Repeated administration of methylphenidate produces reinforcement and downregulates 5-HT-1A receptor expression in...

Methylphenidate (MPD) widely prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), is a psychostimulant and can produce addiction in patients treated with it. In view of growing increase in the use of drug by general population as a cognitive enhancer, the present study is designed to investigate reinforcing and cognition enhancing effects of MPD in rats. Associated changes in serotonin-1A receptor expression are investigated as a potential molecular mechanism involved.

Learning acquisition and memory retention in Morris water-maze test were used to assess cognitive effects of MPD. Reinforcing effects were evaluated in conditioned place-preference (CPP) paradigm. The expression of 5-hydroxytryptamine (5-HT; serotonin)-1A receptor in the nucleus accumbens and prefrontal cortex of repeated MPD treated animals was determined by qRT-PCR.

Lower doses (0.5 and 2.5 mg/kg) of MPD enhanced learning acquisition and memory retention but higher doses (5 mg/kg) impaired these. The drug administered repeatedly at a dose of 2.5 mg/kg was reinforcing in CPP test, but sensitization like effects of this dose were only transient. These animals tested in water-maze test exhibited improved memory retention but no effect occurred on learning acquisition. The expression of 5-HT-1A receptor was markedly attenuated in the nucleus accumbens; attenuation in the prefrontal cortex was not significant.

The findings suggest that clinically relevant doses of MPD can produce drug addiction, but effects of the drug on memory retention are retained. A downregulation of 5-HT-1A receptor in the nucleus accumbens seems important in the reinforcing effects of MPD.