The 5-HT1A receptor selective ligands, (R)-8-OH-DPAT and (S)-UH-301, differentially affect the activity of midbrain dopamine neurons

Abstract

The effects of the selective 5-HT1A receptor agonist (R)-8-hydroxy-2(di-n-propylamino)tetralin [(R)-8-OH-DPAT] and the novel 5-HT1A antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] were studied with regard to the firing pattern of single mesencephalic dopamine (DA) neurons with extracellular recording techniques in chloral hydrate anesthetized male rats. Neuronal activity was studied with respect to firing rate, burst firing and regularity of firing. In the ventral tegmental area (VTA) low doses of (R)-8-OH-DPAT (2-32 micrograms/kg i.v.) caused an increase in all three parameters. The effect on firing rate of DA neurons was more pronounced in the parabrachial pigmentosus nucleus than in the paranigral nucleus, the two major subdivisions of VTA. In the substantia nigra zona compacta (SN-ZC), (R)-8-OH-DPAT (2-256 micrograms/kg i.v.) had no effect on firing rate and regularity of firing and only slightly increased burst firing. High doses of (R)-8-OH-DPAT (512-1024 micrograms/kg i.v.) decreased the activity of DA cells in both areas, an effect that was prevented by pretreatment with the selective DA D2 receptor antagonist raclopride. (S)-UH-301 (100-800 micrograms/kg i.v.) decreased both firing rate and burst firing without affecting regularity of DA neurons in the VTA. In the SN-ZC, (S)-UH-301 decreased the firing rate but failed to affect burst firing and regularity of firing. These effects of (S)-UH-301 were blocked by raclopride pretreatment. Local application by pneumatic ejection of 8-OH-DPAT excited the DA cells in both the VTA and the SN-ZC, whereas (S)-UH-301 inhibited these cells when given locally. These results show that 5-HT1A receptor related compounds differentially affect the electrophysiological activity of central DA neurons. The DA receptor agonistic properties of these compound appear to contribute to the inhibitory effects of high doses of (R)-8-OH-DPAT and (S)-UH-301 on DA neuronal activity. Given the potential use of 5-HT1A receptor selective compounds in the treatment of anxiety and depression their effects on central DA systems involved in mood regulation and reward related processes are of considerable importance.