mGluR antagonists and GABA agonists as novel pharmacological agents for the treatment of autism spectrum disorders

Introduction: The CDC currently estimates the prevalence of autism spectrum disorders (ASD) at 1 in 88 children. Though the exact etiology of ASD is unknown, recent studies implicate synaptic maturation and plasticity in the pathogenesis of ASD leading to an imbalance of excitation and inhibition, and specifically a disproportionately high level of excitation. Pharmacological agents that modulate excitation and inhibition are currently in clinical trials for treatment of ASD and show promising preliminary results.

Areas covered: This paper reviews the literature implicating the role of glutamate and GABA pathways in the pathophysiology of ASD. It also provides a review of the current results from both animal models and human clinical trials of drugs aimed at normalizing the imbalance of excitation and inhibition through the use of metabotropic glutamate receptor (mGluR) antagonists and GABA agonists.

Expert opinion: Both mGluR antagonists and GABA agonists have promising preliminary data from animal model and small-scale Phase II human trials. They show significant efficacy in subpopulations and appear to have favorable side-effect profiles. Though preliminary data are extremely promising, results from ongoing larger, double-blind, placebo-controlled studies will give a more complete understanding of the efficacy and side-effect profile related to these drugs.     

mGluR5 knockout mice display increased dendritic spine densities

Alterations in dendritic spine densities and morphologies have been correlated with the abnormal functioning of the synapse. Specifically the metabotropic glutamate receptor 5 (mGluR5) has been implicated in dendrogenesis and spineogenesis, since its activation triggers various signaling cascades that have been demonstrated to play roles in synaptic maturation and plasticity. Here we used the Golgi impregnation technique to analyze the dendritic spines of mGluR5(-/-) knockout mice in comparison to their heterozygote mGluR5(+/-) littermates. mGluR5(-/-) mice had elevated spine densities irrespective of spine type or location along their dendritic trees in comparison to mGluR5(+/-) animals. Such anatomical changes may underlie the hyperexcitability observed in mGluR5 total knockout mice.     

Ischemic injury decreases parvalbumin expression in a middle cerebral artery occlusion animal model and glutamate-exposed HT22 cells

Measles virus (MV) infection may lead to severe chronic CNS disease processes, including MV-induced encephalitis. Because the intracellular Ca²⁺ concentration ([Ca²⁺]_i) is a major determinant of the (patho-)physiological state in all cells we asked whether important Ca²⁺ conducting pathways are affected by MV infection in cultured cortical rat neurons. Patch-clamp measurements revealed a decrease in voltage-gated Ca²⁺ currents during MV-infection, while voltage-gated K⁺ currents and NMDA-evoked currents were unaffected. Calcium-imaging experiments using 50 mM extracellular KCl showed reduced [Ca²⁺]_i increases in MV-infected neurons, confirming a decreased activity of voltage-gated Ca²⁺ channels. In contrast, the group-I metabotropic glutamate receptor (mGluR) agonist DHPG evoked changes in [Ca²⁺]_i that were increased in MV-infected cells. Our results show that MV infection conversely regulates Ca²⁺ signals induced by group-I mGluRs and by voltage-gated Ca²⁺ channels, suggesting that these physiological impairments may contribute to an altered function of cortical neurons during MV-induced encephalitis.     

Regulation of motivation to self-administer ethanol by mGluR5 in alcohol-preferring (P) rats

Background:  Emerging evidence indicates that Group I metabotropic glutamate receptors (mGluR1 and mGluR5) differentially regulates ethanol self-administration in several rodent behavioral models. The purpose of this work was to further characterize involvement of Group I mGluRs in the reinforcing effects of ethanol using a progressive ratio schedule of reinforcement.
Methods:  Alcohol-preferring (P) rats were trained to self-administer ethanol (15% v/v) versus water on a concurrent schedule of reinforcement, and the effects of the Group I mGluR antagonists were evaluated on progressive ratio performance. The rats were then trained to self-administer sucrose (0.4% w/v) versus water, and the effects of the antagonists were tested on progressive ratio performance.
Results:  The mGluR1 antagonist, 3,4-dihydro-2H-pyrano[2,3]b quinolin-7-yl ( cis -4-methoxycyclohexyl) methanone (JNJ 16259685; 0 to 1 mg/kg) and the mGluR5 antagonist, 6-methyl-2-(phenylethynyl) pyridine (MPEP; 0 to 10 mg/kg) dose-dependently reduced ethanol break point. In separate locomotor activity assessments, the lowest effective dose of JNJ 16259685 (0.3 mg/kg) produced a motor impairment, whereas the lowest effective dose of MPEP (3 mg/kg) did not. Thus, the reduction in ethanol break point by mGluR1 antagonism was probably a result of a motor impairment. JNJ 16259685 (0.3 mg/kg) and MPEP (10 mg/kg) reduced sucrose break point and produced motor impairments. Thus, the reductions in sucrose break point produced by both Group I antagonists were probably because of nonspecific effects on motor activity.
Conclusions:  Together, these results suggest that glutamate activity at mGluR5 regulates motivation to self-administer ethanol.     

Metabotropic glutamate receptors (mGlus) and cellular transformation

Although the glutamatergic system usually functions in the CNS, expression has been observed in non-neuronal tissues and a subset of cancers. Metabotropic glutamate receptors (mGlus) are highly "druggable" GPCRs and thus a priority for validation as therapeutic targets. We have previously reported that the aberrant expression of mGlu1 is sufficient to induce spontaneous melanoma development in vivo. We isolated and characterized several stable mGlu1-mouse melanocytic clones and demonstrated that these clones are transformed and tumorigenic. We hypothesize that expression of mGlus may not be uncommon in the pathogenesis of tumors other than melanoma, and that activity of an otherwise normal glutamate receptor in an ectopic cellular environment involves signaling pathways which dysregulate cell growth, ultimately leading to tumorigenesis. As most human cancers are of epithelial origin (carcinomas), in this review, the possibility that mGlu1 could function as a complete oncogene and transform epithelial cells is also discussed.     

Allosteric potentiators of metabotropic glutamate receptor subtype 1a differentially modulate independent signaling pathways in baby hamster kidney cells

Recent studies suggest that subtype specific activators of metabotropic glutamate receptors (mGluRs) have exciting potential for the development of novel treatment strategies for numerous psychiatric and neurological disorders. A number of positive allosteric modulators (PAMs) have been identified that are highly selective for mGluR1, including the compounds Ro 01-6128, Ro 67-4853, and Ro 67-7476. These PAMs have been previously found to interact with a site distinct from that of negative allosteric modulators (NAMs), typified by R214127. These mGluR1 PAMs do not have an effect on baseline calcium levels but induce leftward shifts in the concentration-response of mGluR1 to agonists. However, their effects on a variety of signaling pathways and their mechanism of action have not been fully explored and are of critical importance for further development of mGluR1 allosteric modulators as novel drugs. In baby hamster kidney (BHK) cells, mGluR1 activates calcium mobilization, cAMP production, and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation; signaling cascades which are distinct and differentially regulated. In contrast to their effects on calcium mobilization, these compounds were found to activate ERK1/2 phosphorylation in the absence of exogenously added agonist, an effect that was fully blocked by both orthosteric (LY341495) and allosteric (R214127) mGluR1 antagonists. The mGluR1 PAMs were also found to activate cAMP production in the absence of agonist. Thus, these mGluR1 PAMs have qualitatively different effects on a variety of mGluR1-mediated signal transduction cascades. Together, these data provide further evidence that allosteric compounds can differentially modulate the coupling of a single receptor to independent signaling pathways or act in a system-dependent manner.     

Glutamatergic substrates of drug addiction and alcoholism

The past two decades have witnessed a dramatic accumulation of evidence indicating that the excitatory amino acid glutamate plays an important role in drug addiction and alcoholism. The purpose of this review is to summarize findings on glutamatergic substrates of addiction, surveying data from both human and animal studies. The effects of various drugs of abuse on glutamatergic neurotransmission are discussed, as are the effects of pharmacological or genetic manipulation of various components of glutamate transmission on drug reinforcement, conditioned reward, extinction, and relapse-like behavior. In addition, glutamatergic agents that are currently in use or are undergoing testing in clinical trials for the treatment of addiction are discussed, including acamprosate, N-acetylcysteine, modafinil, topiramate, lamotrigine, gabapentin and memantine. All drugs of abuse appear to modulate glutamatergic transmission, albeit by different mechanisms, and this modulation of glutamate transmission is believed to result in long-lasting neuroplastic changes in the brain that may contribute to the perseveration of drug-seeking behavior and drug-associated memories. In general, attenuation of glutamatergic transmission reduces drug reward, reinforcement, and relapse-like behavior. On the other hand, potentiation of glutamatergic transmission appears to facilitate the extinction of drug-seeking behavior. However, attempts at identifying genetic polymorphisms in components of glutamate transmission in humans have yielded only a limited number of candidate genes that may serve as risk factors for the development of addiction. Nonetheless, manipulation of glutamatergic neurotransmission appears to be a promising avenue of research in developing improved therapeutic agents for the treatment of drug addiction and alcoholism.     

Homers regulate drug-induced neuroplasticity: implications for addiction

Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state.     

The mGlu2 but not the mGlu3 receptor mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity

Rationale Group II metabotropic glutamate receptors (mGluRs) comprise the mGluR2 and mGluR3 subtypes, the activation and modulation of which has been suggested to be beneficial for treating schizophrenia. Genetic association studies suggest limited association between mGluR2 and schizophrenia but some association between mGluR3 and schizophrenia. Conversely, pre-clinical studies suggest that mGluR2 may be responsible for mediating the antipsychotic activity of mGluR2/3 agonists, although to date, the role of mGluR3 has not been specifically assessed. Objectives The aim of this study is to use recently generated mGluR3 and mGluR2 knockout mice to investigate which of the group II mGluRs mediates the actions of the mGluR2/3 agonist, LY379268, in two mouse models predictive of antipsychotic activity. Materials and methods LY379268 (0.3–10 mg/kg SC), phencyclidine (PCP; 1–5 mg/kg IP), and amphetamine 1–10 mg/kg IP) were assessed on locomotor activity and behaviour in C57Bl/6J and transgenic mice. LY379268 was then assessed on PCP (5 mg/kg IP)- and amphetamine (2.5 mg/kg IP)-induced hyperactivity and behaviour in C57Bl/6J and transgenic mice. Results PCP (5 mg/kg)-evoked hyperactivity and behavioural alterations, i.e. circling, falling, stereotypy and ataxia, as well as amphetamine (2.5 mg/kg)-evoked hyperactivity, were dose-dependently attenuated by LY379268 (0.3–3 mg/kg) in C57Bl/6J mice. One milligram per kilogram of LY379268 reversed PCP-evoked hyperactivity and behavioural alterations in wild-type (WT) and mGluR3 knockout mice but not in mice lacking mGluR2. Similarly, 3 mg/kg LY379268 reversed amphetamine-evoked hyperactivity in WT and mGluR3 knockout mice but not in mice lacking mGluR2. Conclusion The mGlu2 but not the mGlu3 receptor subtype mediates the actions of the mGluR2/3 agonist, LY379268, in mouse models predictive of antipsychotic activity.