Enhanced effects of amphetamine but reduced effects of the hallucinogen, 5-MeO-DMT, on locomotor activity in 5-HT 1A receptor knockout mice: Implications for schizophrenia

Abstract

Serotonin-1A (5-HT 1A) receptors may play a role in schizophrenia and the effects of certain antipsychotic drugs. However, the mechanism of interaction of 5-HT 1A receptors with brain systems involved in schizophrenia, remains unclear. Here we show that 5-HT 1A receptor knockout mice display enhanced locomotor hyperactivity to acute treatment with amphetamine, a widely used animal model of hyperdopaminergic mechanisms in psychosis. In contrast, the effect of MK-801 on locomotor activity, modeling NMDA receptor hypoactivity, was unchanged in the knockouts. The effect of the hallucinogen 5-methoxy- N,N-dimethyltryptamine (5-MeO-DMT) was markedly reduced in 5-HT 1A receptor knockout mice. There were no changes in apomorphine-induced disruption of PPI, a model of sensory gating deficits seen in schizophrenia. Similarly, there were no major changes in density of dopamine transporters (DAT) or dopamine D 1 or D 2 receptors which could explain the behavioural changes observed in 5-HT 1A receptor knockout mice. These results extend our insight into the possible role of these receptors in aspects of schizophrenia. As also suggested by previous studies using agonist and antagonist drugs, 5-HT 1A receptors may play an important role in hallucinations and to modulate dopaminergic activity in the brain.