5-HT3-like receptors in the rat medial prefrontal cortex: further pharmacological characterization.

The aim of the study was to further characterize the pharmacological properties of 5-hydroxytryptamine (5-HT)3-like receptors in the rat medial prefrontal cortex (mPFC) using combinations of biochemical and electrophysiological approaches. Phenylbiguanide (PBG) and three chlorinated derivatives, ortho-chloro-PBG (oCPBG), meta-chloro-PBG (mCPBG) and para-chloro-PBG (pCPBG), dose-dependently stimulated phosphoionositide (PI) turnover in fronto-cingulate cortical slices. All three chloro-isomers of PBG were equipotent in stimulating PI turnover. SR 57227A ((4-amino)-(6-chloro-2-pyridyl) L-piperidine hydrochloride, a novel compound with high affinity and selectivity for peripheral and central 5-HT3 receptors) dose-dependently stimulated PI turnover in fronto-cingulate cortical slices. The rank order of potency of all the 5-HT3 receptor agonists tested in the PI assay as compared to 5-HT was: 5-HT > 2-Me-5-HT > SR57227A > PBG = mCPBG = oCPBG = mCPBG. 5-HT and 5-HT receptor agonists depressed the firing rate of both spontaneously active and glutamate-activated quiescent mPFC cells in a current (dose)-dependent fashion. The rank order of effectiveness of these compounds was: 5-HT > SR57227A = 2-Me-5-HT = mCPBG = oCPBG = pCPBG = PBG. Unlike its action on the 5-HT3 receptors in the periphery or cultured cell lines, D-tubocurarine chloride appears to be non-specific in blocking the depressant action of 2-Me-5-HT, gamma-aminobutyric acid and dopamine. Our results combined support the view that the pharmacological properties of 5-HT3-like receptors in the mPFC are not identical to those located in peripheral tissues and in cultured cell lines.

Effect of pertussis toxin on the response of rat medial prefrontal cortex cells to the iontophoresis of serotonin receptor agonists.

In this study, we examined the response of spontaneously active as well as quiescent cells (L-glutamate-activated) in the rat medial prefrontal cortex (mPFc) to the iontophoresis of 2-methylserotonin (2-Me-5-HT, 5-HT3 receptor agonist), (+/-)-2,5-dimethoxy-(4-iodo-phenyl)-2-aminopropane (DOI, 5-HT2A,2C receptor agonist), 8-hydroxy-N,N-di-propylamino tetralin (8-OH-DPAT, 5-HT1A receptor agonist) and gamma-aminobutyric acid (GABA, a non-selective GABA receptor agonist) after the intracerebral administration of pertussis toxin, an inactivator of the Gi/o protein. This was accomplished using the techniques of extracellular single cell recording and iontophoresis. The administration of pertussis toxin (0.5 microgram, 24 hours before the experiment) into the mPFc did not alter the response of mPFc cells to the iontophoresis of DOI, 2-Me-5HT or GABA compared to saline treated controls. However, the response of mPFc cells to the iontophoresis of 8-OH-DPAT was significantly attenuated in the animals pretreated with pertussis toxin compared to controls. These results suggest that the 5-HT1A but not 5-HT2A,2C or 5-HT3 receptor is coupled to the Gi/o protein.

Electrophysiological characterization of 5-hydroxytryptamine2 receptors in the rat medial prefrontal cortex.

The aim of the present study was to characterize 5-hydroxytryptamine2 (5-HT2) receptors in the rat medial prefrontal cortex (mPFc) by single cell recording and microiontophoretic techniques. This was accomplished using 5-HT2 receptor agonists 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane [(+/-)-DOI] and 1-[2,5-dimethoxy-4-bromophenyl]-2-aminopropane [(+/-)-DOB]. DOI ejected at a low current (0.5 nA) potentiates glutamate (GLU)-induced activation of mPFc neurons and this effect is blocked by spiperone. At higher currents. DOI invariably inhibits GLU-induced neuronal activity. The microiontophoretic ejection of both DOI and DOB predominantly inhibits spontaneously active mPFc cells. The inhibitory action of DOI on spontaneously active cells is dose-dependent and is blocked by putative 5-HT2 receptor antagonists, with a rank order of potency as follows: ritanserin greater than metergoline approximately LY-53857 greater than spiperone greater than mesulergine greater than mianserin approximately ketanserin. Interestingly, ketanserin and mianserin only weakly block the effect of DOI. The suppressant action of DOI is probably not related to its interaction with 5-HT10 sites as spiperone, which has low affinity for these sites, potently blocks the effect of DOI. The suppressant effect of DOI is not blocked by other receptor antagonists such as BRL-43694 (5-HT3), (+/-)-pindolol (5HT 1a,1b, beta adrenergic, beta), prazosin (adrenergic1, alpha-1), pyrilamine (histamine1, H1), l-sulpiride (dopamine2, D2) or SR 95103 (gamma-aminobutyric acid, GABAA). Overall our results indicate that DOI predominantly inhibits mPFc cells in a direct manner and this effect is mediated by 5-HT2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of (+/-)-DOI on medial prefrontal cortical cells: a microiontophoretic study.

The relatively selective 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [+/-)-DOI) ejected by microiontophoresis at low currents potentiates glutamate (GLU)-induced excitation and at higher currents (greater than 20 nA) invariably inhibits both spontaneous and GLU-induced activity of cells in the medial prefrontal cortex (mPFc). The inhibitory action of DOI is blocked by the 5-HT2 antagonists, ritanserin, metergoline and spiperone, but not other receptor antagonists. Microiontophoresis of 1 M Mg2+ for 5-20 min did not alter DOI's inhibitory effect suggesting that DOI's action is a direct one. These results show that DOI predominantly inhibits mPFc neuronal activity and this inhibitory action is mediated by 5-HT2 receptors.