Research reportClozapine increases both acetylcholine and dopamine release in rat ventral hippocampus: role of 5-HT1A receptor agonism
Introduction
The hippocampus (HIP), which has a principal role in learning and memory [18], [19], [50], has been suggested to be important for the neurocognitive deficits and possibly psychotic symptoms in schizophrenia as well [28], [31], [32], [33], [48], [63], complementing the contribution of the prefrontal cortex (PFC) and nucleus accumbens (NAC) to these abnormalities [13]. The neonatal excitotoxic lesions in the ventral (v)HIP of rats have been reported to produce dysfunction of the PFC in adulthood [54]. This may be the result of disrupting glutamatergic pyramidal neurons, which project to the medial (m)PFC [6], [44], [50], [70]. Disruption of the vHIP–mPFC circuit produced by reversible inactivation of the vHIP in rats may produce temporary working memory abnormalities in adults [20], [64], and decreased prepulse inhibition of acoustic startle [77], which has been proposed as a model of the sensorimotor deficit in schizophrenia [73]. Disruption of the vHIP, which receives a dopaminergic projection from the ventral tegmental area (VTA) [24], and is also the origin of glutamatergic pyramidal neurons, which project to the NAC shell [29], [66], [67], [75], has been suggested as a possible animal model for psychosis in schizophrenia [21], [22], [26], [27], [63]. These considerations suggest that the HIP could be another target for the therapeutic benefit for APDs [62]. Specifically, atypical APDs may improve neurocognitive deficits and psychosis in schizophrenia [52], [55], at least in part, via their effects in the vHIP.
Dopamine (DA) [1], [43] and acetylcholine (ACh) [8], [31] are critically important for cognition. Furthermore, there is evidence for decreased cortical dopaminergic [13], [45], [46], [56], [76] and cholinergic [10], [11], [12], [15], [16] activity in patients with schizophrenia. Thus, a possible explanation for the beneficial effect of some atypical APDs on neurocognitive deficits in patients with schizophrenia may be their ability to produce greater increases in DA and ACh release in the mPFC, compared to the NAC, whereas typical APDs such as haloperidol, S(−)-sulpiride and thioridazine have little effect on the release of either neurotransmitter in the mPFC [36], [37], [38], [39], [40], [49], [57].
Despite the interest in the HIP in neurocognition and schizophrenia, little is known about the effect of APDs on DA and ACh release in the vHIP. Shirazi-Southall et al. [65] have recently reported that the atypical APDs, clozapine, olanzapine and risperidone, increased ACh release in the vHIP, whereas another atypical APD, ziprasidone, did not; haloperidol, as well as other typical APDs, thioridazine and chlorpromazine, produced modest increases in ACh release in the vHIP. These authors suggested that the ability to increase ACh release in the vHIP may not distinguish atypical APDs from typical APDs. However, it should be noted that neostigmine, an AChesterase inhibitor, was included in the perfusion medium in that study [65], in order to achieve detectable dialysate ACh concentrations. We have suggested that levels of ACh in this range significantly influence drug-induced ACh release [35], [38]. Interestingly, some, but not all, drugs such as piribedil, an α2 adrenoceptor antagonist, have been reported to produce comparable effects on ACh release in the mPFC and dorsal HIP, in the absence of AChesterase inhibition [25]. Because the highest density of 5-HT1A receptors in rat brain is shown in the HIP, followed by the mPFC [2], [7], it is possible that WAY100635, a selective 5-HT1A receptor antagonist, attenuates clozapine-induced DA release in the vHIP, as well as the mPFC [36]. Stimulation of 5-HT1A receptors has been reported to increase DA and ACh release in the HIP [23], [42], [47], [58], [61], [65] as well as in the mPFC [9], [36], [39], [47], [61]. Some, but not all, drugs produce comparable effects on DA and ACh release in both vHIP and mPFC, and there are mono- and trans-synaptic connections between these two regions: the hippocampo-PFC circuit [51], [71]. It is important to determine whether APDs increase DA and/or ACh release in the vHIP, and whether WAY100635 attenuates clozapine-induced ACh release in the vHIP. Specifically, it should be noted that no in vivo data have been provided regarding the effect of APDs on DA release in the vHIP. The present study was designed to compare the effects of clozapine and haloperidol on the release of DA and ACh in the vHIP and the mPFC, and whether WAY100635 attenuates clozapine-induced DA and ACh release in the vHIP. Preliminary data from this study have been reported in abstract form elsewhere [8].
Section snippets
Animals
Male Sprague–Dawley albino rats (Zivic-Miller Laboratories, Porterville, PA) weighing 250 to 350 g 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 the modified Equithesin mixture (3 ml/kg body weight i.p.) that was made by dissolving 2.125 g chloral hydrate and 1063 g magnesium sulphate, adding 8.1 ml Nembutal (50 mg/ml sodium pentobarbital) and 5.0
Basal levels in the absence of AChesterase inhibition
ACh levels were 6.82±0.46 (fmol/10 μl) in the vHIP (N=48), and 9.84±0.82 in the mPFC (N=44). DA levels were 1.42±0.08 (fmol/10 μl) in the vHIP (N=47), and 2.11±0.11 in the mPFC (N=50). Basal ACh and DA levels are significantly lower in the vHIP than the mPFC (F(1,90)=10.81, p=0.001, and F(1,95)=25.98, p<0.001, respectively). ACh and DA concentrations were not significantly different between treatment groups in each region. Interestingly, basal ACh and DA levels in the mPFC obtained with a
Discussion
A major finding of this study is that clozapine increases DA and ACh in the vHIP. This is the first in vivo evidence that clozapine increases DA release in the vHIP. We confirmed a previous report that clozapine increases ACh release in the vHIP [65]. Activation of 5-HT1A receptor-mediated mechanism(s) contributes to the ability of clozapine to increase DA, but not ACh, release in both the vHIP and mPFC, as indicated by attenuation of the increases in DA release by WAY100635, a selective 5-HT1A
Acknowledgments
This study was supported, in part, by grants from the Ritter Foundation, the Warren Foundation, and Mr. Donald Test.
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