Dextrorphan effects on cocaine and brainstem perturbation.
Dextrorphan is a noncompetitive blocker of N-methyl-D-aspartate (NMDA) receptors. Since NMDA blockers are known to reduce the locomotor stimulatory and toxic effects of cocaine, it was speculated that dextrorphan would attenuate cocaine-induced behavioral excitatory motor activity associated with and without mechanical perturbation of the brainstem.


METHODS
Motor activity was recorded following dextrorphan and/or cocaine challenge in 25 SHR rats. Ten were naive subjects. Mini-osmotic pumps delivering cocaine (2.5 mg/0.49 ul/hr) were placed in 15 subjects, and infusion was halted after the third infusion day. On the fifth day either a dextrorphan (25 mg/kg, subcutaneous) or a dextrorphan and cocaine (40 mg/kg, intraperitoneal) challenge was done. Ten rats had bipolar electrode implants in the bilateral brainstem. Five were treated with DC current lesions in each of 12 days over a 3-week period. The effects of brainstem lesions on escape behavior were also evaluated in those five subjects.


RESULTS
In the naive subjects, dextrorphan reduced motor activity (P = .0001), whereas combined cocaine and dextrorphan increased motor activity (P = 0.04). In lesioned subjects, dextrorphan decreased motor activity (P = 0.0001). In electrode implant subjects, combined dextrorphan and cocaine challenge decreased the motor activity (P = 0.04). Hyperactivity in the electrode implant group was greater than in the lesioned subjects. Midbrain electrolytic lesions attenuated escape behavior. A variety of behaviors were produced by brainstem lesions.


CONCLUSIONS
Dextrorphan and brainstem lesions reduced motor hyperactivity and escape behavior. In electrode implant subjects dextrorphan counteracted the expected cocaine excitatory motor effects. Dextrorphan did not activate nor facilitate seizures.
Dept. of Neurosurgery, U. of Mississippi Med Center, Jackson 39126, USA.
M
M
Lundien
O J
OJ
Andy
R W
RW
Rockhold
M
M
Andrews
C
C
Dearman
D000818:Animals; D001143:Arousal / Q000187:drug effects*; D001933:Brain Stem / Q000187:drug effects*; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003917:Dextrorphan / Q000494:pharmacology*; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D004924:Escape Reaction / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007260:Infusion Pumps; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D009043:Motor Activity / Q000187:drug effects*; D009294:Narcotics / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
D018691:Excitatory Amino Acid Antagonists; D009294:Narcotics; D016194:Receptors, N-Methyl-D-Aspartate; D003917:Dextrorphan; D003042:Cocaine