Serotonin 5-HT1A, 5-HT2A and dopamine D2 receptors strongly influence prefronto-hippocampal neural networks in alert mice: Contribution to the actions of risperidone

Abstract

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.

Phencyclidine-induced psychosis causes hypersynchronization and disruption of connectivity within prefrontal-hippocampal circuits that is rescued by antipsychotic drugs

“…6a,b). Notably, a prior study we conducted showed that DPAT given alone, in the absence of PCP, suppressed the power of high gamma and HFOs in both the PFC and HPC and such decreases were reversed by the selective 5-HT 1A R antagonist WAY-100635 (PFC high gamma, HFO: F 1,6 = 10, 9.12 p = 0.003, 0.001; HPC high gamma, HFO: F 1,6 = 12.45, 21.66 p = 0.003, 0.001; one-way ANOVA; n = 7 mice)(Gener et al, 2019). This indicates that 5-HT 1A Rs indeed play a role in shaping high gamma and HFO within the PFC and the HPC.…”

“…Sedation has been attributed to APDs’ affinity for histamine H 1 receptors (Miller, 2004). However, a recent study from our group also indicated that sedative effects may result from the cooperation between 5-HT 2A /D2R antagonism and 5-HT 1A agonism (Gener et al, 2019).…”

“…We used similar procedures to those in Gener et al, 2019. Briefly, mice were induced with ketamine/xylazine and anesthesia was maintained with isoflurane at 0.5-4%.…”

“…We have recently shown that risperidone alone reduces local and cross-regional synchronization of prefrontal-hippocampal circuits in freely moving mice, with 5-HT 1A R, 5-HT 2A R and D2R shaping distinct frequency bands (Gener et al, 2019). Here we investigate the neural dynamics of prefrontal-hippocampal circuits under the psychotomimetic conditions produced by an acute dose of PCP.…”

Prefrontal–hippocampal functional connectivity encodes recognition memory and is impaired in intellectual disability

“…We recorded single-unit activity (SUA) and local field potentials (LFPs) with the Open Ephys system with a sampling rate of 30 kHz. We used the accelerometer's signals to monitor general mobility of mice (65). SUA was estimated by referencing the signal, filtering between 450 and 6,000 Hz and sorting the spikes with Offline Sorter.…”