Research report5-HT1A and 5-HT2A receptors minimally contribute to clozapine-induced acetylcholine release in rat medial prefrontal cortex
Introduction
Greater antagonism of serotonin (5-HT)2A relative to dopamine (DA) D2 receptors [2], [43], and the ability to preferentially increase DA release in the medial prefrontal cortex (mPFC) are characteristic of most atypical antipsychotic drugs (APDs), e.g., clozapine, but not typical APDs, e.g., haloperidol [38], [40], [46], [67]. We have also found that the atypical APDs clozapine, olanzapine, risperidone, and ziprasidone, but not the typical APDs haloperidol, S(−)-sulpiride, or thioridazine, increased acetylcholine (ACh) release in rat mPFC, whereas none of these seven APDs affected ACh release in the nucleus accumbens (NAC) or striatum (STR), in the absence of AChesterase (AChE) inhibition [33]. Based upon the evidence for the role of ACh in cognitive function [58] and negative symptoms [64] in schizophrenia, and in the action of APDs [7], [10], [65], the effect on cortical ACh release may contribute to the ability of the atypical, but not typical, APDs, to improve cognition [44] and negative symptoms [39]. If so, it is important to determine the basis for the ability of the atypical APDs to increase ACh release in the mPFC, and whether the mechanism(s) are the same for the atypical APDs which have this effect.
Neither thioridazine, a potent M1 and M2 muscarinic ACh receptor (mAChR) antagonist [7], nor S(−)-sulpiride, a D2/3 receptor antagonist [61], increases ACh release in the mPFC [33]. Thus, blockade of M1 and M2, or D2 receptors seems to be less likely to contribute to the ability of atypical APDs to increase ACh release in the mPFC, although clozapine and olanzapine have agonist and antagonist effects on various mAChRs [11], [33], [59]. Similarly, although some, but not all, typical and atypical APDs are 5-HT2C receptor antagonists [45], [55], 5-HT2A or 5-HT2C receptor antagonism on its own may minimally contribute to that ability because ketanserin, a 5-HT2A receptor antagonist [25], and ritanserin, a 5-HT2A/2C receptor antagonist [12], [69], [70], had no effect on ACh release in the mPFC. However, 5-HT2A receptor antagonism, when it is combined with relatively weak D2 receptor blockade, has been recently reported to increase DA release in the mPFC [8], [30], [41]. We have proposed that clozapine, olanzapine, and risperidone increase DA release in the mPFC via an indirect 5-HT1A receptor agonism resulting from concomitant 5-HT2A/D2 receptor blockade [30]. In fact, some atypical APDs, e.g., clozapine, quetiapine, and ziprasidone, are also 5-HT1A receptor partial agonists [4], [49], [59], [60], and 5-HT1A receptor stimulation increases cortical release of ACh [13], [37], [62] as well as DA [30]. Therefore, it is possible that atypical APDs may increase cortical ACh release via direct and/or indirect 5-HT1A receptor stimulation, as has been suggested for the DA release [30].
CY-208243, and dihydrexidine, both of which are D1 receptor agonists, apomorphine, a D1/2/3 receptor agonist, and quinpirole, a D2/3 receptor agonist, have been reported to increase cortical ACh release [16], [63]. In analogy to the STR [17], [34], [63], ACh release in the mPFC could also result from the stimulation of D1 and D2 receptors, secondary to the DA release produced by atypical APDs [30]. However, this seems to be less effective since most atypical APDs are D1/2 receptor antagonists [43], [59]. Similarly, although m-chlorophenyl-piperazine (mCPP), a 5-HT2A/2C receptor agonist, has been reported to increase cortical and hippocampal ACh release [73], [74], it is unlikely that risperidone, a 5-HT2A and 5-HT2C receptor antagonist, increases ACh release in the mPFC via stimulation of 5-HT2A or 5-HT2C receptors secondary to risperidone-induced 5-HT release [24], [28].
Clozapine significantly increased ACh release in the mPFC, NAC and STR in the presence of AChE inhibition by neostigmine [33], [50], whereas, in its absence, clozapine significantly increased ACh release only in the mPFC, with the effect smaller than that observed in the presence of neostigmine [33]. These results suggest that the effects of drugs on ACh release are best studied under physiological conditions, in the absence of AChE inhibition [29]. Thus, this study examined the effects of 5-HT1A and 5-HT2A receptor agonists and antagonists on basal and clozapine-induced ACh release in the mPFC, as well as the NAC and STR, in the absence of AChE inhibition. We also examined whether the combination of the 5-HT2A receptor antagonist M100907 plus haloperidol, which increase DA release in the mPFC [8], [41], can also increase ACh release in that region.
Section snippets
Animals
Male Sprague–Dawley albino rats (Zivic-Miller Laboratories, Porterville, PA) weighing 250–350 g were used. They were housed two to three per cage and maintained in a controlled 12–12-h light–dark cycle and under constant temperature at 22 °C, with free access to food and water.
Surgery
Rats were anesthetized with an intraperitoneal injection (i.p.) of a combination of xylazine (13 mg/kg, Rompun; Shawnee Mission, KS) and ketamine hydrochloride (87 mg/kg, Ketaset; Fort Dodge Laboratories, Fort Dodge, IA)
Results
Basal dialysate ACh concentrations (fmol/20 μl/30 min) were 22.1±0.8 in the mPFC (n=137), 25.0±2.1 in the NAC (n=39), and 53.8±3.2 in the STR (n=39), respectively. There were no significant differences in basal ACh concentrations between treatment groups in each region.
(±)-DOI (0.6, 1.25 and 2.5 mg/kg), a mixed 5-HT2A/2C receptor agonist, increased dialysate ACh concentrations in the mPFC (Fig. 1). M100907 (1 mg/kg), a selective 5-HT2A receptor antagonist, which by itself had no effect at 0.03,
Discussion
The major findings in the present study in the mPFC are: (1) 5-HT1A receptor stimulation by R(+)-8-OH-DPAT and blockade by WAY100635 both increased ACh release while WAY100635 abolished the effect of R(+)-8-OH-DPAT; (2) 5-HT2A receptor stimulation by DOI, increased ACh release, whereas 5-HT2A receptor blockade by M100907 had no effect; (3) WAY100635 did not affect the ability of clozapine to increase ACh release; and (4) the combination of M100907 and haloperidol failed to increase ACh release.
Acknowledgements
This study was supported, in part, by a Grant from Eli Lilly and Co.
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