Search

The novel antiepileptic and neuroprotective drug felbamate (1 mM) caused a marked inhibition of voltage-dependent Na+ currents expressed in Xenopus oocytes upon injection of the cRNA encoding alpha-subunits from rat and human brain. This inhibition was present only if felbamate was perfused on the intracellular side of the membrane. In addition, felbamate seems to preferentially bind to and stabilize the inactivated state of the channel, resembling the action of local anesthetics. This study provides an additional mechanism by which felbamate might exert its wide-spectrum anticonvulsant and neuroprotective action.

Zn(2+) is effective in the treatment of acute diarrhea, but its mechanisms are not completely understood. We previously demonstrated that Zn(2+) inhibits the secretory effect of cyclic adenosine monophosphate but not of cyclic guanosine monophosphate in human enterocytes. The aim of the present study was to investigate whether Zn(2+) inhibits intestinal ion secretion mediated by the Ca(2+) or nitric oxide pathways. To investigate ion transport we evaluated the effect of Zn(2+) (35 microM) on electrical parameters of human intestinal epithelial cell monolayers (Caco2 cells) mounted in Ussing chambers and exposed to ligands that selectively increased intracellular Ca(2+) (carbachol 10(-6)M) or nitric oxide (interferon-gamma 300 UI/ml) concentrations. We also measured intracellular Ca(2+) and nitric oxide concentrations. Zn(2+) significantly reduced ion secretion elicited by carbachol (-87%) or by interferon-gamma (-100%), and inhibited the increase of intracellular Ca(2+) and nitric oxide concentrations. These data indicate that Zn(2+) inhibits ion secretion elicited by Ca(2+) and nitric oxide by directly interacting with the enterocyte. They also suggest that Zn(2+) interferes with three of the four main intracellular pathways of intestinal ion secretion that are involved in acute diarrhea.

We studied the effects of various doses of the opiate derivative buprenorphine on serum prolactin levels and whether these effects could be counteracted by pretreatment with the opiate receptor blocker naloxone. The administration of increasing doses of buprenorphine exerted a dual effect on serum prolactin levels. At low doses (3, 10 and 30 micrograms/kg) this agent increased serum prolactin levels. This effect disappeared with increasing doses (100 and 300 micrograms/kg), and at the highest doses (1000 and 3000 micrograms/kg) the levels of serum prolactin decreased. Naloxone (30 mg/kg) decreased serum prolactin levels and reversed both the stimulatory and the inhibitory action of buprenorphine. These data are compatible with the hypothesis that buprenorphine could interfere with two different, but inter-dependent receptors: at low doses the oripavine derivative could act at one receptor site to cause an increase of serum prolactin, whereas at higher doses it could interact with a second site of lower affinity that is responsible for the inhibition of prolactin secretion. When buprenorphine (at high doses) activates the lower affinity site, the interaction with this receptor counteracts and reverses the effects of the high affinity site. On the basis of this hypothesis, naloxone should block both receptors.

A single s.c. injection of penfluridol (3 mg/kg) to rats elevated serum concentrations of prolactin for more than 96 h whereas it increased striatal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and inhibited apomorphine-induced circling behavior for less than 48 h. The dose of penfluridol needed to elevate serum concentrations of prolactin (0.1 mg/kg) was less than that required to elevate striatal concentrations of DOPAC (1 mg/kg) or inhibit apomorphine-induced circling (3 mg/kg). Furthermore, the penfluridol-induced increase of striatal DOPAC was more susceptible to reversal by apomorphine than was the increase of serum prolactin concentrations. These results suggest that the dopamine receptors in the pituitary, which are normally activated by dopamine released from tuberoinfundibular neurons, are more sensitive to the blocking actions of systemically administered penfluridol than are dopamine receptors in the striatum.

The present study was undertaken to characterize the type of serotonin (5-HT) receptors involved in the control of prolactin (PRL) secretion in male rats. d-Fenfluramine (10 mg/kg i.p.), a potent 5-HT releaser and quipazine, (20 mg/kg i.p.) a 5-HT agonist, caused a marked increase in serum PRL levels. Ritanserin (200 micrograms/kg i.p.), a specific antagonist of 5-HT2 receptors, administered 1 h before the administration of d-fenfluramine or quipazine, completely prevented the PRL-releasing effect of these drugs. Furthermore, the administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT) (1.5, 3 and 6 mg/kg i.p.), a compound considered to be a prototypical 5-HT1A agonist, failed to induce any change in serum PRL levels. The same lack of effect on PRL secretion was observed after the administration of 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridin-4-yl)-1-H-indole (RU 24969) (1, 3 and 10 mg/kg i.p.), a compound which has been shown to possess a higher selectivity for 5-HT1B receptor subtypes than for 5-HT1A subtypes. These results suggest that 5-HT receptors involved in the control of PRL secretion are of the 5-HT2 type.

m-Chlorophenylpiperazine (m-CPP), a serotonin receptor agonist, induced dose-related increases in plasma prolactin levels in the rat. This effect was significantly prevented by pretreatment with metergoline, a serotonin receptor blocker. Long-term degeneration of hypothalamic serotonin nerve endings induced by intraventricular injection of 5,7-dihydroxytryptamine, significantly enhanced the PRL-releasing action of m-CPP, as revealed by the shift to the left in the dose-response curve that relates the dose of m-CPP to plasma PRL levels. Thus the evidence suggests the possible development of supersensitivity of central serotonin receptors involved in the control of prolactin release.