6-methyl-2-(phenylethynyl)pyridine and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic-acid

Distinct lines of evidence indicate that glutamate plays a primary role in modulating cognitive functions. Notably, competitive glutamate receptor antagonists acting at ionotropic N-methyl-d-aspartate (NMDA) or metabotropic glutamate 5 (mGlu5) receptors impair cognitive performance. Conversely, nicotine and other psychostimulants stimulate glutamatergic mechanisms and can act as cognitive enhancers. Hence we analysed the role of glutamate in performance of an attentional task and in nicotine-induced enhancement of attention by using the rodent five-choice serial reaction time task (5-CSRTT). Rats were trained to criterion performance and were then pre-dosed with either vehicle, the NMDA receptor antagonist (+)3-(2-carboxypiperazin-4-propyl)-1-propenyl-1-phosphonic acid (CPP, 0.3-2.0 mg/kg) or the mGlu5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 1.0-9.0 mg/kg) and challenged with nicotine (0.2 mg/kg). Nicotine improved attentional performance, an effect that was weakened by doses of CPP that themselves had little impact on performance; importantly, CPP dose-dependently blunted the ability of nicotine to improve response accuracy, the major measure of signal detection in the paradigm. MPEP dose-dependently impaired signal detection under conditions with a high attentional load, an effect that was reversed by nicotine; thus, MPEP did not block nicotine-induced attentional enhancement. Co-administration of either CPP or MPEP with nicotine also produced a general slowing of performance characterised by increases in omission errors and response latencies and reduced anticipatory responding. It is concluded that activation of NMDA receptors may be an important determinant of the effects of nicotine in the 5-CSRTT. Stimulation of nicotinic receptors may also reverse attentional deficits associated with the impaired function of the glutamate network.

Topics: Analysis of Variance; Animals; Attention; Behavior, Animal; Choice Behavior; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Male; Nicotine; Nicotinic Agonists; Piperazines; Pyridines; Rats; Reaction Time; Task Performance and Analysis

In this study, we investigated the effects of group I metabotropic glutamate (mglu) receptor ligands on glutamate and gamma-aminobutyric acid (GABA) extracellular concentrations at the periaqueductal grey level by using in vivo microdialysis. An agonist of group I mglu receptors, (S)-3,5-dihydroxyphenylglycine [(S)-3,5-DHPG, 1 and 2 mM], as well as a selective agonist of mglu(5) receptors, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG, 2 and 4 mM), both increased dialysate glutamate and GABA concentrations. 7-(Hydroxyimino)cyclopropa-[b]-chromen-1alpha-carboxylate ethyl ester (CPCCOEt, 1 mM), a selective mglu(1) receptor antagonist, and 2-methyl-6-(phenylethynyl)pyridine (MPEP, 0.5 mM), a selective mglu(5) receptor antagonist, perfused in combination with DHPG, antagonized the effect induced by DHPG on the extracellular glutamate and GABA concentrations. MPEP (0.5 mM), perfused in combination with CHPG, antagonized the increased glutamate and GABA extracellular levels induced by CHPG. MPEP (1 mM) decreased the extracellular concentrations of glutamate but did not modify the dialysate GABA concentrations. Moreover, as the intra-periaqueductal grey perfusion of (RS)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid [(RS)-CPP, 100 microM], a selective N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, did not change the extracellular concentrations of glutamate, this suggests that the MPEP-induced decrease in glutamate is not a consequence of NMDA receptor blockade. These data show that group I mglu receptors in the periaqueductal grey may modulate the release of glutamate and GABA in awake, freely moving rats. In particular, mglu(5), but not mglu(1), receptors seem to be functionally active on glutamate terminals.

Topics: Animals; Chromones; Dendrites; Excitatory Amino Acid Agonists; gamma-Aminobutyric Acid; Glutamates; Glycine; Male; Microdialysis; Microscopy, Electron; Periaqueductal Gray; Phenylacetates; Piperazines; Pyridines; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Resorcinols; Tetrodotoxin