Involvement of group II metabotropic glutamate receptors in stress-induced behavioural sensitization

Rationale A short session of repeated foot shocks in rats causes long-lasting sensitization of behavioural, hormonal and autonomic responses to novel stressful challenges. The behavioural sensitization can be reduced by anxiolytics and mimics aspects of stress-induced changes in patients with post-traumatic stress disorder. Objectives The aim of this study was to test the efficacy of a group II metabotropic glutamate receptor (mGluR) agonist and assess altered brain mGluR receptor expression in shock-sensitized rats. Materials and methods Male Wistar rats were exposed to a 15-min session with ten 6-s foot shocks (preshocked). One and 2 weeks later, rats were intraperitoneally injected with the group II metabotropic glutamate receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) or vehicle, and 30 min later exposed to 5 min of 85 dB noise. For in situ hybridization with probes for mGluR1, mGluR2, mGluR3 and mGluR5, preshocked and control rats were killed under basal conditions 2 weeks after foot shocks and their brains cryosectioned. Results APDC had no clear effect in controls, but dose-dependently reduced high immobility and increased low locomotion and rearing seen in preshocked rats to the levels of controls. mGluR3 expression was increased in the basolateral nucleus of the amygdala, and mGluR2 expression was increased in the agranular insular cortex of preshocked rats compared to controls. Conclusions Shock-induced behavioural sensitization in rats is reduced by acute treatment with a group II metabotropic glutamate receptor agonist. This effect may depend on the increased expression of amygdala mGluR3, which could be hypothesized as an endogenous mechanism to counteract stress-induced neuronal sensitization.     

Roles of group II metabotropic glutamate receptors in modulation of seizure activity

Evidence suggests that metabotropic glutamate receptors (mGluR) are involved in mediating seizures and epileptogenesis. In the present experiments, the selective, group II mGluR agonist (+)-2-aminobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid (LY354740, 0.1-1.0 microM) inhibited spontaneous epileptiform discharges which developed in rat cortical slices in Mg2+-free medium. LY354740 (4-16 mg/kg) administered prior to an injection of pentylenetetrazol (80 mg/kg) or picrotoxin (3.2 mg/kg) produced a dose-dependent decrease in the number of mice exhibiting clonic convulsions, but had no effect on N-methyl-D-aspartate (NMDA, 150 mg/kg)-induced convulsions. LY354740 (4-16 mg/kg) did not affect lethality induced in mice by pentylenetetrazol, picrotoxin or NMDA. LY354740 potentiated the anticonvulsant activity of the conventional antiepileptic drug diazepam, significantly decreasing the ED50 for that drug's effect on pentylenetetrazol-induced convulsions by 30%, but had no influence on anticonvulsant activity of ethosuximide and valproic acid. A pharmacokinetic interaction between LY354740 and diazepam, leading to the lowering of the plasma level of free diazepam, was also demonstrated. Our data suggest that the group II mGluR agonist LY354740 possesses anti-seizure activity and may modify the effects of some conventional antiepileptic drugs.     

Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking.

Using a rat relapse model, we previously reported that re-exposing rats to a drug-associated context, following extinction of operant responding in a different context, reinstates heroin seeking. In an initial pharmacological characterization, we found that the mGluR2/3 agonist LY379268, which acts centrally to reduce evoked glutamate release, attenuates context-induced reinstatement of heroin seeking when injected systemically or into the ventral tegmental area, the cell body region of the mesolimbic dopamine system. Here, we tested whether injections of LY379268 into the nucleus accumbens (NAc), a terminal region of the mesolimbic dopamine system, would also attenuate context-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin; drug infusions were paired with a discrete tone-light cue. Subsequently, lever pressing was extinguished in the presence of the discrete cue in a context that differed from the drug self-administration context in terms of visual, auditory, tactile, and circadian cues. After extinction of responding, LY379268 was injected to different groups of rats into the NAc core or shell or into the caudate-putamen, a terminal region of the nigrastriatal dopamine system. Injections of LY379268 into the NAc shell (0.3 or 1.0 microg) dose-dependently attenuated context-induced reinstatement of heroin seeking. Injections of 1.0 microg of LY379268 into the NAc core had no effect, while a higher dose (3.0 microg) decreased this reinstatement. Injections of LY379268 (3.0 microg) 1.5 mm dorsal from the NAc core into the caudate-putamen were ineffective. Results suggest an important role of glutamate transmission in the NAc shell in context-induced reinstatement of heroin seeking.     

Therapeutic potential of group III metabotropic glutamate receptors

Metabotropic glutamate (mGlu) receptors have received much attention, driven by a strong belief in the potential of these modulatory glutamate receptors as drug targets. So far, major drug discovery programs have largely focused on group I (mGlu1 and 5) and II (mGlu2 and 3) mGlu receptors, which have been implicated in neuropathological and various psychiatric disorders. The four group III representatives (mGlu4, mGlu6, mGlu7 and mGlu8) are less understood, mainly due to the paucity of specific compounds. Recent advances in the identification of selective or specific compounds, and the generation of transgenic animals have, however, revealed important insights into the potential role of group III receptors in the pathophysiology of neurological and mood disorders. Activation of the mGlu4 receptor seems to be beneficial for treating Parkinson-like symptoms and a potential role in the treatment of mood disorders is slowly growing. Similarly, genetic inactivation studies and usage of relatively selective agonists strongly support the involvement of the mGlu8 receptor for anxiety disorders. In contrast, controversial data have been obtained for the mGlu7 receptor. While mGlu7 receptor-deficient animals show an anxiolytic profile in several in vivo readouts, the first selective allosteric agonist AMN082 has also been reported to improve anxiety-like behaviour despite activating the stress axis. The least investigated receptor remains the mGlu6 receptor, which is mostly based on its predominant expression in the retina.     

Activation of glutamate metabotropic receptors induces long-term potentiation.

The specific glutamate metabotropic receptor agonist 1S,3R-aminocyclopentane dicarboxylate (ACPD), but not its inactive enantiomer 1R,3S-ACPD, induced a slowly developing potentiation of synaptic transmission in rat hippocampal slices. This effect was independent of its ability to potentiate responses mediated by the activation of N-methyl-D-aspartate receptors. Perfusion with 1S,3R-ACPD provides, therefore, a means of chemically inducing a form of long-term potentiation.     

Regulation of cocaine-induced reinstatement by group II metabotropic glutamate receptors in the ventral tegmental area

Rationale  

A high rate of relapse is a daunting challenge facing clinical treatment of cocaine addiction. Recent studies have shown that drugs of abuse enhance glutamate neurotransmission in dopamine neurons in the ventral tegmental area (VTA) and such enhancement may contribute to the risk of relapse.     

Increased binding of cortical and hippocampal group II metabotropic glutamate receptors in isolation-reared mice

Post-weaning social isolation in rodents induces behavioral alterations, including hyperlocomotion, depression- and anxiety-like behaviors, aggression, and learning and memory deficits. These behavioral abnormalities may be related to the core symptoms in patients with neuropsychiatric disorders, such as schizophrenia and depression. In view of the recent studies that the group II metabotropic glutamate receptor (mGluR2/3) is involved in neuropsychiatric disorders, the present study examined the effect of isolation rearing on the binding of the mGluR2/3 antagonist [(3)H]LY341495 to mGluR2/3 in the mouse brain by in vitro autoradiography. The [(3)H]LY341495 binding in the prefrontal cortex, cerebral cortical layers I-III and hippocampus was significantly increased by rearing in social isolation while the binding in other brain regions was not altered. A saturation binding study of hippocampal membranes from isolation-reared mice revealed that the B(max) value increased significantly without any changes in the K(d) value. Moreover, the mGluR2/3 antagonist MGS0039 (1.0mg/kg, intraperitoneally) decreased the immobility time of isolation-reared mice in the forced swim test. These results suggest that isolation rearing causes an increase in mGluR2/3 densities in the prefrontal cortex and hippocampus and that the increased receptor function may contribute to pathogenic mechanisms for depression-like behavior of the isolation-reared mice.     

Antagonism of metabotropic glutamate group II receptors in the potential treatment of neurological and neuropsychiatric disorders

The metabotropic glutamate Group II receptors (mGlu2 and mGlu3 receptors) regulate the synaptic availability of glutamate and thus control the broad‐ranging neural transmission of glutamate as well as glutamate‐modulated transmission. The present review focuses on the potential role of Group II mGlu receptor antagonism in neurological and neuropsychiatric disorders. Recent findings have determined that agonists of metabotropic glutamate type 2/3 receptors (mGlu2/3) have antianxiety efficacy. Although it could be assumed that blockade of these receptors might engender anxiogenic responses, new data have indicted that these compounds produce antidepressant‐like, wake‐promoting, and pro‐cognitive effects in rodents. However, there are almost no data available to define the relative importance of mGlu2 versus mGlu3 receptors in these activities. Although there are some hints that antagonism of mGlu2/3 receptors could have additional therapeutic impact, the preponderance of data suggests that agonists of the mGlu2/3 receptors would be more likely to have efficacy in anxiety disorders, positive symptoms of schizophrenia, neurodegenerative disorders, and stroke, pain, and epilepsy. The pharmacology of antagonists of mGlu2/3 receptors suggests that such compounds could have a unique place in the medicinal arsenal for mood disorders as well as disorders of cognition and arousal. Given the activity surrounding the discovery of orally available antagonists for these receptors, there may be an opportunity for clinical investigation of these possibilities in the future. Drug Dev. Res. 67:757–769, 2006. © 2006 Wiley‐Liss, Inc.     

Activation of metabotropic glutamate receptors induces propagating network oscillations in the intact cerebral cortex of the newborn mouse

Activation of metabotropic glutamate receptors (mGluRs) with (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) elicited in the frontal or occipital pole of the intact cerebral cortex preparation of the newborn mouse (P0-P3) a transient oscillatory field potential activity in the frequency range of 11-14Hz. These oscillations propagated over the whole cortical hemisphere and were blocked by tetrodotoxin, indicating that action potentials are required for the generation of this activity. Blockade of GABA-A receptors with gabazine did not influence the ACPD-induced network activity, but the glycine antagonist strychnine caused a significant decrease in the frequency, amplitude and duration of the oscillations. Bath application of kynurenic acid, the AMPA/kainate antagonist CNQX or the NMDA antagonist CPP induced a significant reduction in the response amplitude by 15-18%, indicating that ionotropic glutamate receptors are involved in this network activity. The selective mGluR-1a antagonist LY367385 and the mGluR-5 antagonist MPEP reversibly blocked the field potential oscillations, whereas the group II mGluR antagonist LY341495 did not block the activity. The network oscillations were also blocked by the gap junction inhibitors carbenoxolone and quinidine. These data indicate that ACPD-induced oscillatory network activity in the neonatal mouse cerebral cortex depends on action potential discharge, activation of group I mGluRs of type 1a and type 5 and intact gap junctional coupling. We suggest that this propagating large-scale network activity may play an important role in the functional formation of early neocortical circuits.     

Blockade of group II metabotropic glutamate receptors produces hyper-locomotion in cocaine pre-exposed rats by interactions with dopamine receptors

It was previously reported that blockade of group II metabotropic glutamate receptors (mGluRs) produces hyper-locomotion in rats previously exposed to amphetamine, indicating that group II mGluRs are well positioned to modulate the expression of behavioral sensitization by amphetamine. The present study further examined the locomotor activating effects of specific blockade of these receptors after cocaine pre-exposures. First, rats were pre-exposed to seven daily injections of cocaine (15mg/kg, IP). When challenged the next day with an injection of either saline or the group II mGluR antagonist LY341495 (0.5, 1.0 or 2.5mg/kg, IP), they produced hyper-locomotor activity, measured by infrared beam interruptions, to LY341495 compared to saline in a dose-dependent manner. Second, rats were pre-exposed to either saline or seven daily injections of cocaine (15mg/kg, IP). Three weeks later, when they were challenged with an injection of either saline or LY341495 (1.0mg/kg, IP), only rats pre-exposed to cocaine produced hyper-locomotor activity to LY341495 compared to saline. These effects, however, were not present when dopamine D1 (SCH23390; 5 or 10mug/kg), but not D2 (eticlopride; 10 or 50mug/kg), receptor antagonist was pre-injected, indicating that this cocaine-induced hyper-locomotor activity to LY341495 may be mediated in dopamine D1 receptor-dependent manner. These results suggest that group II mGluRs may be adapted to interact with dopaminergic neuronal signaling in mediating the sensitized locomotor activity produced by repeated cocaine pre-exposures.     

Stimulation of endocannabinoid formation in brain slice cultures through activation of group I metabotropic glutamate receptors

Activation of group I metabotropic glutamate (mGlu) receptors drives the endocannabinoid system to cause both short- and long-term changes of synaptic strength in the striatum, hippocampus, and other brain areas. Although there is strong electrophysiological evidence for a role of endocannabinoid release in mGlu receptor-dependent plasticity, the identity of the endocannabinoid transmitter mediating this phenomenon remains undefined. In this study, we show that activation of group I mGlu receptors triggers the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG), but not anandamide, in primary cultures of corticostriatal and hippocampal slices prepared from early postnatal rat brain. Pharmacological studies suggest that 2-AG biosynthesis is initiated by activation of mGlu5 receptors, is catalyzed by phospholipase C (PLC) and 1,2-diacylglycerol lipase (DGL) activities, and is dependent on intracellular Ca2+ ions. Realtime polymerase chain reaction and immunostaining analyses indicate that DGL-beta is the predominant DGL isoform expressed in corticostriatal and hippocampal slices and that this enzyme is highly expressed in striatal neurons, where it is colocalized with PLC-beta1. The results suggest that 2-AG is a primary endocannabinoid mediator of mGlu receptor-dependent neuronal plasticity.     

Positive and negative modulation of group I metabotropic glutamate receptors

A discriminating pharmacophore model for noncompetitive metabotropic glutamate receptor antagonists of subtype 1 (mGluR1) was developed that facilitated the discovery of moderately active mGluR1 antagonists. One scaffold was selected for the design of several focused libraries where different substitution patterns were introduced. This approach facilitated the discovery of potent mGluR1 antagonists, as well as positive and negative mGluR5 modulators, because both receptor subtypes share similar binding pockets. For mGluR1 antagonists, a homology model of the mGlu1 receptor was established, and a putative binding mode within the receptor's transmembrane domain was visualized.     

II、III组亲代谢型谷氨酸受体激动剂对脂多糖抑制C6胶质瘤细胞摄取谷氨酸的影响

目的：探讨II、III组亲代谢型谷氨酸受体（metabotropic glutamate receptors，mGluRs）激动剂对脂多糖（LPS）抑制C6胶质瘤细胞摄取谷氨酸（glutamate，GIu）的影响。方法：应用同位素标记法测定C6胶质瘤细胞对[^3H]-D，L-Glu的摄取。应用Hoechst染色法、噻唑蓝比色法（MTT）分别检测C6胶质瘤细胞的亡、细胞活力。结果：LPS（4、6μg／mL）显著抑制C6胶质瘤细胞摄取[^3H]-D，L-Glu，抑制率分别达17．6％和22．2％。Ⅱ组mGluRs激动剂DCG-IV100μmol／L和III组mGluRs激动剂L-AP4 100pznol／L逆转LlX3对C6胶质瘤细胞摄取[^3H]．D，L-GIu的抑制作用，这种逆转作用分别被Ⅱ、ⅡI组mGluRs拮抗剂APICA和MSOP取消。结论：DCG-IV和L-AP引起的C6胶质瘤细胞Glu摄取抑制，提示II、III组mGluRs激动剂通过促进Glu摄取，降低细胞外Glu浓度，从而发挥神经保护作用。     

Activation of group III metabotropic glutamate receptors in selected regions of the basal ganglia alleviates akinesia in the reserpine-treated rat

1. This study examined whether group III metabotropic glutamate (mGlu) receptor agonists injected into the globus pallidus (GP), substantia nigra pars reticulata (SNr) or intracerebroventricularly (i.c.v.) could reverse reserpine-induced akinesia in the rat. 2. Male Sprague-Dawley rats, cannulated above the GP, SNr or third ventricle, were rendered akinetic with reserpine (5 mg kg(-1) s.c.). 18 h later, behavioural effects of the group III mGlu receptor agonists L-serine-O-phosphate (L-SOP) or L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) were examined. 3. In reserpine-treated rats, unilateral injection of L-SOP (2000 and 2500 nmol in 2.5 microl) into the GP produced a significant increase in net contraversive rotations compared to vehicle, reaching a maximum of 83+/-21 rotations 120 min(-1) (n=8). Pretreatment with the group III mGlu receptor antagonist methyl-serine-O-phosphate (M-SOP; 250 nmol in 2.5 microl) inhibited the response to L-SOP (2000 nmol) by 77%. Unilateral injection of L-SOP (250-1000 nmol in 2.5 microl) into the SNr of reserpine-treated rats produced a dose-dependent increase in net contraversive rotations, reaching a maximum of 47+/-6 rotations 30 min(-1) (n=6). M-SOP (50 nmol in 2.5 microl) inhibited the response to L-SOP (500 nmol) by 78%. 4. Following i.c.v. injection, L-SOP (2000-2500 nmol in 2.5 microl) or L-AP4 (0.5-100 nmol in 2 microl) produced a dose-dependent reversal of akinesia, attaining a maximum of 45+/-17 (n=8) and 72+/-3 (n=9) arbitrary locomotor units 30 min(-1), respectively. 6. These studies indicate that injection of group III mGlu receptor agonists into the GP, SNr or cerebral ventricles reverses reserpine-induced akinesia, the mechanism for which remains to be established.     

Anxiolytic action of group II and III metabotropic glutamate receptors agonists involves neuropeptide Y in the amygdala

Several lines of evidence indicate that activation of group II and III metabotropic glutamate (mGlu) receptors produces anxiolytic-like effects in rodents. On the other hand neuropeptide Y (NPY) induces an anxiolytic effect in rats after intraventricular or intraamygdalar administration. Therefore, in the present study we investigated whether the anxiolytic action of (2S,3S,4S)-(carboxycyclopropyl)glycine (L-CCG-I), an mGlu2/3 receptor agonist, and (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-1), an mGluR4/6/7/8 receptor agonist, was mediated by a mechanism involving NPY receptor. In behavioral studies, the anxiolytic activity of L-CCG-I (10 microg/0.5 microl/site) and ACPT-1 (1.5 microg/0.5 microl/site) was examined using plus-maze tests. The Y1 receptor antagonist BIBO 3304 was given at a dose of 128 ng/0.5 microl/site. All the compounds tested were injected bilaterally into the amygdala, BIBO 40 min and mGluR agonists 30 min before the test. It was found that the anxiolytic effects of mGluR agonists were abolished by BIBO 3304 {((R)-N-[[4-(aminocarbonylaminomethyl) phenyl] methyl]-N2-(diphenylacetyl)-argininamide trifluoroacetate)3304} administration. Immunohistochemical studies showed a moderate density of mGlu2/3 receptor immunoreactivity (IR) in the amygdala. The effect of L-CCG-I and ACPT-1 on NPY expression in the amygdala was studied using immunohistochemistry (IH), while NPYmRNA expression was studied using in situ hybrydization. We showed a diminution in NPY-IR after L-CCG-I administration and decrease in NPYmRNA expression after both L-CCG-I and ACPT-1 treatment, to about 77% (IH) or 32-41% (mRNA) of the control level 18 h after injection of these mGluR agonists. Our results indicate that the anxiolytic action of both compounds is conveyed by NPY neurons with the involvement of Y1 receptors in the amygdala, and that NPY neurons seem to be regulated by the glutamatergic system.     

Activation of brainstem metabotropic glutamate receptors inhibits spinal nociception in adult rats

In this study, we provide evidence that focal electrical stimulation applied to the rostroventral medulla (RVM) at a high frequency (100 Hz) produced inhibition of the spinal nociceptive tail-flick (TF) reflex in lightly anesthetized adult rats. Chemical activation of metabotropic glutamate (mGlu) receptors by local injection of (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (tACPD), the mGlu receptor agonist, produced a dose-related inhibition of the TF reflex. Injection of the Group II mGlu receptor agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine (DCGIV) produced strong inhibition, while injection of the Group III mGlu receptor agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) did not produce any effect. (RS)-alpha-Methyl-4-carboxyphenylglycine (MCPG), a selective mGlu receptor antagonist, but not naloxone reversed the inhibitory effects of DCGIV. Our results provide physiological evidence in vivo that activation of Group II mGlu receptors in the brainstem is antinociceptive and drugs targetting these receptors may help to control pain in humans.     

Basal ganglia group II metabotropic glutamate receptors specific binding in non-human primate model of L-Dopa-induced dyskinesias

L-Dopa-induced dyskinesias (LIDs), the disabling abnormal involuntary movements induced by chronic use of L-Dopa, limit the quality of life in Parkinson's disease (PD) patients. Modulation of group II metabotropic glutamate receptors (mGluR2/3) in the basal ganglia, a brain region critically involved in motor control, is considered as an alternative approach in therapy of PD. In this study, receptor binding autoradiography of [3H]LY341495, a mGluR2/3 selective radioligand, was used to investigate possible changes in mGluR2/3 in the basal ganglia of L-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys having developed LIDs compared to animals in which LIDs were prevented by adjunct treatments with CI-1041, a selective antagonist of the NR1A/2B subtype of NMDA receptor, or low doses of the dopamine D2 receptor agonist, cabergoline. Our study is the first to provide evidence of: (1) the similar localization of [3H]LY341495 specific binding to mGluR2/3 in the primate basal ganglia as compared to receptor distribution measured by immunohistochemistry in human and rat as well as this ligand binding in intact rat brain; (2) no change of [3H]LY341495 specific binding in basal ganglia after nigrostriatal denervation by MPTP; and (3) a widespread reduction of [(3)H]LY341495 specific binding to mGluR2/3 in the caudate nucleus (-17% to -31%), putamen (-12% to -45%) and globus pallidus (-56 to -59%) of non-dyskinetic animals treated with L-Dopa+cabergoline as compared to controls, MPTP monkeys treated with saline, L-Dopa alone (dyskinetic) or L-Dopa+CI-1041 (non-dyskinetic). This study is the first to propose a close interaction between mGluR2/3 and dopamine D2 receptors activation in the basal ganglia.     

Activation of group I metabotropic glutamate receptors induces long-term depression at sensory synapses in superficial spinal dorsal horn

Low-frequency stimulation of primary afferent Adelta-fibers can induce long-term depression of synaptic transmission in rat superficial spinal dorsal horn. Here, we have identified another form of long-term depression in superficial spinal dorsal horn neurons that is induced by specific group I but not group II metabotropic glutamate receptor (mGluR) agonists. Synaptic strength between Adelta-fibers and dorsal horn neurons was examined by intracellular recordings in a spinal cord-dorsal root slice preparation from young rat. In the presence of bicuculline and strychnine, bath application of (1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid ((1S,3R)-ACPD) or the specific group I mGluR agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) but not the specific group II mGluR agonist (2S,2'R,3'R)-2-(2', 3'-dicarboxycyclopropyl)glycine (DCG-IV) for 20 min produced an acute and a long-term depression of synaptic strength. Bath application of the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid did not affect these depressions by (1S,3R)-ACPD. After pre-incubation of slices with pertussis toxin, a G-protein inhibitor, (1S,3R)-ACPD still induced acute and long-term depressions. The phospholipase C inhibitor U73122 stereoselectively blocked the induction of long-term depression without affecting acute synaptic inhibition. This study demonstrates that, in the spinal cord, direct activation of group I mGluRs that are coupled to phospholipase C through pertussis toxin-insensitive G-proteins induces a long-term depression of synaptic strength. This may be relevant to the processing of sensory information in the spinal cord, including nociception.     

Activation of striatal group II metabotropic glutamate receptors has a differential effect on dopamine-D1 and -D2 receptor antagonist-induced hypokinesia in the rat

Motor function of group II metabotropic glutamate receptors was investigated by quantifying motor effects of bilateral infusions of the preferential group II metabotropic glutamate receptor agonist (2S,3S,4S)-alpha-carboxycyclopropyl-glycine (15, 30, 60 nmol/0.5 microl) into the striatum of conscious rats. (2S,3S,4S)-alpha-carboxycyclopropyl-glycine reduced spontaneous sniffing activity in an experimental chamber, but did not affect spontaneous locomotor (line crossings) or exploratory behaviour (rearings, hole visits) in an open field equipped with a hole-board. Intrastriatal infusion of the selective group III metabotropic glutamate receptor agonist L-2-amino-4-phosphobutyric acid (15, 30, 60, 120 nmol/0.5 microl) did not influence spontaneous motor behaviour. Intrastriatal infusion of (2S,3S,4S)-alpha-carboxycyclopropyl-glycine (15 nmol/0.5 microl and 30 nmol/0.5 microl) further depressed spontaneous motor behaviour in rats pretreated with the dopamine-D1 receptor antagonist (-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H- benzo[d]naphtho-(2,1-b)azepine, but not if rats were pretreated with the preferential dopamine-D2 receptor antagonist haloperidol. It appears likely that the depression of spontaneous motor behaviour evoked by the preferential group II agonist (2S,3S,4S)-alpha-carboxycyclopropyl-glycine is mediated by activation of group II metabotropic glutamate receptors, since activation of group I metabotropic glutamate receptors has been shown to stimulate motor behaviour, and activation of group III metabotropic glutamate receptors had no effect, as shown in this study. Therefore, it is reasonable to speculate that the striatum may contribute to the motor-depressant effects of systemically applied group II metabotropic glutamate receptor agonists, as reported by us recently. The present findings further suggest that a functional dopamine-D1 antagonism contributes to the motor effects of group II metabotropic glutamate receptor agonists.