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Serotonin (5-HT) agonists, selective for 5-HT1, 5-HT2 or 5-HT3 receptor subtypes, were tested for their ability to mimic 5-HT in narrowing the tetraethylammonium-induced calcium-dependent plateau of action potentials recorded from frog sensory neurons. 5-Carboxamidotryptamine, 5-HT, alpha-methyl 5-HT and 5-methoxy-tryptamine possessed full agonist activity, with EC50S of 19 nM, 210 nM, 3.7 microM and 1.7 microM, respectively. 2-Methyl 5-HT was inactive. This agonist profile indicates that the calcium-dependent plateau in these sensory somata is modulated by a 5-HT1-like receptor.

The actions of serotonin (5-HT) were studied in the isolated frog spinal cord and dorsal root ganglion preparations. In the spinal cord, 5-HT increased the spontaneous activity recorded from dorsal roots, facilitated evoked spinal reflexes and produced fast and slow primary afferent depolarization (PAD). A direct action of 5-HT on primary afferent terminals is likely since 5-HT induced PAD remained in the presence of 1 microM tetrodotoxin and 2 mM Mn2+. The direct action of 5-HT on primary afferent terminals was blocked by methysergide and attenuated by concentrations of Mn2+ in excess of that required to block transmitter release. Cell bodies of the dorsal root ganglion were also depolarized by 5-HT. A slow hyperpolarization occasionally followed the initial depolarization. The depolarizing action of 5-HT in the dorsal root ganglion was also attenuated by treatment with Mn2+. It is concluded that 5-HT acts directly on frog primary afferents and that this influence may involve a calcium sensitive process. The dorsal root ganglion response to 5-HT appears to be a suitable model of the afferent terminal response.

The putative 5-HT1A agonists 8-hydroxy-dipropylaminotetralin (DPAT), buspirone and p-aminophenylethyl-m-trifluoromethylphenyl piperazine (PAPP) were tested for their ability to narrow the action potentials of bullfrog sensory neurons, a serotonergic response observed to be blocked by the 5-HT1A antagonists spiperone and spiroxitrine. Given alone, DPAT, buspirone, and PAPP were ineffective 5-HT agonists. When applied concomitantly with 5-HT, however, they significantly antagonized the original response. Thus, in some systems these putative 5-HT1A agonists function as antagonists.

The 5-HT3 receptor antagonists, ICS 205-930 and MDL 72222, displace 47-55% of the specific [3H]serotonin (100 nM) binding to synaptosomal membranes derived from the dorsal, but not ventral, spinal cord of rats with IC50s less than 1.0 nM. Methiothepin (10 microM) increased displacement to 86-94% without shifting these IC50s. Scatchard plots of [3H]5-HT binding in the presence of methiothepin (10 microM) reveal a single population of sites (KD = 11.5 nM, Bmax = 282 fmol mg-1 protein). These results indicate the presence of 5-HT3 binding sites in dorsal spinal cord.