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.

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

“…Stimulation of DA neurons was also observed with the agonists flesinoxan and S 15535 and these effects were blocked by the selective antagonist WAY 100,635 (Lejeune and Millan, 1998). The iontophoretic application of 8-OHDPAT into the midbrain excited DA neurons in VTA and SNpc in vivo (Arborelius et al, 1993a), suggesting a midbrain site of action.…”

“…8-OHDPAT administration was reported to preferentially increase cortical DA relative to the dorsal striatum and NA (Arborelius et al, 1993a). While administration of 8-OHDPAT reverses D2 antagonist-induced catalepsy (Wadenberg and Ahlenius, 1991), others have provided evidence that this effect is not mediated by alterations in DA neurotransmission (Neal-Beliveau et al, 1993;Lucas et al, 1997).…”

Dissociation of rewarding and dopamine transporter-mediated properties of amphetamine

“…As one intriguing example, several studies in vivo have shown that stimulation of 5-HT 1A receptors can enhance the activity of VTA but not substantia nigra DA neurons, whereas application of 5-HT 1A antagonists induces the opposite effect (38, 39, 44). For example 8-OH-DPAT, a 5-HT 1A receptor agonist, increased the firing rate, regularity of firing, and burst firing of VTA DA neurons in rats (38,39). In contrast, the same drug did not alter any of the firing patterns of DA neurons in the substantia nigra (38).…”

“…For example 8-OH-DPAT, a 5-HT 1A receptor agonist, increased the firing rate, regularity of firing, and burst firing of VTA DA neurons in rats (38,39). In contrast, the same drug did not alter any of the firing patterns of DA neurons in the substantia nigra (38). This result raises the possibility that serotonergic afferents into the midbrain may mediate, in part, the DA-elevating actions of AMPH in the NAc of DAT-KO mice.…”

“…However, AMPH-induced increases in the firing rate of DA neurons may be more important for the development of addiction, and these appear only after repeated drug administration and are not related to effects of AMPH on the DAT. AMPH is a potent inhibitor of the serotonin transporter (37), and 5-HT is well known to be a strong modulator of DA neurotransmission, with various receptors causing different and often opposite effects (36,(38)(39)(40)(41)(42)(43)(44)(45). Therefore, a consideration of 5-HT receptors as candidates for the AMPH-induced increase in dopaminergic activity of DAT-KO mice may be promising.…”