Targeting striatal metabotropic glutamate receptor type 5 in Parkinson's disease: bridging molecular studies and clinical trials.

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors expressed primarily on neurons and glial cells modulating the effects of glutamatergic neurotransmission. The pharmacological manipulation of these receptors has been postulated to be valuable in the management of some neurological disorders. Accordingly, the targeting of mGlu5 receptors as a therapeutic approach for Parkinson's disease (PD) has been proposed, especially to manage the adverse symptoms associated to chronic treatment with classical PD drugs. Thus, the specific pharmacological blocking of mGlu5 receptors constitutes one of the most attractive non-dopaminergic-based strategies for PD management in general and for the L-DOPA-induced dyskinesia (LID) in particular. Overall, we provide here an update of the current state of the art of these mGlu5 receptor-based approaches that are under clinical study as agents devoted to alleviate PD symptoms.

Regulation of α2-adrenoceptor gene expression by chronic lithium treatment in rat brain.

One of the approaches for the treatment of bipolar disorder involves the coadministration of lithium, a mood stabilizer, with α2-adrenoceptor antagonists possessing an antidepressant effect. Since lithium accelerates the recovery of α2(D)-adrenoceptors following their irreversible inactivation with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), our aim was to examine if it could be to some changes in Adra2A gene expression which codifies these adrenoceptors. Animals were treated with lithium chloride (120 mg/kg i.p.) or saline once a day for 10 days. A group of lithium- or saline-treated rats was killed 48 h after the last injection. The remaining animals were treated with EEDQ and were killed at 0.25, 4 and 14 days following this administration. Total RNA was extracted from cerebral cortex and Adra2A gene expression was measured by RT-QPCR. The results show that chronic lithium raised the Adra2A gene expression (P < 0.05), and after EEDQ administration this expression decreased to the basal level. No change in Adra2A gene expression was detected in the saline-treated group. However, EEDQ administration produced an insignificant increase in α2-adrenoceptors mRNA levels followed by a progressive decrease until basal levels. Lithium produced an overexpression of the Adra2A gene after chronic treatment that made the neuron ready to produce α2-adrenoceptors to deal with their inactivation.

Effect of chronic lithium treatment on the turnover of alpha2-adrenoceptors after chemical inactivation in rats.

One of the most effective psychotherapeutic agents in the treatment of bipolar disease is lithium. Chronic lithium treatment affects some signal transduction mechanisms such as cAMP, cGMP, inositol 1,4,5 P(3), Gi protein, protein kinase C and can also modify gene expression in rat brain. In a previous study, we observed a greater inhibitory effect of lithium on cAMP production after blockade of alpha(2)-adrenoceptors in rat cerebral cortex. Here we examine the influence of chronic lithium treatment on turnover of alpha(2)-adrenoceptors after their inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) in rat cerebral cortex. After treatment with lithium for 10 days (120 mg/kg/day, i.p.), there was a significant increase in the appearance and disappearance rate constants of these adrenoceptors and a significant reduction of their half-life. These results suggest that chronic lithium administration alters the alpha(2)-adrenoceptor turnover in rat brain.

Demonstration of inhibition of cyclic AMP accumulation in brain by very low concentrations of lithium in the presence of alpha-adrenoceptor blockade.

In the present paper, we have studied the effect of lithium on cAMP levels induced by isoprenaline and norepinephrine in the presence of alpha- or beta-adrenoceptor antagonists. Our results show that low lithium concentrations, starting at 0.3 x 10(-3) M, have a significant inhibitory effect on cAMP content induced by isoprenaline in brain tissue pretreated with the alpha-adrenoceptor blocker phenoxybenzamine. On the other hand, the inhibitory effect of lithium on cAMP levels induced by norepinephrine when beta-adrenoceptors are blocked with propranolol, is observed at concentrations starting at 2.5 x 10(-3) M. These results show that in the presence of alpha blockade, low lithium concentrations which are within the therapeutic plasma range for treatment of manic patients, are able to act on an adenylate cyclase-cAMP system coupled to beta-adrenoceptors.

Effects of some antipsychotic drugs on cardiovascular catecholamine receptors in the rat.

1. Experiments were performed to determine the activity of four antipsychotic drugs on several catecholamine receptors that control the sympathetic cardiovascular responses in rats. 2. Chlorpromazine, thioridazine (0.03 and 0.1 mg kg-1) and haloperidol (0.3 and 1 mg kg-1) inhibited methoxamine-induced diastolic blood pressure increases in the pithed rat, whereas sulpiride (1 and 3 mg kg-1) was without effect. 3. Only sulpiride (3 mg kg-1) antagonized the pressor responses induced by xylazine. 4. Xylazine inhibited the heart rate increase induced by electrical stimulation of the spinal cord (C7-Th1) in the pithed rat. This effect was partially prevented by sulpiride (1 and 3 mg kg-1) and chlorpromazine (0.3 mg kg-1). A higher dose of chlorpromazine (1 mg kg-1) abolished the inhibitory effect of xylazine. 5. Apomorphine infusion inhibited the pressor responses induced by electrical stimulation (Th5-L4) in pithed rats. This effect was reversed by sulpiride (0.01, 0.03 and 0.1 mg kg-1) and partially antagonized by haloperidol (0.1 mg kg-1). 6. The depressor response to fenoldopam in anaesthetized rats was only inhibited by the higher dose of chlorpromazine and thioridazine (3 mg kg-1). 7. Our results suggest that, in the peripheral nervous system of the rat, haloperidol and sulpiride act as antagonists of DA2 receptors while chlorpromazine and thioridazine antagonized DA1 receptors. Furthermore, thioridazine and haloperidol show alpha 1-adrenoreceptor antagonist properties, whereas sulpiride antagonizes alpha 2-adrenoreceptors. Chlorpromazine shows mixed alpha 1/alpha 2-adrenoreceptor antagonism.

Increased peripheral alpha 1-adrenoceptor sensitivity following chronic thioridazine treatment in the pithed rat.

The effect of chronic treatment (10 days) with thioridazine (25 mg/kg per day, i.p.) on the increase in diastolic blood pressure induced by methoxamine and xylazine was studied in the pithed rat. The dose-response curve for methoxamine, but not for xylazine, was shifted to the left by the neuroleptic. These results indicate that postjunctional alpha 1-adrenoceptors in the rat blood vessels become supersensitive after long-term treatment with thioridazine.