5-HT_2A receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner

Abstract

Combined serotonin (5-HT)_2A and dopamine (DA) D₂ blockade has been shown to contribute to the ability of atypical antipsychotic drugs (APDs) to increase DA release in rat medial prefrontal cortex (mPFC). We provide additional support for this hypothesis by examining the effect of the selective 5-HT_2A antagonist M100907 plus haloperidol, a potent D₂ antagonist APD, on DA release in the mPFC and nucleus accumbens (NAC). Haloperidol (0.01–1.0 mg/kg) produced an inverted U-shaped increase in DA release in the mPFC, with a significant increase only at 0.1 mg/kg. Haloperidol (0.1 and 1.0 mg/kg) significantly increased DA release in the NAC. M100907 (0.1 mg/kg) by itself had no effect on DA release in either region. This dose of M100907 potentiated the ability of low (0.01–0.1 mg/kg), but not high dose (0.3–1.0 mg/kg) haloperidol to increase mPFC DA release, whereas it abolished the effect of both 0.1 and 1.0 mg/kg haloperidol on NAC DA release. These results suggest that the relatively higher ratio of 5-HT_2A to D₂ antagonism may contribute to the potentiation of haloperidol-induced mPFC DA release, whereas 5-HT_2A antagonism can diminish haloperidol-induced NAC DA release, even when combined with extensive D₂ antagonism, which may not be synergistic with 5-HT_2A antagonism in the mPFC.

Introduction

The distinguishing feature of atypical antipsychotic drugs (APDs) is their ability to produce an antipsychotic action at doses which produce little or no extrapyramidal symptoms (EPS) [48]. Serotonin (5-hydroxytryptamine, 5-HT)_2A receptor antagonism has been suggested to be an important feature of all currently available atypical APDs, including clozapine, risperidone, olanzapine, melperone, quetiapine, sertindole and ziprasidone, as well as other novel antipsychotic compounds in development, e.g. iloperidone and ORG 5222 [7], [44], [45], but not amisulpride, which is a selective dopamine (DA) D_2/3 receptor antagonist [14] or aripiprazole, a partial D_2/3 receptor agonist [51]. It has been hypothesized that 5-HT_2A receptor antagonism should be more potent than D₂ receptor antagonism to achieve an antipsychotic action with low EPS [3], [30], [44], [46], [55], and the ability to improve negative symptoms and cognition [24], [45]. Positron emission tomography (PET) studies have established that at clinically effective doses which produce low EPS, atypical APDs such as clozapine, quetiapine, olanzapine, risperidone and ziprasidone, usually produce lower occupancy of D₂ receptors and higher occupancy of 5-HT_2A receptors than do the typical APDs, and that higher doses of some of these atypical APDs produce D₂ occupancy as high as that of the typical APDs, in which case they may cause EPS [9], [17], [18], [29], [32], [33], [50], [54]. Nevertheless, the hypothesis that high affinity for 5-HT_2A receptors is relevant to the low EPS and other actions of the atypical APDs, e.g. positive and negative symptoms, has been challenged [11], [34], [58].

While much of the interest with regard to the importance of 5-HT_2A and D₂ receptor affinities of the atypical APDs has focused on the striatum (STR) and EPS, there has also been consideration of their importance for the ability of these drugs to modulate dopaminergic function in the meso-cortical and meso-limbic system, since DA release in these areas is believed to be relevant to cognition and negative symptoms, and antipsychotic activity, respectively [45], [47]. Atypical APDs, but not the typical APDs such as haloperidol, have been demonstrated to produce preferential or equivalent increases in DA release in rat medial prefrontal cortex (mPFC) compared to the nucleus accumbens (NAC) [36] or the bed nucleus of stria terminalis [10]. Preferential DA releases in the mPFC correlate with the ratio of the affinities for 5-HT_2A relative to D₂ receptors rather than to either alone [36]. In vivo voltammetric studies which examined the effects of various doses of ritanserin, a mixed 5-HT_2A/2C receptor antagonist, haloperidol, clozapine and risperidone on DA release, suggested that the preferential increase in DA release in the NAC shell, which is related to the meso-limbic system, compared to the core, which is related to the motor system, could be due to high 5-HT_2A relative to D₂ receptor blockade [41]. It has also been reported that ritanserin potentiates the D_2/3 receptor antagonist raclopride-induced increase in both the DA release in the mPFC and NAC, but not the STR, and the burst firing of DA neurons in the ventral tegmentum (VTA), but not the substantia nigra zona compact (SNC) [4]. We also reported that M100907, a more selective 5-HT_2A receptor antagonist, potentiates S-(−)-sulpiride, a D_2/3 receptor antagonist, induced DA release in the mPFC [26]. M100907 also potentiated raclopride-induced DA release in the mPFC [65]. Thus, it is possible that 5-HT_2A receptor blockade potentiates the ability of D₂ receptor blockade to increase DA release in the mPFC. Furthermore, we have recently suggested that concomitant blockade of 5-HT_2A/D₂ receptors increases DA release in the mPFC via 5-HT_1A receptor activation [26], which has itself been shown to increase DA release in that region [5], [26]. However, SR 46349B, a 5-HT_2A/2C receptor antagonist, which alone had no effect on DA release in the STR, has been reported to inhibit the ability of haloperidol (0.01 and 0.1, but not 1.0, mg/kg), a potent D₂ receptor antagonist, to increase DA release in the STR [39], [59]. These results [4], [59] suggest that, under stimulated, but not basal, conditions, blockade of 5-HT_2A receptors can modulate DA release in the mPFC, NAC (mainly the shell) and STR, and that the ratio of 5-HT_2A to D₂ receptor blockade may have an important influence on the effectiveness.

The purpose of this study was to determine: (1) the effects of haloperidol, a relatively selective D₂ receptor antagonist, and M100907, a selective 5-HT_2A receptor antagonist, alone and in combination, on extracellular DA concentrations in the mPFC and NAC; and (2) whether any such effects on DA release in these two brain regions were a function of the dose of haloperidol relative to that of M100907, at doses of haloperidol which produce a variable extent of D₂ receptor blockade.