Research report5-HT2A receptor antagonism potentiates haloperidol-induced dopamine release in rat medial prefrontal cortex and inhibits that in the nucleus accumbens in a dose-dependent manner
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) D2/3 receptor antagonist [14] or aripiprazole, a partial D2/3 receptor agonist [51]. It has been hypothesized that 5-HT2A 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-HT2A 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-HT2A 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-HT2A 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-HT2A 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-HT2A/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-HT2A relative to D2 receptor blockade [41]. It has also been reported that ritanserin potentiates the D2/3 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-HT2A receptor antagonist, potentiates S-(−)-sulpiride, a D2/3 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-HT2A 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-HT2A/D2 receptors increases DA release in the mPFC via 5-HT1A receptor activation [26], which has itself been shown to increase DA release in that region [5], [26]. However, SR 46349B, a 5-HT2A/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-HT2A receptors can modulate DA release in the mPFC, NAC (mainly the shell) and STR, and that the ratio of 5-HT2A 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-HT2A 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.
Section snippets
Animals
Male Sprague–Dawley albino rats (Zivic-Miller Labs., Porterville, PA, USA) weighing 250–350 g were used throughout the experiment. The procedures used in these studies were approved by the Institutional Animal Care and Use Committee of Vanderbilt University School of Medicine.
Surgery
Rats were anaesthetized with an i.p. injection of a combination of xylazine and ketamine and mounted in a stereotaxic frame. 21-G stainless guide cannula with a dummy probe was placed onto the cortex dorsal to the mPFC or
Results
There were no significant differences in basal dialysate concentrations of DA in the mPFC (3.08±0.19 fmol/10 μl/30 min, n=70) and NAC (26.8±1.9 fmol/20 μl/30 min, n=36) between treatment groups. M100907 (0.1 mg/kg) had no significant effect on basal dialysate concentrations of DA in either the mPFC or NAC (Fig. 1, Fig. 2).
Only 0.1 mg/kg haloperidol among the doses of 0.01, 0.03, 0.1, 0.3 and 1 mg/kg, significantly increased dialysate DA concentrations in the mPFC (Fig. 1, Fig. 3) whereas
Discussion
The major findings of this study are: (1) the typical APD haloperidol produced a shallow, inverted U-shaped dose-dependent increase in DA release in the mPFC, with a significant increase only at 0.1 mg/kg; (2) haloperidol produced greater increases in DA release in the NAC compared to the mPFC, at doses of 0.1 and 1.0 mg/kg; (3) M100907 (0.1 mg/kg) did not increase DA release in the mPFC or NAC on its own; (4) the combination of 0.1 mg/kg M100907 and low (0.01, 0.03 and 0.1 mg/kg), but not high
Acknowledgements
This study was supported, in part, by grants from the Warren Medical Foundation, Mr. and Mrs. Donald Test, and the Lattener Foundation. J.-F.L. is Research Associate of the Fonds National de la Recherche Scientifique de Belgique (FNRS) and was supported by awards from the FNRS, the Ministère de l’Éducation et de la Recherche Scientifique de la Communauté Française de Belgique, and the Patrimoine de l’Université de Liège.
References (67)
Catecholamine modulation of prefrontal cortical cognitive function
Trend Cognit. Sci.
(1998)- et al.
Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence
Neuropsychopharmacology
(1998) - et al.
Increase of dialysate dopamine in the bed nucleus of stria terminalis by clozapine and related neuroleptics
Neuropsychopharmacology
(2000) - et al.
Hypothesis testing: is clozapine’s superior efficacy dependent on moderate D2 receptor occupancy?
Biol. Psychiat.
(1998) - et al.
SB 242084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system
Neuropharmacology
(1999) - et al.
Regional specific effects of clozapine and haloperidol on GABA and dopamine release in rat basal ganglia
Eur. J. Pharmacol.
(1990) - et al.
Serotonin (5-HT)2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats
Neuropharmacology
(1999) - et al.
DOI, a 5-HT2C/2A receptor agonist, potentiates amphetamine-induced dopamine release in rat striatum
Brain Res.
(1995) - et al.
The effect of serotonin1A receptors on antipsychotic drug-induced dopamine release in rat striatum and nucleus accumbens
Brain Res.
(2000) - et al.
Dopamine D2 receptor blockade by haloperidol 3H-raclopride reveals much higher occupancy than EEDQ
Neuropsychopharmacology
(2000)
R-(+)-8-OH-DPAT, a selective 5-HT1A receptor agonist, attenuated amphetamine-induced dopamine synthesis in rat striatum, but not nucleus accumbens or medial prefrontal cortex
Brain Res.
Increased dopamine transmission in schizophrenia: relationship to illness phases
Biol. Psychiat.
The effect of serotonergic agents on haloperidol-induced striatal dopamine release in vivo: opposite role of 5-HT2A and 5-HT2C receptor subtypes and significance of the haloperidol dose used
Neuropharmacology
Differential actions of typical and atypical antipsychotic drugs on dopamine release in the core and shell of the nucleus accumbens
Eur. Neuropsychopharmacol.
The role of serotonin in antipsychotic drug action
Neuropsychopharmacology
M100,907, a selective 5-HT2A antagonist, attenuates dopamine release in the rat medial prefrontal cortex
Brain Res.
In vivo determination of striatal dopamine D2 receptor occupancy in patients treated with olanzapine
Psychiatry Res.
In vivo dopamine-D2 and serotonin-5-HT2 receptor binding study of risperidone and haloperidol
Pharmacol. Biochem. Behav.
Is synaptic dopamine concentration the exclusive factor which alters the in vivo binding of [11C]raclopride?: PET studies combined with microdialysis in conscious monkeys
Brain Res.
Enhancement of antipsychotic-like properties of the dopamine D2 receptor antagonist, raclopride, by the additional treatment with the 5-HT2 receptor blocking agent, ritanserin, in the rat
Eur. Neuropsychopharmacol.
Enhancement of antipsychotic-like properties of raclopride in rats using the selective serotonin2a receptor antagonist MDL 100,907
Biol. Psychiat.
Antipsychotic drugs classified by their effects on the release of dopamine and noradrenaline in the prefrontal cortex and striatum
Eur. J. Pharmacol.
Increased striatal dopamine transmission in schizophrenia: confiramation in a second cohort
Am. J. Psychiatry
Increased baseline occupancy of D2 receptors by dopamine in schizophrenia
Pro. Natl. Acad. Sci. USA
Typical and atypical antipsychotic occupancy of D2 and S2 receptors: an autoradiographic analysis in rat brain
Brain Res. Bull.
Ritanserin potentiates the stimulatory effects of raclopride on neuronal activity and dopamine release selectivity in the mesolimbic dopaminergic system
Naunyn-Schmiedeberg’s Arch. Pharmacol.
(R)-8-OH-DPAT preferentially increases dopamine release in rat medial prefrontal cortex
Acta Psychiatr. Scand.
Dopamine D2 receptor blockade in vivo with the novel antipsychotics risperidone and remoxipride—an 123I-IBZM single photon emission tomography (SPET) study
Psychopharmacology
Dopamine in schizophrenia: a review and reconceptualization
Am. J. Psychiat.
Role of serotonin2A and serotonin2B/2C receptor subtypes in the control of accumbal and striatal dopamine release elicited in vivo by dorsal raphe nucleus electrical stimulation
J. Neurochem.
Effects of acute and repeated administration of amisulpride, a dopamine D2/D3 receptor antagonist, on the electrical activity of midbrain dopaminergic neurons
J. Pharmacol. Exp. Ther.
Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs
Arch. Gen. Psychiat.
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