3-cyano-n-(1-3-diphenyl-1h-pyrazol-5-yl)benzamide and 3-5-dihydroxyphenylglycine

We previously reported that animals withdrawn from repeated cocaine exposure exhibited a selective deficit in the ability to elicit metabotropic glutamate receptor 5 (mGluR5)-dependent long-term depression (LTD) in the nucleus accumbens (NAc) shell. To determine whether such impairment occurs in the NAc in a cell-type-specific manner, we used bacterial artificial chromosome (BAC) transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of gene regulatory elements for the dopamine D1 receptor (Drd1) or dopamine D2 receptor (Drd2) to identify distinct subpopulations of medium spiny neurons (MSNs). We found that bath application of group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) reliably induced LTD in both NAc shell and core MSNs of wild-type, hemizygous Drd1-eGFP, and Drd2-eGFP mice. Confirming our previous results, cocaine withdrawal selectively impaired DHPG-LTD in NAc shell Drd1-expressing direct and Drd2-expressing indirect pathway MSNs. We also found that the expression of DHPG-LTD in NAc MSNs was not affected by the Ca(2+)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist 1-naphthyl acetyl spermine. Furthermore, systemic administration of mGluR5-negative allosteric modulator fenobam before the daily injection of cocaine preserved mGluR5 function and significantly reduced the expression of cocaine-induced behavioral sensitization. These results reveal that withdrawal from repeated cocaine exposure may result in the impairment of NAc mGluR5-LTD in a subregion- but not cell-type-specific manner and suggests that pharmacological antagonism of mGluR5 may represent a potential strategy for reducing cocaine-induced addictive behaviors.

Topics: Animals; Benzamides; Chromones; Cocaine; Cocaine-Related Disorders; Dopaminergic Neurons; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Genes, Reporter; Glycine; Imidazoles; Long-Term Synaptic Depression; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Nucleus Accumbens; Pyrazoles; Pyridazines; Pyridines; Receptor, Metabotropic Glutamate 5; Receptors, Dopamine D1; Receptors, Dopamine D2; Resorcinols; Substance Withdrawal Syndrome

Exciting advances have been made in the discovery of selective positive allosteric modulators of the metabotropic glutamate receptor (mGluR) mGluR5. These compounds may provide a novel approach that could be useful in the treatment of certain central nervous system disorders. However, because of their low potencies, previously described mGluR5 potentiators are not useful for functional studies in native preparations. In addition, binding sites at which these compounds act have not been identified. It has been suggested that two allosteric potentiators, 3,3'-difluorobenzaldazine and 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), act by binding to the same allosteric site as the negative allosteric modulators of mGluR5 such as 2-methyl-6-(phenylethynyl)pyridine (MPEP). However, another mGluR5 potentiator, N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)m-ethyl]phenyl}-2-hydroxybenzamide, does not bind to this site, bringing this hypothesis into question. We have synthesized a series of CDPPB analogs and report that these compounds bind to the MPEP site with affinities that are closely related to their potencies as mGluR5 potentiators. Furthermore, allosteric potentiation is antagonized by a neutral ligand at the MPEP site and reduced by a mutation of mGluR5 that eliminates MPEP binding. Together, these data suggest that interaction with the MPEP site is important for allosteric potentiation of mGluR5 by CDPPB and related compounds. In addition, whole-cell patch-clamp studies in midbrain slices reveal that a highly potent analog of CDPPB, 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), selectively potentiates mGluR5 but not mGluR1-mediated responses in midbrain neurons, whereas a previously identified allosteric potentiator of mGluR1 has the opposite effect.

Topics: Allosteric Regulation; Allosteric Site; Animals; Benzamides; Binding, Competitive; Cell Line; Drug Synergism; Glycine; Humans; Male; Mutation; Neurons; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Resorcinols; Substantia Nigra; Substrate Specificity; Subthalamic Nucleus