PubMed · 7293853
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G Calhoun, J Bolton. 1981. Hyperactivity and hyperkinesis: another perspective.. https://pubmed.ncbi.nlm.nih.gov/7293853/
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Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It is proposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors.
In this study, we examined the effect of the 5-HT2A,C receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on locomotor activity and the head twitch response in rats by the repeated (twice daily for 4 days) subcutaneous administration of 0.9% saline (1 ml/kg) or (+/-)-3,4-Methylenedioxymethamphetamine (MDMA) (20 mg/kg), a compound that selectively destroys serotonergic nerve terminals. There was no difference between the MDMA- and saline-treated rats regarding the (+/-)-DOI-induced (0.625, 1.25 or 2.5 mg/kg, i.p.) increase and decrease in the head twitch response and horizontal locomotor activity, respectively. Overall, repeated MDMA does not alter the behavioral response of rats to (+/-)-DOI.
Oxidative stress is thought to play an important role in the pathogenesis of Parkinson's disease (PD). Glutathione (GSH), a major cellular antioxidant, is decreased in the substantia nigra pars compacta of PD patients. The aim of the present study was to investigate whether deprenyl and its desmethyl metabolite, putative neuroprotective agents in the treatment of PD, could protect cultured rat mesencephalic neurons from cell death caused by GSH depletion due to treatment with L-buthionine-(S,R)-sulfoximine (BSO). BSO (10 microM) caused extensive cell death after 48 hr, as demonstrated by disruption of cellular integrity and release of lactate dehydrogenase into the culture medium. Both deprenyl and desmethylselegiline, at concentrations of 5 and 50 microM, significantly protected dopaminergic neurons from toxicity without preventing the BSO-induced loss in GSH. Protection was not associated with monoamine oxidase type B inhibition in that pargyline, a potent MAO inhibitor, was ineffective and pretreatment with pargyline did not prevent the protective effects of deprenyl. Protection was not associated with inhibition of dopamine uptake by deprenyl because the dopamine uptake inhibitor mazindol did not diminish BSO toxicity. The antioxidant ascorbic acid (200 microM) also protected against BSO-induced cell death, suggesting that oxidative events were involved. This study demonstrates that deprenyl and its desmethyl metabolite can diminish cell death associated with GSH depletion.