A comparison of the effects of loxapine with ziprasidone and thioridazine on the release of dopamine and acetylcholine in the prefrontal cortex and nucleus accumbens |
| |
Authors: | Email author" target="_blank">Zhu?LiEmail author Junji?Ichikawa Herbert?Y?Meltzer |
| |
Institution: | (1) Division of Psychopharmacology, Departments of Psychiatry & Pharmacology, Vanderbilt University School of Medicine, TN 37212, Nashville, USA,;(2) , The Psychiatric Hospital at Vanderbilt, Suite 306, 1601 23rd Avenue South, TN 37212, Nashville, USA, |
| |
Abstract: | Rationale. Atypical, but not typical, antipsychotic drugs (APDs), produce preferential increases in dopamine (DA) and acetylcholine
(ACh) release in rat medial prefrontal cortex (mPFC) compared to the nucleus accumbens (NAC). The increase in DA release has
been attributed, in part, to their greater serotonin (5-HT)2A relative to D2 receptor occupancy, while the basis for the increase in ACh has not yet been determined. Loxapine, a dibenzoxazepine congener
of clozapine, is generally considered to be a typical APD because it produces significant extrapyramidal symptoms (EPS) in
humans, at generally recommended clinical doses (60–100 mg/day), and catalepsy in rodents, although several studies have found
it to be effective at lower doses which do not produce significant EPS. Moreover, loxapine, like its congener clozapine, has
higher affinity for serotonin (5-HT)2A than dopamine D2 receptors, in vitro, suggesting the possibility it could be an atypical APD with clozapine-like potential.
Objectives. The purpose of this study was to compare the effects of loxapine on DA and ACh release in the mPFC and NAC with those of
ziprasidone, a novel atypical APD, and thioridazine, which is generally classified as a typical APD.
Results. Loxapine, 0.03–10 mg/kg, increased prefrontal dopamine release with the magnitude of this increase exceeding that in the
NAC, at all doses, other than the 10 mg/kg dose. The effect of loxapine (0.3 mg/kg) on DA release in the prefrontal cortex
was attenuated by WAY 100635 (0.2 mg/kg), a 5-HT1A antagonist, as is the case for other atypical APDs. Ziprasidone (0.1–3 mg/kg) also preferentially increased DA release in
the mPFC compared to NAC. Thioridazine (5 and 20 mg/kg) did not increase DA release in either the mPFC or NAC. Loxapine (3 mg/kg)
and ziprasidone (1 and 3 mg/kg), but not thioridazine (10 and 20 mg/kg), significantly increased cortical ACh release.
Conclusion. Loxapine has effects on cortical and NAC DA and ACh release which are comparable to those of known atypical APDs. Ziprasidone
and thioridazine have effects on cortical DA and ACh characteristic of atypical and typical APDs, respectively. It is concluded
that further clinical studies of the atypical APD properties of loxapine are indicated.
Electronic Publication |
| |
Keywords: | Loxapine Ziprasidone Thioridazine Dopamine Acetylcholine Serotonin |
本文献已被 PubMed SpringerLink 等数据库收录! |
|