Electrophysiological evidence for a functional differentiation between subtypes of the 5-HT1 receptor.

Serotonin (5-HT) neurons in the dorsal (DRN) and median (MRN) raphe nuclei, and dopamine (DA) neurons in the substantia nigra (SN) were recorded extracellularly in the anesthetized rat. Compounds which have a relatively high affinity for the 5-HT1A or 5-HT1B subtypes of the 5-HT1 receptor were administered and their effect on the firing rate of the monoamine cells was determined. 5-HT1A ligands were more potent in inhibiting impulse activity in the DRN than in the MRN, but had little effect in the SN. In contrast, 5-HT1B ligands increased the firing rate of MRN 5-HT units at low doses, and were also effective inhibitors of DA cell firing in the SN. These results could be correlated with recently described differences in the distribution of the 5-HT1A and 5-HT1B receptor subtypes, and were interpreted as indicating possible functional differentiation between these subtypes. In particular, agonist activity at the 5-HT1B autoreceptor site may decrease 5-HT release, suggesting a presynaptic locus for this receptor in the somatodendritic region. The site also appears to be implicated in 5-HT modulation of nigral DA impulse flow.

Biochemical and pharmacological characterization of CGS 12066B, a selective serotonin-1B agonist.

CGS 12066B is a novel pyrroloquinoxaline with selectivity for the serotonin-1B (5HT1B) recognition site as assessed by binding, biochemical and electrophysiological studies. The compound had an IC50 value of 51 nM at the 5HT1B recognition site as determined using the binding of [3H]5HT in the presence of 1 microM spiperone. At the 5HT1A receptor the compound had an IC50 value of 876 nM, providing a 5HT1A/5HT1B ratio of 17 in contrast to the putative 5HT1B selective agent trifluoromethylphenylpiperazine (TFMPP) which had a corresponding ratio of 3.6. The compound had minimal affinity for alpha 1-, alpha 2- and beta-adrenoceptors and for dopamine D-1 and D-2 receptors. CGS 12066B, in contrast to TFMPP, which was inactive, was found to inhibit dorsal raphe cell firing with an ED50 value of 358 nmol/kg i.v. The corresponding values for the 5HT1A selective agonists 8-OH-DPAT and ipsapirone were 1.3 and 33 nmol/kg. CGS 12066B was also effective in decreasing rat brain 5-HTP concentrations and inhibiting in vitro 5HT release. The data obtained indicate that CGS 12066B is a reasonably active 5HT1B site agonist, which due to its selectivity as compared to compounds such as TFMPP, will be a useful tool for evaluating the physiological role of such receptors in the mammalian CNS.