Nor was there appreciable attenuation of 5 HT autoreceptor respon

Nor was there appreciable attenuation of 5 HT autoreceptor responsiveness after the singfedose 8 OH DPAT pretreatment, when the partial 5 HT receptor agonists ipsapirone or BMY 7378 were used as challenge drugs. At feast two explanations may be offered to account for the apparent discrepancy between the in vitro radiofigand binding data of Beer et al. 0990 and the present functional data: either the binding does not reflect a functionally relevant pool of 5 HT refease reguiating 5 HTlA autore epto or a 25 reduction in the number of 5 HT autoreceptors does not result in a significant loss of the agonist partial agonist responsiveness, due to substantial overcapacity of the system. Indeed, at least with regard to the 5 HT autoreceptor mediated control of 5 HT synthesis, it appears that under normal conditions the activation of only a smafi fraction W 20 of the total available receptor pool is sufficient to elicit a full inhibitory response to 8 OH DPAT will also elicit apparently maximal or near maximal effects by interacting with S HT receptor populations with excess spare sites, provided that receptor responsiveness is not markedly impaired.
Thus, the present findings may well be explained by the existence of a receptor ?reserve? large enough to accommodate at feast a 25 reduction in the number of 5 HT release controlling somatodendritic 5 HTr, autoreceptors without appreciably modifying the functional consequences Telaprevir of agonist interaction with these sites. Apparently contradictory to this conclusion, S OHDPAT bolus pretreatment has also been reported to result in attenuation of the acute brainstem raphe 5 HIAA reducing effect of the compound . It remains to be clarified whether or not cell body 5 HT autoreceptors are involved in controlling somacodendritic output of the transmitter , and therefore also to what extent the S OH SPAT induced inhibitor chemical structure decrease in 5 HIAA in the raphe is mediated by cell body 5 I IT autoreceptors. In addition to the reduction in raphe S OH DPAT binding, Kennett and co workers reported elevated frontal cortex concentrations of 5 HIAA in 8 OHDPAT vs.
vehicle pretreated control groups purchase Veliparib kinase inhibitor , possit!v suggesting a somewhat increased basal S HT turnover, rate. Larsson et al, found a modest rise in 5 HT synthesis and turnover indices in rat hippocampal, hypothalamic and medutlary tissue 48 h after one week of repeated administration ?f S OH DPAT , but saw no tolerance in the biochemical responsiveness to acute challenge with the drug under these conditions. In the present study, there were no significant differences between the baseline 5 HT output of the 8 OH DPAT pretreated rats compared to that of the vehicle pretreated controls, although there was a slight general trend towards higher values in the former vs. the latter groups .

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