PubMed · 14137524
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O MUSTALA. 1964. ["DOPING"].. https://pubmed.ncbi.nlm.nih.gov/14137524/
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The neonatal lesion with 6-hydroxydopamine (6-OHDA) in rodents induces juvenile hyperactivity and paradoxical hypolocomotor response to psychostimulants, in striking contrast to what is observed when similar lesions are carried out in adults. The early disruption of central dopaminergic pathways is followed by increased striatal serotonin (5-HT) contents although the functional role of this neurodevelopmental adaptation remains unclear. The aim of the present study is to investigate the participation of this neurochemical imbalance in the main behavioral phenotypes of this model. To this end, mice received a neonatal administration of 6-OHDA that induced an 80% striatal dopamine depletion together with 70% increase in 5-HT. Serotoninergic hyperinnervation was evidenced further by increased [(3)H] citalopram autoradiographic binding and 5-HT transporter immunohistochemistry in striatal sections. To investigate whether elevated 5-HT was implicated in hyperactivity, we treated control and 6-OHDA neonatally lesioned mice with the selective irreversible tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) to induce 5-HT depletion. Normalization of striatal 5-HT in 6-OHDA neonatally lesioned mice to control levels reversed hyperactivity to normal locomotor scores, whereas the same extent of 5-HT depletion did not affect spontaneous locomotor activity of control mice. In turn, the paradoxical response to amphetamine in neonatal DA-depleted mice was not prevented by PCPA treatment. Taken together, our results suggest that the increased striatal 5-HT that follows neonatal DA depletion is involved in hyperlocomotor behavior but not in the paradoxical calming response to amphetamine observed in this mouse model.
Guanosine has been shown to modulate glutamate system by stimulating astrocytic glutamate uptake. Recent evidence suggest that the locomotor effects of NMDA receptor antagonists, an animal model of schizophrenia, is associated with activation of non-NMDA glutamatergic receptors caused by increased glutamate release. The present work was undertaken to evaluate whether guanosine could have influence on the hyperlocomotion induced in mice by dizocilpine (MK-801), a NMDA antagonist. We also evaluated the effect of guanosine on the hyperlocomotion induced by the indirect dopamine agonist amphetamine, and by the non-selective adenosine receptor antagonist caffeine. Guanosine (7.5 mg/kg) produced an attenuation of about 60% on the hyperlocomotion induced by dizocilpine (0.25 mg/kg), whereas it did not affect the hyperlocomotion induced by amphetamine (5 mg/kg) or caffeine (30 mg/kg). Guanosine pre-treatment did not affect total spontaneous locomotion in all experiments. To test neuronal pathway selectivity, we evaluated MK-801 against guanosine in a working memory paradigm (spontaneous alternation task). Guanosine did not reverted the impairment caused by MK-801 in the spontaneous alternation test, and when administered alone also presented an amnesic effect. The results are discussed based on the current hypothesis of locomotor activation induced by the psychoactive drugs studied. Further studies are necessary to evaluate if guanosine could have clinical utility for the treatment of schizophrenia.
Prenatal administration of synthetic estrogens in humans as well as lower mammals was reported to alter behavior in adulthood. The alterations remain to be characterized according to specific pathophysiological hypotheses. In this study, three common behavioral models of schizophrenia were tested, i.e., latent inhibition (LI), prepulse inhibition of the startle response (PPI) and hyperlocomotion under amphetamine. Female Long-Evans rats were injected i.p. with a solution of 17alpha-ethinylestradiol (15 microg kg(-1)) everyday from day 9 to 14 of pregnancy, and behavioral characteristics of their offspring, raised by Wistar foster mothers, were compared to those of rats born from dams injected with the vehicle only, over the same gestation period. LI was tested in a conditioned taste aversion and a conditioned passive avoidance paradigm followed by a parametric study of PPI and an evaluation of locomotion in an open field under saline or amphetamine (1.5 mg kg(-1)). Histological brain measurements were also carried out in a subset of the same rats. Neither LI nor PPI was altered using methods that had proven sensitive in previous pharmacological studies. Treated rats' locomotion was impaired, but amphetamine did not elicit a differential enhancement. A thinner Amon's horn layer was observed in their hippocampus. This indicates that standard models of schizophrenia did not fit to the behavioral abnormalities found by others and confirmed in this study. They were not due to the abnormal maternal care to pups elicited by the treatment.