Blockade of sensitization to methylphenidate by MK-801: partial dissociation from motor effects.
The role of MK-801's locomotor effect in blocking the development of sensitization to methylphenidate was investigated utilizing a computerized locomotor activity monitoring system. After 7 days of acclimation to a 12:12 light-dark cycle (lights on at 07:00), male Sprague-Dawley rats (n=62) were housed in test cages and motor activity was recorded continuously for 16 days. The first 2 days of recording served as a baseline for each rat, and on day 3 each rat received a saline injection. On days 4 to 9 rats were randomly divided into seven groups: Rats received either six daily s.c. injections of methylphenidate (2.5 mg/kg; Group 1), or six daily i.p. injections of 0.30 mg/kg, 0.05 mg/kg MK-801 (Groups 2 and 3, respectively); two MK-801 pre-treatment groups received a single i.p. injection of 0.05, or 0.30 mg/kg MK-801 one hour prior to 2.5 mg/kg methylphenidate (n=8 each) on day 4 followed by five daily injections of 2.5 mg/kg methylphenidate; and finally, two cotreatment groups received a challenge dose of 2.5 mg/kg methylphenidate on day 4 followed by either 0.05 or 0.30 mg/kg MK-801 i.p. one hour prior to 2.5 mg/kg methylphenidate from days 5 to 9. All groups were allowed five days of no treatment before being re-challenged on day 15 with the same treatment they received on day 4. Methylphenidate and 0.30 mg/kg MK-801 sensitized to their own locomotor effects, but 0.05 mg/kg MK-801, which had no acute motor effects, did not. The administration of MK-801 (0.30 mg/kg) prior to methylphenidate either singly on day 4, or coadministered throughout the repeated methylphenidate treatment phase, blocked the development of sensitization to methylphenidate. However, MK-801 at 0.05 mg/kg delayed the development of sensitization when co-administered on days 5 to 9, but a single injection 1 h prior to methylphenidate on day 4 did not prevent sensitization to subsequent methylphenidate administration. In conclusion, MK-801 prevents sensitization to methylphenidate; motor stimulation by MK-801 is not necessary for short-term prevention or delay of sensitization to methylphenidate but may be necessary for a persistent blockade of sensitization.
Gaytan
O
O
Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, P.O. Box 20708, Houston, TX 77225, USA.
Sripada
S
S
Swann
A
A
Dafny
N
N
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D008774:Methylphenidate; D016291:Dizocilpine Maleate