Oral and transdermal DL-methylphenidate-ethanol interactions in C57BL/6J mice: potentiation of locomotor activity with oral delivery

Abstract

Purpose: Many abusers of dl-methylphenidate co-abuse ethanol. The present animal study examined behavioral effects of oral or transdermal DL-methylphenidate in combination with a high, depressive dose of ethanol to model co-abuse.

Methods: Locomotor activity of C57BL/6J mice was recorded for 3 h following dosing with either oral DL-methylphenidate (7.5 mg/kg) or transdermal DL-methylphenidate (Daytrana®;1/4 of a 12.5 cm(2) patch; mean dose 7.5 mg/kg), with or without oral ethanol (3 g/kg). Brains were enantiospecifically analyzed for the isomers of methylphenidate and the transesterification metabolite ethylphenidate.

Results: An otherwise depressive dose of ethanol significantly potentiated oral DL-methylphenidate induced increases in total distance traveled for the first 100 min (p<0.05). Transdermal DL-methylphenidate increased total distance traveled after a latency of 80 min, though this effect was not potentiated by concomitant ethanol. Mean 3 h brain D-methylphenidate concentrations were significantly elevated by ethanol in both the oral (65% increase) and transdermal (88% increase) groups. The corresponding L-ethylphenidate concentrations were 10 ng/g and 130 ng/g.

Conclusions: Stimulant induced motor activity in rodents may correlate with abuse liability. Potentiation of DL-methylphenidate motor effects by concomitant ethanol carries implications regarding increased abuse potential of DL-methylphenidate when combined with ethanol.

Figure 1

Enantioselective de-esterification of dl-MPH to ritalinic acid (top right) and transestification to l-ethylphenidate.

Figure 2

(A) Oral dl-MPH + dH₂0 significantly increased total distance traveled (*, p<0.05) and this effect was potentiated by a depressive dose of ethanol (+, p<0.05). (B) Oral dl-MPH significantly increased vertical activity of mice over the first 100 min (*, p<0.05).

Figure 3

(A) Transdermal dl-MPH induced locomotor activity after a lag phase of 100 min (**, p<0.01). While this effect was not potentiated by ethanol, transdermal dl-MPH + ethanol was significantly greater than placebo patch + dH₂0 after a lag phase of 140 min (++, p<0.01). (B) Transdermal dl-MPH significantly increased vertical activity of mice after 100 min lag time (*, p<0.05).

Figure 4

(A&B) Ethanol significantly increased brain concentrations of d-MPH and l-MPH relative to dH₂0 in mice dosed orally or transdermally (*, p<0.05; ***, p<0.001).