Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study

Abstract

Metabotropic glutamate receptors (mGluRs) are a major class of excitatory amino acid receptors. Eight mGluR subtypes, coupled to a variety of effector systems, have been cloned. These receptors have been classified into three groups based on amino acid sequence homology, effector systems, and pharmacological profile. Group I mGluRs increase phosphoinositide turnover, whereas groups II and III mGluRs are negatively coupled to adenylyl cyclase. The striatum possesses a high density of mGluR binding sites, and several mGluR mRNAs and proteins are expressed by striatal neurons. In rats, unilateral striatal injection of the nonsubtype selective mGluR agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) results in contralateral rotation with delayed onset, thought to be secondary to an increase in dopamine release. We sought to determine the mGluR subtype(s) involved, the modulation of the rotation by other basal ganglia neurotransmitter systems, and the functional anatomy underlying the rotational behavior. The group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) induced contralateral rotation in a dose-dependent manner, whereas group II and group III agonists were ineffective. Rotation induced by DHPG or 1S,3R-ACPD was attenuated by group I antagonists, but not by group II or group III antagonists. This suggests that the rotation is mediated by group I mGluRs. Rotation induced by DHPG or 1S,3R-ACPD was attenuated by pretreatment with antagonists at muscarinic cholinergic, adenosine A 2 , dopamine D 2 , or dopamine D 1 receptors. Examination of FOS-like immunoreactivity after group I and group II mGluR agonist administration suggests increased activity in the striatopallidal pathway. However, [ 14 C]-2-deoxyglucose uptake studies indicate increased activity in nuclei of the striatopallidal (indirect) pathway, particularly in the subthalamic nucleus, only after group I mGluR activation. Key words: metabotropic glutamate receptor; basal ganglia; subthalamic nucleus; striatum; dopamine; adenosine A2 receptors; muscarinic receptorsExcitatory amino acids (EAAs) are important neurotransmitters in the basal ganglia, and EAAergic agents are being investigated actively as possible pharmacotherapies for basal ganglia disorders. A major class of EAA receptors are the metabotropic glutamate receptors (mGluRs), coupled to second messenger systems via G-proteins. Eight mGluR subtypes have been cloned, several of which possess splice variants. These mGluR subtypes have been categorized into three groups based on their amino acid sequence homology, effector systems, and pharmacological profile. When expressed and activated in transfection systems, group I receptors (mGluRs 1 and 5) stimulate phosphoinositide hydrolysis. Group II (mGluRs 2 and 3) and group III (mGluRs 4 -8) receptors inhibit adenylyl cyclase, although with different pharmacological profiles (for review, see Pin and Duvosin, 1995;Roberts, 1995). Ligand-binding studies have shown the striatum to possess a high density of mGluR binding sites (Albin et al....

Metabotropic mGlu5 receptors regulate adenosine A 2A receptor signaling

“…In striatum, mGlu receptors have been shown to contribute to a variety of processes including neural plasticity (27), motor behavior (28), and glutamate excitotoxicity (29). Behavioral effects observed in response to perturbing signaling through the mGlu5 receptor pathway can be explained by the results of the present study.…”

“…Behavioral effects observed in response to perturbing signaling through the mGlu5 receptor pathway can be explained by the results of the present study. For instance, intrastriatal injection of nonselective or group I mGlu receptor agonists induced delayed contralateral turning behavior, which is possibly mediated by the potentiation of action of adenosine A 2A receptors in striatopallidal neurons followed by the disinhibition of subthalamic nucleus neurons, with the consequent increase in output of dopaminergic nigrostriatal neurons (28). In 6-hydroxydopamine-lesioned rats, the intracerebroventricular injection of an mGlu5 agonist counteracted the contralateral turning behavior elicited by a dopamine D2 agonist, which could be explained by the potentiation of reciprocal interaction between adenosine A 2A and dopamine D2 receptors (30).…”

The Selective mGlu5 Receptor Agonist CHPG Inhibits Quinpirole-Induced Turning in 6-Hydroxydopamine-Lesioned Rats and Modulates the Binding Characteristics of Dopamine D2 Receptors in the Rat Striatum Interactions with Adenosine A2a Receptors

“…In 6-hydroxydopamine(6-OH-DA)-lesioned rats, which represent a rodent model of Parkinson's disease (Schwarting and Huston 1996;Ungerstedt 1971), the intracerebroventricular (ICV) injection of 1S,3R ACPD selectively counteracted the turning behavior elicited by a dopamine D 2 receptor agonist . Both effects of mGlu receptor agonists (antagonism of D 2 -dependent rotations and induction of contralateral rotations) seemed to involve adenosine A 2A receptors (Kearney and Albin 1995;Kearney et al 1997;Ferré et al 1999). Moreover, in rat striatal membranes, DHPG modulated the binding characteristics of dopamine D 2 receptors in a similar manner as the adenosine A 2A receptor agonist CGS 21680, with a significant decrease in the affinity of the high-affinity state of D 2 receptors for dopamine Rimondini et al 1999).…”

“…In particular, group I mGlu receptors are highly expressed in the striatum (Romano et al 1995;Tallaksen-Greene et al 1998;Testa et al 1994Testa et al , 1995, where they contribute to neuronal plasticity (Calabresi et al 1996), motor behavior Kearney et al 1997) and excitotoxic injury (Calabresi et al 1999). The intrastriatal injection of 1S-3R-ACPD (a group I and II mGlu receptor agonist) or of DHPG (a selective group I receptor agonist) induced delayed contralateral turning behavior, which seems to depend on an excessive activation of the subthalamic nucleus (Sacaan et al 1992; Kaatz and Albin 1995;Kearney and Albin 1995;Kearney et al 1997Kearney et al ,1998. In 6-hydroxydopamine(6-OH-DA)-lesioned rats, which represent a rodent model of Parkinson's disease (Schwarting and Huston 1996;Ungerstedt 1971), the intracerebroventricular (ICV) injection of 1S,3R ACPD selectively counteracted the turning behavior elicited by a dopamine D 2 receptor agonist .…”

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

“…Manipulation of metabotropic glutamate receptors has been associated with altered expression of c-Fos (Kaatz and Albin, 1995;Kearney et al, 1997;Zhao et al, 2006;Besheer et al, 2009), a member of a family of immediate early gene transcription factors that is commonly used as a biomarker for mapping neuronal activity Cole et al, 1989;Morgan et al, 1987;Olive et al, 2001). Furthermore, the nucleus accumbens and the amygdala are critically involved in modulating the discriminative stimulus effects of alcohol (Hodge and Aiken, 1996;Hodge and Cox, 1998;Besheer et al, 2003).…”