The indirect dopamine agonist, pemoline (120–300 mg/kg s.c.), can induce self-biting behavior in the rat. The present study demonstrates that the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, dizocilpine (MK-801, 0.2 mg/kg s.c.), significantly attenuates pemoline-induced self-biting behavior, while simultaneously increasing locomotor activity. When animals received a fixed dose of MK-801 with increasing doses of pemoline, a competitive relationship emerged such that high-dose pemoline surmounted the antagonistic effect of MK-801. In contrast to spiperone, delayed administration of MK-801 was ineffective in blocking the subsequent expression of self-biting behavior, suggesting that dizocilpine exerts its protective effect early in the cascade of events which eventually leads to self-biting behavior in this paradigm.
Pemoline-induced self-biting behavior has been compared to similar self-injurious behavior (SIB) that occurs in the context of some mental retardation syndromes. The opiate antagonist, naltrexone, has been used successfully in the treatment of SIB in individuals with autism or mental retardation. This is the first report of the effect of naltrexone in an animal model of self-biting behavior. Naltrexone (0.01 mg/kg s.c.) significantly reduced the severity of self-biting behavior, but higher doses (0.10-10 mg/kg s.c.) had no such effect. Consistent with these results in the rat, a review of the clinical use of naltrexone in SIB is also suggestive of a relative loss of efficacy at higher doses (apparent therapeutic window). Naltrexone has higher affinity for mu receptors than other opioid receptor subtypes. Thus, the effect of naltrexone in treating SIB appears to be due to (mu-receptor interactions, with the loss of effect at higher doses due to supervening kappa receptor binding. Speculatively, one may ask if dosage reduction would convert naltrexone nonresponders to responders by lowering kappa receptor-mediated effects. Given the co-localization of opioids and dopamine inputs in some neurons, opioid-dopamine system interactions may also be important in pemoline-induced self-biting behavior.
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