Semax, an ACTH(4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents.

Corticotrophin (ACTH) and its analogues, particularly Semax (Met-Glu-His-Phe-Pro-Gly-Pro), demonstrate nootropic activity. Close functional and anatomical links have been established between melanocortinergic and monoaminergic brain systems. The aim of present work was to investigate the effects of Semax on neurochemical parameters of dopaminergic- and serotonergic systems in rodents. The tissue content of 5-hydroxyindoleacetic acid (5-HIAA) in the striatum was significantly increased (+25%) 2 h after Semax administration. The extracellular striatal level of 5-HIAA gradually increased up to 180% within 1-4 h after Semax (0.15 mg/kg, ip) administration. This peptide alone failed to alter the tissue and extracellular concentrations of dopamine and its metabolites. Semax injected 20 min prior D: -amphetamine dramatically enhanced the effects of the latter on the extracellular level of dopamine and on the locomotor activity of animals. Our results reveal the positive modulatory effect of Semax on the striatal serotonergic system and the ability of Semax to enhance both the striatal release of dopamine and locomotor behavior elicited by D-amphetamine.

Delta-sleep inducing peptide and neuronal activity after glutamate microiontophoresis: the role of NMDA-receptors.

The influence of microiontophoretic application of delta-sleep inducing peptide (DSIP) on a neuronal activity of sensorimotor brain cortex, dorsal hippocampus, ventral anterior thalamic nucleus and lateral hypothalamus was studied under the effects of glutamate and MK-801, a N-methyl-d-aspartate non-competitive antagonist, on male Wistar rats. DSIP microiontophoresis predominantly activated neurons of various brain regions, in particular, dorsal hippocampus and ventral anterior thalamic nucleus. A preliminary DSIP microiontophoresis prevented the augmentation of a neuronal activity in the studied structures under glutamate microiontophoresis. After MK-801 microiontophoresis the number of neurons activated by the DSIP significantly decreased. It is suggested that DSIP effects on the neuronal activity in the sensorimotor brain cortex, dorsal hippocampus, ventral anterior thalamic nucleus and lateral hypothalamus might be mediated by the NMDA-receptors.

Chronic neonatal N-methyl-D-aspartate receptor blockade induces learning deficits and transient hypoactivity in young rats.

A blockade of N-methyl-D-aspartate (NMDA)-type of glutamate receptor in rodents is believed to provide a pharmacological model of schizophrenia-related psychosis. Since neurodevelopmental abnormality, at least partly, could contribute to the pathogenesis of schizophrenia, the aim of this study was to recapitulate cognitive impairments accompanying this disorder in rats by a chronic neonatal treatment with a noncompetitive NMDA antagonist MK-801. Rat pups were treated with a low dose of MK-801 (0.05 mg/kg s.c.) chronically from early postnatal period (PD 7-49) known to be critical for glutamatergic system maturation. Locomotor activity in the "open-field" test, anxiety level in the elevated plus-maze test, and learning capacity in food rewarded spatial task were examined in young animals. Chronic MK-801 treatment produced a decrease of spontaneous motor and exploratory activity in 16- to 28-day-old rats. At the same time, a hyperlocomotion in response to acute administration of MK-801 was observed as well. Spatial learning of MK-801-treated rats was found to be negatively affected. Treated rats were able to respond to stress stimuli in the adequate manner but their anxiety level was found to be lower than in controls. Behavioral disturbances appeared to be temporary, and no such abnormalities could be detected at the age of 16 weeks. Thus, even mild chronic neonatal blockade of NMDA receptors may lead to a specific pattern of cognitive abnormalities presumably resulting from impairments of sensory information processing at the cortical-basal ganglia level.

Effect of sulpiride on the amphetamine-induced changes in extracellular dopamine, DOPAC, and hydroxyl radical generation in the rat striatum.

The neurotoxic effects of psychostimulants are mediated by several mechanisms, which together lead to neuronal damage. These mechanisms include an increase in the extracellular content of dopamine, stimulation of dopamine oxidation, accumulation of extracellular glutamate, and an increase in body temperature. In the present study, the dopamine receptor antagonist sulpiride proved able to prevent the delayed loss of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) and depressed the gradual generation of hydroxyl radicals induced in the rat striatum by D-amphetamine. However, sulpiride at a dose of 75 mg/kg x 2, coadministered with D-amphetamine (7.5 mg/kg x 4), potentiated the increase in extracellular dopamine and initially slightly enhanced D-amphetamine-induced stereotypy. The gradual increase in hydroxyl radical generation predicts the depletion of dopamine and DOPAC in the rat striatum after D-amphetamine administration, but the increase in extracellular dopamine is not a pivotal factor in the enhanced production of hydroxyl radicals.