Evaluation of ADCI against convulsant and locomotor stimulant effects of cocaine: comparison with the structural analogs dizocilpine and carbamazepine.
Both the antiepileptic, carbamazepine, and the N-methyl-D-aspartate receptor antagonist, dizocilpine, have shown preclinical efficacy against behavioral and toxic effects of cocaine. Nonetheless, side effects or toxicity of these compounds either alone or in conjunction with cocaine are problematic. 5-Aminocarbonyl-10,11-dihydro-5h-dibenzo[a,d]cyclohepten-5,1 0-imine (ADCI), a molecular hybrid of these compounds, has been shown to have a broad anticonvulsant profile with a good protective index (behavioral TD50/anticonvulsant ED50). In male Swiss Webster mice, ADCI and dizocilpine produced dose-dependent protection against the convulsant effects of cocaine that were insensitive to carbamazepine. However, in contrast to dizocilpine, ADCI did not produce behavioral impairment on the inverted screen test demonstrating a protective index of greater than 15; the protective index for dizocilpine was 1.2. All three compounds attenuated the locomotor stimulant effects of cocaine without significantly decreasing locomotor activity on their own, although the cocaine antagonism was not always dose dependent. Only dizocilpine increased spontaneous locomotor activity when given alone and augmented the locomotor stimulant effects of cocaine. The results confirm the novel anticonvulsant activity of ADCI and its lack of phencyclidine-like behavioral side effects. The data also suggest a modest blocking action of these compounds against the locomotor stimulatory effects of cocaine.
Psychobiology Section, National Institute on Drug Abuse, Baltimore, MD 21224.
B K
BK
Seidleck
A
A
Thurkauf
J M
JM
Witkin
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002220:Carbamazepine / Q000494:pharmacology; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D019966:Substance-Related Disorders / Q000188:drug therapy
D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; C071316:5-aminocarbonyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine; D002220:Carbamazepine; D016291:Dizocilpine Maleate; D003042:Cocaine