Research reportDopamine and 5-HT turnover are increased by the mGlu2/3 receptor agonist LY379268 in rat medial prefrontal cortex, nucleus accumbens and striatum
Introduction
Metabotropic glutamate (mGlu) receptors are a heterogeneous family of G-protein coupled receptors that function to modulate glutamate and non-glutamate neuronal transmission by presynaptic, postsynaptic and glial mechanisms [4], [16] Our earlier studies demonstrated that systemic injection of the potent, selective group II metabotropic glutamate (mGlu2/3) receptor agonist, LY379268 [14] increased extracellular levels of dopamine, dopamine metabolites DOPAC and HVA, and the major 5-HT metabolite 5-HIAA in the medial prefrontal cortex (mPFC) of the freely-moving rat [3]. In eliciting these effects on monoamines and their metabolites in the mPFC, LY379268 shares a similar profile to the atypical antipsychotics, clozapine and risperidone [3], [6], [7]. In addition to increasing extracellular levels of dopamine, clozapine and the classical neuroleptic haloperidol, also increase brain tissue levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) [10], [13], [19], [20]. Specifically, Karoum and Egan [10] showed that clozapine increased ex vivo tissue levels of DOPAC in three of the brain regions that have been implicated in the actions of antipsychotics: PFC, nucleus accumbens and the striatum. Clozapine also increased HVA levels in the striatum and nucleus accumbens [19].
Although metabolite tissue levels do not necessarily correlate directly with neurotransmitter release, many studies have indicated that levels of the dopamine metabolites DOPAC and HVA in tissue are useful as indexes of neurotransmitter function [15], [18]. In particular, the tissue metabolite:neurotransmitter ratios such as DOPAC:dopamine ratio have been calculated to study drug-induced changes neurotransmitter utilization across different brain regions [8], [9].
Given the similarities between the effects of LY379268 and atypical antipsychotics on monoamine levels in the extracellular fluid of the mPFC [3], along with earlier observation that LY379268 acts like clozapine in animal behavioral tests of psychosis [2], here we have examined the effects of LY379268 on ex vivo tissue levels of dopamine, 5-HT and their metabolites DOPAC and HVA, and 5-hydroxyindoleacetic acid (5-HIAA). By calculating the tissue DOPAC:dopamine, HVA:dopamine and 5-HIAA:5-HT ratios, we were able to obtain an indication of dopamine and 5-HT turnover/utilization in tissue regions of the rat brain. We have also compared the effects of LY379268 in the medial prefrontal cortex with two different atypical antipsychotics, clozapine and risperidone. Furthermore, we studied the actions of LY379268 (10 mg/kg s.c.) in two other brain regions, the nucleus accumbens and striatum. Overall, these studies are aimed at further understanding the possible role of mGlu2/3 receptor activation in psychiatric disorders.
Section snippets
Materials and methods
Experiments were essentially performed as described by Fuller and Perry [5] and Bymaster et al. [1] with some modifications.
Time course of LY379268 effect in mPFC
LY379268 (10 mg/kg s.c.) increased dopamine and 5-HT turnover in the mPFC as shown by the ratios of DOPAC:dopamine (Fig. 1A), HVA:dopamine (Fig. 1B) and 5-HIAA:5-HT (Fig. 1C). These increases were time-dependent, the ratios were maximal 2 h following administration of LY379268 (the HVA:dopamine ratio was statistically significant at this time only) and the increases were abolished at the four h time point (Fig. 1).
Table 1 shows that absolute levels of DOPAC were increased at 0.5, 1 and 2 h
Discussion
In earlier studies using in vivo microdialysis we have demonstrated that systemic administration of the selective mGlu2/3 receptor agonist LY379268 evoked similar effects on the monoaminergic systems of the mPFC as the atypical antipsychotic clozapine [3]. In this paper, we have compared the effects of LY379268 with two different atypical antipsychotics, clozapine and risperidone, on dopamine and 5-HT turnover in ex vivo mPFC tissue.
There are a number of methods to measure monoamine
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