Antipsychotic drugs reverse the AMPA receptor‐stimulated release of 5‐HT in the medial prefrontal cortex

Abstract

The prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. PFC neuronal activity is modulated by monoaminergic receptors for which antipsychotic drugs display moderate-high affinity, such as 5-HT 2A and a 1 -adrenoceptors. Conversely, PFC pyramidal neurons project to and modulate the activity of raphe serotonergic neurons and serotonin (5-HT) release. Under the working hypothesis that atypical antipsychotic drugs may partly exert their action in PFC, we assessed their action on the in vivo 5-HT release evoked by increasing glutamatergic transmission in rat medial PFC (mPFC). This was achieved by applying S-AMPA in mPFC (reverse dialysis) or by disinhibiting thalamic excitatory afferents to mPFC with bicuculline. The application of haloperidol, chlorpromazine, clozapine and olanzapine in mPFC by reverse dialysis (but not reboxetine or diazepam) reversed the S-AMPA-evoked local 5-HT release. Likewise, the local (in mPFC) or systemic administration of these antipsychotic drugs reversed the increased prefrontal 5-HT release produced by thalamic disinhibition. These effects were shared by the 5-HT 2A receptor antagonist M100907 and the a 1 -adrenoceptor antagonist prazosin. However, raclopride (DA D2 antagonist) had very modest effects. These results suggest that, besides their action in limbic striatum, antipsychotic drugs may attenuate glutamatergic transmission in PFC, possibly by interacting with 5-HT 2A and/or a 1 -adrenoceptors. Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists are widely accepted as pharmacological models of schizophrenia. The behavioral deficits induced by these agents resemble schizophrenic symptoms, which suggests a glutamatergic hypofunction in schizophrenia. However, neurochemical (Moghaddam et al. 1997) and electrophysiological observations (Suzuki et al. 2002;Jackson et al. 2004) indicate that these agents increase glutamatergic transmission in mPFC, possibly by acting in afferent areas, such as the hippocampus (Jodo et al. 2005).The activity of projection (pyramidal) neurons in PFCwhich make up c. 75% of all neurons in PFC-depends on glutamatergic inputs from cortical and subcortical areas and is locally modulated by GABA interneurons. Main subcortical excitatory inputs arise from the mediodorsal/centromedial nuclei of the thalamus (MD/CM), the hippocampus and the amygdala, which are reciprocally connected with the PFC (Kuroda et al. 1998;Groenewegen and Uylings 2000;Van der Werf et al. 2002). Interestingly, the PFC and the Received June 8, 2006; revised manuscript received February 6, 2007; accepted February 6, 2007. Address correspondence and reprint requests to Francesc Artigas, PhD; Department of Neurochemistry and Neuropharmacology, Institut d' Investigacions Biomèdiques de Barcelona (CSIC), IDIBAPS, Rosselló, 161, 6th floor, 08036 Barcelona, Spain. E-mail: fapnqi@iibb.csic.esAbbreviations used: 5-HT, 5-hydroxytryptamine or serotonin; AMPA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate; CM, centromedial nucleus of the thalamus...

Effects of asenapine, olanzapine, and risperidone on psychotomimetic-induced reversal-learning deficits in the rat

“…PCP and other NMDA antagonists increase 5-HT release in the prefrontal cortex [37], which may lead to excessive glutamatergic activity [5]. Excessive prefrontal cortical glutamatergic activity associated with enhanced 5-HT efflux is also reversed by antagonism at the 5-HT 2A receptor [6]. In regard to 5-HT receptor antagonism, asenapine also displays high affinity for the 5-HT 2C , 5-HT 6 , 5-HT 7 receptors [47], which may be of relevance to its ability to attenuate PCPinduced cognitive dysfunction.…”

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…5-HT2A-R are located on the dendrites of glutamatergic pyramidal neurons and interneurons in the rodent mPFC (Aghajanian and Marek, 1997;Cornea-Hebert et al, 1999;Hamada et al, 1998;Jansson et al, 2001;Miner et al, 2003;Willins et al, 1997;Xu and Pandey, 2000). Electrophysiological studies have demonstrated that selectively stimulating 5-HT2A-Rs (typically by co-applying a mixed 5-HT2A-R/5-HT2C-R agonist and a 5-HT2C-R antagonist to isolate 5-HT2A-Rs) can either excite or inhibit the activity of neurons in the rat mPFC, although an excitatory action appears to predominate under most conditions Marek, 1997, 1999;Amargos-Bosch et al, 2007;Araneda and Andrade, 1991;Arvanov et al, 1999;Ashby et al, 1990Ashby et al, , 1994Liu and Aghajanian, 2008;Marek et al, 2006;Puig et al, 2003;Zhou and Hablitz, 1999). On the basis of what appears to be an extrasynaptic localization of 5-HT2A-Rs on mPFC neurons (Jansson et al, 2001), some authors have proposed that the excitatory action of this receptor may be particularly prominent under conditions of high serotonin release .…”

Serotonin in antipsychotic drugs action

“…For example, olanzapine decreased both basal and stimulated extracellular 5-HT levels in the medial prefrontal cortex [93,95,97,103], while other studies report either no changes in the medial prefrontal cortex, hippocampus, nucleus accumbens and hypothalamus [93,99,100,[103][104][105] or even an increase in the caudate-putamen [103] Similar figuers were reckoned for haloperidol and aripiprazole. Haloperidol is reported to decrease both basal and stimulated extracellular 5-HT levels in the medial prefrontal cortex in a number of studies [93,94,96,97,104,105]. Other studies, however, show that it did not change extracellular 5-HT levels neither in the medial prefrontal cortex, hippocampus or nucleus accumbens [93,99,100,106,107].…”

“…Although based on a lower number of studies also other compounds showed well-defined results. For example, chlorpromazine [96,97] and nemonapride [98,99] reduced the extracellular 5-HT levels in the medial prefrontal cortex and hippocampus, respectively. Instead, no changes on extracellular 5-HT levels were observed upon treatment with ziprasidone (hippocampus, [99]), lurasidone (medial prefrontal cortex and nucleus accumbens [100]), blonanserin (medial prefrontal cortex and nucleus accumbens [100,101]) and tandospirone (medial prefrontal cortex and nucleus accumbens [100]).…”