6-cyano-7-nitroquinoxaline-2-3-dione and 4-iodo-2-5-dimethoxyphenylisopropylamine

Modulation of dopamine (DA) released by serotonin-2 (5-HT2) receptors has been implicated in the mechanism of action of antipsychotic drugs. The mesocortical DA system has been implicated particularly in the cognitive deficits observed in schizophrenia. Agonism at 5-HT2A receptors in the prefrontal cortex (PFC) is associated with increases in cortical DA release. Evidence indicates that 5-HT2A receptors in the cortex regulate mesocortical DA release through stimulation of a "long-loop" feedback system from the PFC to the ventral tegmental area (VTA) and back. However, a causal role for VTA glutamate in the 5-HT2-induced increases in PFC DA has not been established. The present study does so by measuring 5-HT2 agonist-induced DA release in the cortex after infusions of glutamate antagonists into the VTA of the rat. Infusions of a combination of a N-methyl-d-aspartic acid (NMDA) (AP-5: 2-amino-5-phosphopentanoic acid) and an AMPA/kainate (CNQX: 6-cyano-7-nitroquinoxaline-2,3-dione) receptor antagonist into the VTA blocked the increases in cortical DA produced by administration of the 5-HT2 agonist DOI [(±)-2,5-dimethoxy-4-iodoamphetamine] (2.5mg/kg s.c.). These results demonstrate that stimulation of glutamate receptors in the VTA is necessary for 5-HT2 agonist-induced increases in cortical DA.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amphetamines; Animals; Dopamine; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Microdialysis; N-Methylaspartate; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, Serotonin, 5-HT2; Serotonin 5-HT2 Receptor Agonists; Valine; Ventral Tegmental Area

Previous studies have outlined an important role for serotonin (5-HT) in the development of synaptic connectivity and function in the cerebral cortex. In this study, we have examined the effects of 5-HT on synaptic function in prefrontal cortex at a time of intense synapse formation and remodelling. Whole-cell recordings in slices derived from animals aged postnatal (P) days 16-20 showed that administration of 5-HT induced a robust increase in synaptic activity that was blocked by CNQX but not by bicuculline. This 5-HT-induced increase in glutamate-mediated synaptic activity was pharmacologically heterogeneous as it was differentially inhibited by the receptor subtype-selective antagonists SB-269970, MDL 100907 and GR 113808 and thus involved 5-HT(7), 5-HT(2A) and 5-HT(4) receptors. These results, obtained in juvenile cortex, contrast with those seen in adults where the increase in spontaneous excitatory postsynaptic currents (sEPSCs) was mediated solely by 5-HT(2A) receptors. In developing cortex, activation of 5-HT(7), but not 5-HT(2A) or 5-HT(4) receptors, elicited a robust inward current. However, the facilitation of synaptic activity mediated by all three of these receptors involved increases in both the amplitude and frequency of sEPSCs and was blocked by TTX. These results are best interpreted as indicating that all three receptor subtypes increase synaptic activity by exciting neuronal elements within the slice. No evidence was found for a postsynaptic facilitation of synaptic currents by 5-HT. Together, these results show that the repertoire of electrophysiologically active 5-HT receptors in prefrontal cortex is developmentally regulated, and that 5-HT(7) and 5-HT(4) receptors play a previously unsuspected role in regulating synaptic activity in this region.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amphetamines; Animals; Bicuculline; Fluorobenzenes; GABA-A Receptor Antagonists; Glutamic Acid; Indoles; Lidocaine; Male; Patch-Clamp Techniques; Phenols; Pindolol; Piperidines; Prefrontal Cortex; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, AMPA; Receptors, Metabotropic Glutamate; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin 5-HT4 Receptor Antagonists; Serotonin Antagonists; Sodium Channel Blockers; Sulfonamides; Synapses; Tetrodotoxin; Time Factors

The glutamatergic mossy fibre-->granule cell pathway has been investigated in rat cerebellar slices. Exposure to 35 mM KCl, a concentration of K+ known to elicit Ca(2+)-dependent releases of excitatory amino acids from cerebellar slices, raised cGMP levels. The cGMP response was decreased in a concentration-dependent manner by D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) and by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) indicating the involvement of ionotropic glutamate receptors of both the N-methyl-D-aspartate (NMDA) and the non-NMDA type. The K(+)-evoked production of cGMP was potently inhibited (EC50 = 1.21 nM) by 1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI), a selective 5-HT2 receptor agonist. The effect of DOI (0.01 microM) was antagonized by 0.03 microM of the 5-HT2 receptor antagonists ketanserin and methiothepin. At concentrations higher than 0.1 microM, both antagonists increased on their own the cGMP response elicited by high-K+. This effect was insensitive to tetrodotoxin. It had been previously shown that rat mossy fibre endings release glutamate upon depolarization and that such release can be inhibited by activation of 5-HT2 receptors sited on the mossy fibre endings. Altogether the available data suggest the following conclusions: a) the glutamate/aspartate endogenously released in cerebellar slices during K+ depolarization increase cGMP synthesis through the activation of both NMDA and non-NMDA receptors; b) a portion of the cGMP response can be prevented by 5-HT2 receptor activation and may reflect the activity of the mossy fibre--granule cell pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Amphetamines; Animals; Cerebellum; Cyclic AMP; Cytoplasmic Granules; In Vitro Techniques; Ketanserin; Male; Methiothepin; Nerve Fibers; Potassium; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Synaptic Transmission; Tetrodotoxin

We examined the effects of the 5-hydroxytryptamine2 receptor agonist, (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, on spontaneous and evoked discharge of locus coeruleus neurons in the rat. Extracellular recordings were obtained from single locus coeruleus neurons while (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane was injected systemically or locally into the locus coeruleus. Systemic, but not local, administration of (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane decreased spontaneous discharge of locus coeruleus neurons in a dose-dependent manner while simultaneously increasing responses evoked by somatosensory stimulation, consistent with previous studies using 5-hydroxytryptamine2 agonists. Increased responsiveness was observed after both low- and high-intensity stimulation and, in the latter, resulted from the addition of a second, longer latency response after (+-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane administration, when cells typically responded to each stimulation with two driven spikes instead of one. Both of these effects could be completely reversed by systemic administration of the 5-hydroxytryptamine2 receptor antagonist, ketanserin. Furthermore, we report that: (i) the (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-induced decrease in spontaneous firing was blocked by local infusion of the GABA antagonists bicuculline or picrotoxin into the locus coeruleus, but not by local infusion of the alpha-2 adrenoceptor antagonist, idazoxan; and (ii) the enhancement of locus coeruleus sensory responses after high-intensity stimulation was blocked by local application of the selective antagonist of N-methyl-D-aspartate receptors, 2-amino-5-phosphonopentanoic acid, but not by local infusion of the preferential antagonist of non-N-methyl-D-aspartate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione. Together, these results lead us to propose that systemic 5-hydroxytryptamine2 agonists influence locus coeruleus indirectly, causing tonic activation of a GABAergic input to the locus coeruleus, and facilitating sensory inputs that act via excitatory amino acid receptors within locus coeruleus.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Amphetamines; Analysis of Variance; Animals; Electric Stimulation; Electrophysiology; Evoked Potentials; gamma-Aminobutyric Acid; Ketanserin; Locus Coeruleus; Male; Neurons; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Serotonin Receptor Agonists