THE 5-HT(1A) RECEPTOR SELECTIVE LIGANDS, (R)-8-OH-DPAT AND (S)-UH-301, DIFFERENTIALLY AFFECT THE ACTIVITY OF MIDBRAIN DOPAMINE NEURONS

The effects of the selective 5-HT1A receptor agonist (R)-8-hydroxy-2(d i-n-propylamino)tetralin [(R)-8-OH-DPAT] and the novel 5-HT1A antagoni st (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-3011 were studied with regard to the firing pattern of single mesencephalic dop amine (DA) neurons with extracellular recording techniques in chloral hydrate anesthetized male rats. Neuronal activity was studied with res pect to firing rate, burst firing and regularity of firing. In the ven tral tegmental area (VTA) low doses of (R)-8-OH-DPAT (2 - 32 mug/kg iv .) caused an increase in all three parameters. The effect on firing ra te of DA neurons was more pronounced in the parabrachial pigmentosus n ucleus than in the paranigral nucleus, the two major subdivisions of V TA. In the substantia nigra zona compacta (SN-ZC), (R)-8-OH-DPAT (2-25 6 mug/kg iv.) had no effect on firing rate and regularity of firing an d only slightly increased burst firing. High doses of (R)-8-OH-DPAT (5 12 - 1024 mug/kg i.v.) decreased the activity of DA cells in both area s, an effect that was prevented by pretreatment with the selective DA D2 receptor antagonist raclopride. (S)-UH-301 (100-800 mug/kg iv.) dec reased both firing rate and burst firing without affecting regularity of DA neurons in the VTA. In the SN-ZC, (S)-UH-301 decreased the firin g rate but failed to affect burst firing and regularity of firing. The se effects of (S)-UH-301 were blocked by raclopride pretreatment. Loca l 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 cell s when given locally. These results show that 5-HT1A receptor related compounds differentially affect the electrophysiological activity of c entral DA neurons. The DA receptor agonistic properties of these compo und 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 potentia l use of 5-HT1A receptor selective compounds in the treatment of anxie ty and depression their effects on central DA systems involved in mood regulation and reward related processes are of considerable importanc e.