world, though preclinical studies suggest weaker evidence for abuse-related effects than stimulants with high abuse liability, such as amphetamine or cocaine. Intracranial self-stimulation (ICSS) is 1 procedure used to assess the abuse liability of drugs, and previous studies have produced mixed results regarding whether caffeine produces an abuse-related facilitation of ICSS. This study assessed both caffeine and its main metabolite in humans, paraxanthine, using a frequency-rate ICSS procedure and compared their effects to those of amphetamine and cocaine. Male Sprague-Dawley rats were implanted with intracranial electrodes targeting the medial forebrain bundle and trained to respond under a fixed-ratio 1 schedule for brain stimulation that varied across a range of frequencies (56-158 Hz in 0.05 log increments). Data analysis focused on 3 dependent measures: reinforced responding (defined as responses that produced brain stimulation), nonreinforced responding (defined as responses that occurred during each 0.5 s brain stimulation and that did not produce additional stimulation), and total responding (reinforced plus nonreinforced responding). Both amphetamine and cocaine produced robust increases in total, reinforced, and nonreinforced responses. Caffeine also increased total, reinforced, and nonreinforced responses, but the caffeine dose-effect curve had an inverted-U shape, and peak ICSS facilitation was less than that produced by amphetamine or cocaine. Paraxanthine increased only total responses and nonreinforced responses. These results suggest that paraxanthine has low abuse liability and does not mediate abuse-related effects of caffeine.