Serotonin 5-HT 1A , 5-HT 2A and dopamine D 2 receptors strongly influence prefronto-hippocampal neural networks in alert mice: Contribution to the actions of risperidone.

Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT _2A R and dopamine receptors D ₂ R and stimulate 5-HT _1A R directly or indirectly. However, the exact cellular mechanisms mediating their therapeutic actions remain unresolved. We recorded neural activity in the prefrontal cortex (PFC) and hippocampus (HPC) of freely-moving mice before and after acute administration of 5-HT _1A R, 5-HT _2A R and D ₂ R selective agonists and antagonists and atypical APD risperidone. We then investigated the contribution of the three receptors to the actions of risperidone on brain activity via statistical modeling and pharmacological reversal (risperidone + 5-HT _1A R antagonist WAY-100635, risperidone + 5-HT _2A/2C R agonist DOI, risperidone + D ₂ R agonist quinpirole). Risperidone, 5-HT _1A R agonism with 8-OH-DPAT, 5-HT _2A R antagonism with M100907, and D ₂ R antagonism with haloperidol reduced locomotor activity of mice that correlated with a suppression of neural spiking, power of theta and gamma oscillations in PFC and HPC, and reduction of PFC-HPC theta phase synchronization. By contrast, activation of 5-HT _2A R with DOI enhanced high-gamma oscillations in PFC and PFC-HPC high gamma functional connectivity, likely related to its hallucinogenic effects. Together, power changes, regression modeling and pharmacological reversals suggest an important role of 5-HT _1A R agonism and 5-HT _2A R antagonism in risperidone-induced alterations of delta, beta and gamma oscillations, while D ₂ R antagonism may contribute to risperidone-mediated changes in delta oscillations. This study provides novel insight into the neural mechanisms for widely prescribed psychiatric medication targeting the serotonin and dopamine systems in two regions involved in the pathophysiology of schizophrenia.
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