CP 135807

CP-135,807, a selective 5-HT1D agonist: effects in drug discrimination and punishment procedures in the pigeon.[Pubmed:8972551]

Psychopharmacology (Berl). 1996 Dec;128(3):313-9.

CP-135,807 [3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2- yl)amino-1H-indole] binds with high affinity to central 5-HT1D receptors, and in functional studies produces dose-dependent decreases in extracellular serotonin. These and other findings have suggested that CP-135,807 may act as a terminal 5-HT autoreceptor agonist. In an attempt to characterize the behavioral activity of selective 5-HT1D ligands, adult male Carneau pigeons were trained to discriminate IM injections of 0.1 mg/kg CP-135,807 from saline under a two-key, fixed ratio schedule of food-reinforced key pecking. CP-135,807 and the structurally unrelated 5-HT1D agonist CP-286,601 fully and dose-dependently substituted for the training dose. In contrast, little substitution was observed following administration of 8-OH-DPAT, a potent 5-HT1A agonist, the 5-HT1B agonist CP-94,253, or the serotonin reuptake inhibitor sertraline. In addition, the discriminative stimulus produced by CP-135,807 was not blocked by WAY 100,635, a selective 5-HT1A antagonist, but was completely and dose-dependently antagonized by the selective 5-HT1D antagonist, GR 127935. In subjects trained under a multiple schedule of punished and unpunished responding, 8-OH-DPAT produced large increases in punished responding while having little effect on unpunished responding. In contrast, CP-135,807 and CP-94,253 produced no antipunishment effects, while GR 127935 produced modest increases in punished responding. Collectively, these results suggest that CP-135,807 produces centrally mediated psychoactive effects that differ distinctly from those of 5-HT1A agonists.

The antipsychotic drug risperidone interacts with auto- and hetero-receptors regulating serotonin output in the rat frontal cortex.[Pubmed:10462130]

Neuropharmacology. 1999 Aug;38(8):1175-84.

We have previously shown that the antipsychotic drug risperidone enhances serotonin (5-HT) output in the rat frontal cortex (FC), but the precise underlying mechanism has not been revealed. Consequently, the present study using in vivo microdialysis was undertaken to (i) characterize the effects of alpha2D, 5-HT1B and 5-HT1D receptor stimulation or blockade on 5-HT efflux in the FC given the purported regulatory role of these sites on 5-HT release, and (ii) to investigate the ability of risperidone to interfere with these receptors in order to examine their putative role in the facilitatory action or risperidone on cortical 5-HT output. Cortical perfusion with risperidone or the alpha2A/D, 5-HT1B and 5-HT1B/1D receptor antagonists idazoxan, isamoltane or GR 127,935, respectively, dose-dependently increased 5-HT efflux in the FC. Conversely, agonists at these receptors, i.e. clonidine, CP 93,129 or CP 135,807, respectively, decreased extracellular 5-HT concentrations. The agonist-induced decreases in 5-HT efflux were antagonized by coadministration of respective receptor antagonists. Risperidone attenuated the decrease in cortical 5-HT efflux elicited by clonidine or CP 135,807 but failed to affect the decrease elicited by CP 93,129. The present in vivo biochemical data indicate that the output of 5-HT in the FC is negatively regulated via alpha2D, 5-HT1B and tentatively also via 5-HT1D receptors located in the nerve terminal area. Moreover, the results indicate that risperidone acts as an antagonist at alpha2D and possibly 5-HT1D receptors in vivo, two properties which most likely contribute to its stimulatory effect on cortical 5-HT efflux. The facilitatory effect of risperidone on cortical serotonergic neurotransmission may be of significance for its therapeutic effect in schizophrenia, particularly when associated with affective symptomatology and/or intense anxiety. The effect may also contribute to alleviate signs of cortical dysfunction such as impaired cognition.

Combined administration of a 5-hydroxytryptamine (5-HT)1D antagonist and a 5-HT reuptake inhibitor synergistically increases 5-HT release in guinea pig hypothalamus in vivo.[Pubmed:8863532]

J Neurochem. 1996 Nov;67(5):2204-7.

In vivo microdialysis in guinea pig hypothalamus was used to study the effect of serotonin [5-hydroxytryptamine (5-HT)] subtype 1D autoreceptor blockade on the increase in extracellular 5-HT levels produced by a selective 5-HT reuptake inhibitor (SSRI). Administration of the selective 5-HT1D antagonist GR127935 at 0.3 mg/kg had no effect, but 5 mg/kg significantly increased extracellular levels of 5-HT and 5-hydroxyindoleacetic acid to 135% of basal values. Moreover, at these doses GR127935 significantly attenuated the decrease in extracellular 5-HT levels following local perfusion with the selective 5-HT1D agonist CP-135,807. The SSRI sertraline at 2 mg/kg increased 5-HT levels to 130% of basal levels. The combination of this low dose of sertraline with either dose of GR127935 resulted in a pronounced, long-lasting increases in 5-HT levels to 230% of basal values. These results indicate that the effects of an SSRI on terminal 5-HT are significantly enhanced by coadministration of a 5-HT1D antagonist and confirm that in addition to somatodendritic 5-HT1A autoreceptors, terminal 5-HT1D autoreceptors mitigate the effect of SSRIs on terminal 5-HT. As such, antagonists of the 5-HT1D autoreceptor could be useful as rapidly acting antidepressants and may shorten the onset of antidepressant action when combined with SSRIs.