The behavioral effects of NMDA antagonists in serotonin depleted rats

The influence of serotonin (5-HT) depletion (5,7-dihydroxytryptamine, 5,7-DHT, 250.0 micrograms, ICV), on behavioral effects of non-competitive (MK-801) and competitive (CGP 37849) NMDA antagonists, was examined in rats. 5,7-DHT induced very potent and long lasting decrease in the 5-HT concentration in the brainstem and limbic forebrain. One week after 5,7-DHT administration, dopamine metabolism was found enhanced in the brainstem. The lesion did not change rat baseline motor and exploratory activity, but it significantly disinhibited animals' behavior suppressed by shock, in the Vogel test. Serotonin depletion revealed locomotor stimulating effect of MK-801, administered IP at the doses of 0.05 and 0.2 mg/kg. However, no change in striatal dopamine metabolism was detected in rats injected with the same dose of MK-801 (0.2 mg/kg), and examined one week after serotonergic denervation. Serotonergic lesions antagonized both enhancements of exploratory behavior, and motor suppression produced by the dose of 1.0 and 10.0 mg/kg of CGP 37849, respectively. Thus, 5,7-DHT-induced lesions influenced in a complex way the effects of NMDA antagonists. It is reasoned, that enhancement of motor stimulating effects of MK-801 in neurotoxin pretreated animals, reflects synergistic disinhibition of activity of dopaminergic neurons by MK-801 and serotonin depletion. On the other hand, antagonism of CGP 37849-caused motor depression can be explained by the lowering influence of 5,7-DHT on serotonin content. It is known that the release of serotonin is strongly stimulated by higher doses of CGP 37849, and takes part in the expression of some symptoms of the serotonin-like syndrome, including motor disturbances.