Joanna M. Wierońska

Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats.

Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic and antidepressant drugs. The involvement of group I mGlu receptors in anxiety and depression has also been proposed. In view of the recent discovery of anxiolytic- or antidepressant-like effects of acute injections of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective and brain penetrable mGlu5 receptor antagonist, we designed the present study to examine anxiolytic- and/or antidepressant-like effects of multiple administrations of this drug. The anxiolytic-like effects of MPEP were evaluated in rats using the conflict drinking test. The antidepressant-like effect was estimated using the rat olfactory bulbectomy model of depression. Seven subsequent injections of MPEP (1 mg/kg) significantly (by 320%) increased the number of shocks accepted during the experimental session in the Vogel test. MPEP given once daily at a dose of 10 mg/kg, restored the learning deficit of bulbectomized rats after 14 days of treatment, remaining without any effect in the sham-operated animals. N-methyl-D-aspartic acid (NMDA)-induced convulsions in mice were not affected by a single injection of MPEP (30 mg/kg) indicating that at this dose MPEP did not block NMDA receptors. The results indicate that the prolonged blockade of mGlu5 receptors exerts anxiolytic- and antidepressant-like effects in rats. No tolerance to anxiolytic-like action occurs. The previously mentioned results further indicate that antagonists of group I mGlu receptors may play a role in the therapy of both anxiety and depression.

Blockade of the metabotropic glutamate receptor subtype 5 (mGluR5) produces antiparkinsonian-like effects in rats

The aim of the present study was to examine a potential beneficial effect of the blockade of metabotropic glutamate receptor subtype 5 (mGluR5) by the selective non-competitive antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), in models of parkinsonian symptoms in rats. Haloperidol, 0.25, 0.5 and 1mg/kg ip, was used to induce hypolocomotion, catalepsy and muscle rigidity, respectively. The locomotor activity was estimated by an open-field test, the catalepsy -- by a 9-cm cork test. The muscle rigidity was measured as an increased resistance of a hind leg to passive extension and flexion at the ankle joint. Additionally, increases in the electromyographic activity were recorded in the gastrocnemius and tibialis anterior muscles. MPEP (1.0-10mg/kg ip) inhibited the muscle rigidity, electromyographic activity, hypolocomotion and catalepsy induced by haloperidol. MPEP administered alone (5mg/kg ip) did not induce catalepsy, nor did it influence the muscle tone or locomotor activity in rats. The present results suggest that blockade of mGluR5 receptors may be important to amelioration of both parkinsonian akinesia and muscle rigidity.

Group III mGlu receptor agonists produce anxiolytic- and antidepressant-like effects after central administration in rats

It was well established that compounds which decrease glutamatergic transmission via blockade of NMDA or group I mGlu receptors produce anxiolytic- and antidepressant-like action in animal tests and models. Since group III metabotropic glutamate receptor (mGluR) agonists are known to reduce glutamatergic neurotransmission by the inhibition of glutamate release, we decided to investigate potential anxiolytic- and/or antidepressant-like effects of group III mGluR agonists, after central administration in rats. It was found that group III mGluR agonists, (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) and 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (HomoAMPA), given intrahippocampally, produced a dose-dependent anxiolytic-like effect in the conflict drinking test. The effects of ACPT-I and HomoAMPA were reversed by (RS)-alpha-cyclopropyl-4-phosphonophenyl glycine (CPPG), group III mGluR antagonist. Moreover, a dose-dependent antidepressant-like action of group III mGluR agonists, ACPT-I and (RS)-4-phosphonophenylglycine (RS-PPG), but not HomoAMPA, was found in behavioral despair test, after intracerebroventricular injections, and the effect of ACPT-I was reversed by CPPG. The results obtained indicate that group III mGluR agonists produce anxiolytic- as well as antidepressant-like effects in behavioral tests, after central administration in rats. The reduction of glutamate release by group III mGluR activation may be a possible mechanism underlying anxiolytic- and antidepressant-like properties of the tested compounds. In conclusion, the results of our studies indicate that group III mGlu receptor agonists may play a role in the therapy of both anxiety and depression.

A slowly developing dysfunction of dopaminergic nigrostriatal neurons induced by long-term paraquat administration in rats: an animal model of preclinical stages of Parkinson's disease?

The aim of the present study was to examine the influence of the long‐term paraquat administration on the dopaminergic nigrostriatal system in rats. Paraquat was injected at a dose of 10 mg/kg i.p. for 4–24 weeks. We found that this pesticide reduced the number of tyrosine hydroxylase‐immunoreactive neurons of the substantia nigra; after the 4‐week treatment the reduction (17%, nonsignificant) was confined to the rostrocentral region of this structure but, after 24 weeks, had spread along its whole length and was ≈ 37%. Moreover, it induced a biphasic effect on dopaminergic transmission. First, levels of dopamine, its metabolites and turnover were elevated (4–8 weeks) in the caudate–putamen, then all these parameters returned to control values (12 weeks) and dropped by 25–30% after 24 weeks. The binding of [3H]GBR 12,935 to dopamine transporter in the caudate–putamen was decreased after 4–8 weeks, then returned to control values after 12 weeks but was again decreased after 24 weeks. Twenty‐four‐week paraquat administration also decreased the level of tyrosine hydroxylase (Western blot) in the caudate–putamen. In addition, paraquat activated serotonin and noradrenaline transmission during the first 12 weeks of treatment but no decreases in levels of these neurotransmitters were observed after 24 weeks. The above results seem to suggest that long‐term paraquat administration produces a slowly progressing degeneration of nigrostriatal neurons, leading to delayed deficits in dopaminergic transmission, which may resemble early, presymptomatic, stages of Parkinsons disease.

Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist

The involvement of glutamate in the pathophysiology of depression has been suggested by a number of experiments. It was well established that compounds, which decreased glutamatergic transmission via blockade of NMDA receptor, produced antidepressant-like action in animal tests and models. The present study was carried out to investigate whether a selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) induces antidepressant-like effects after intraperitoneal injections in male Wistar rats or male C57BL/6J mice. Potential antidepressant-like activity of MTEP was evaluated using the forced swimming test (FST) in rats, the tail suspension test (TST) in mice and the olfactory bulbectomy (OB) model of depression in rats. The results of our studies showed, that MTEP (0.3-3 mg/kg) produced a significant dose-dependent decrease in the immobility time of mice in the TST, however, at doses of 1 or 10 mg/kg, it did not influence the behavior of rats in the FST in rats. Moreover, the repeated administration of MTEP (1 mg/kg) attenuated the OB-related hyperactivity of rats in the open field test, in the manner similar to that seen following chronic (but not acute) treatment with typical antidepressant drugs. These data suggest that MTEP, which is considered to be a potential therapeutic agent, may play a role in the therapy of depression.

Metabotropic glutamate receptors in the tripartite synapse as a target for new psychotropic drugs

Mental disorders, such as depression, anxiety and schizophrenia, has become a large medical and social problem recently. Studies performed in animal tests and early clinical investigations brought a new insight in the pharmacotherapy of these disorders. Latest investigations are focused mainly on the glutamatergic system, a main excitatory amino acid neurotransmitter in the brain. Evidence indicates that metabotropic glutamate receptors ligands have excellent antidepressant, anxiolytic and antipsychotic effects. Metabotopic glutamate receptors (mGlu) divaded into three groups (group I, II and III) are localized on nerve terminals, postsynaptic sites and glial cells and thus they can influence and modulate the action of glutamate on different levels in the synapse. Recent advances in the identification of selective and specific compounds (both ortho- and allosteric ligands), and the generation of transgenic animals enabled to have new insight into the pathophysiology and therapy of mood disorders. At present, the most potent seem to be negative allosteric modulators of the first group (mGlu1 and mGlu5), and positive allosteric modulators of the second (mGlu2 and mGlu3) and third (mGlu4/7/8) group of mGlu receptors.

Glutamate-Based Antidepressants: Preclinical Psychopharmacology

Over the past 20 years, converging lines of evidence have both linked glutamatergic dysfunction to the pathophysiology of depression and demonstrated that the glutamatergic synapse presents multiple targets for developing novel antidepressants. The robust antidepressant effects of the N-methyl-D-aspartate receptor antagonists ketamine and traxoprodil provide target validation for this family of ionotropic glutamate receptors. This article reviews the preclinical evidence that it may be possible to develop glutamate-based antidepressants by not only modulating ionotropic (N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) and metabotropic glutamate (mGlu) receptors, including mGlu2/3, mGLu5 and mGlu7 receptors, but also by altering synaptic concentrations of glutamate via specialized transporters such as glial glutamate transporter 1 (excitatory amino-acid transporter 2).

Antidepressant‐like activity of CGP 36742 and CGP 51176, selective GABAB receptor antagonists, in rodents

A crucial role for the GABAB receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant‐like activity of the selective GABAB receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice.

Toxic influence of subchronic paraquat administration on dopaminergic neurons in rats.

Paraquat is a toxin suggested to contribute to pathogenesis of Parkinsons disease. The aim of the present study was to examine toxic influence of subchronic treatment with this pesticide (5 days, one injection per day, 2-3 days of withdrawal) on dopaminergic, serotonergic, noradrenergic and GABAergic neurons. Paraquat decreased the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra by 22% (measured 3 days after withdrawal). Two days after withdrawal the levels of the dopamine metabolites and dopamine turnover in the caudate-putamen, substantia nigra and prefrontal cortex were reduced by ca. 20-60%, and the binding of [(3)H]GBR 12,935 to dopamine transporter dropped by 25-40% in the caudate-putamen. Three days after paraquat withdrawal, the level of dopamine in the caudate-putamen was significantly increased, and earlier decreases in DOPAC and HVA in the substantia nigra, as well as [(3)H]GBR 12,935 binding in the caudate-putamen were reversed. Moreover, an increase in serotonin turnover in the caudate-putamen and prefrontal cortex, and noradrenaline level in the former structure was observed 2-3 days after paraquat withdrawal. Three days after the last paraquat injection 24-35% decreases in the proenkephalin mRNA levels and 5-7% reduction in glutamic acid decarboxylase (GAD)67 mRNA were found in the caudate-putamen. The present study suggests that subchronic paraquat administration triggers processes characteristic of early stages of dopaminergic neuron degeneration, and activates compensatory mechanisms involving dopaminergic, noradrenergic, serotonergic and GABAergic transmissions.

Degeneration of dopaminergic mesocortical neurons and activation of compensatory processes induced by a long-term paraquat administration in rats : Implications for Parkinson's disease

A deficiency of the dopaminergic transmission in the mesocortical system has been suggested to contribute to cognitive disturbances in Parkinsons disease. Therefore, the aim of the present study was to examine whether the long-term administration of a commonly used herbicide, paraquat, which has already been found to induce a slowly progressing degeneration of the nigrostriatal neurons, influences mesocortical dopaminergic neurons in rats. Paraquat at a dose of 10 mg/kg i.p. was injected either acutely or once a week for 4, 8, 12 and 24 weeks. Acute treatment with this pesticide increased the level of homovanillic acid (HVA) and HVA/dopamine ratio in the prefrontal cortex. After 8 weeks of administration paraquat increased the number of stereologically counted tyrosine hydroxylase-immunoreactive (TH-ir) neurons and their staining intensity in the ventral tegmental area (VTA), which is a source of the mesocortical dopaminergic projection. At the same time, few TH-ir neurons appeared in different regions of the cerebral cortex: in the frontal, cingulate, retrosplenial and parietal cortices. Chronic paraquat administration did not influence the level of dopamine in the prefrontal cortex but increased the levels of its metabolites: 3,4-dihydroxyphenylacetic acid (after 8-12 weeks), HVA (after 4 and 12 weeks) and HVA/dopamine ratio (4 weeks). After 24 weeks this pesticide reduced the number of TH-ir neurons in the VTA by 42% and of the Nissl-stained neurons by 26%, and induced shrinkage of this structure by ca. 25%. Moreover, TH-ir neurons in the cortex were no more visible after such a long period of administration and levels of dopamine metabolites returned to control values. The present results suggest that the long-term paraquat administration destroys dopaminergic neurons of the VTA. However, compensatory activation of the VTA neurons and cortex overcomes progressing degeneration and maintains cortical dopaminergic transmission.