Electrophysiological Evidence for the Tonic Activation of 5-HT1A Autoreceptors in the Rat Dorsal Raphe Nucleus

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) and norepinephine (NE) neurons have reciprocal connections. These may thus interfere with anticipated effects of selective pharmacological agents targeting these neurons. The main goal of the present study was to assess whether the somatodendritic 5-HT 1A autoreceptor is tonically activated by endogenous 5-HT in anesthetised rats, using in vivo extracellular unitary recordings. In rats with their NE neurons lesioned using 6-hydroxydopamine (6-OHDA) and in controls administered the NE reuptake inhibitor desipramine to suppress NE neuronal firing, the a 2 -adrenoceptor agonist clonidine no longer inhibited 5-HT neuron firing, therefore indicating the important modulation of the firing activity of 5-HT neurons by NE neurons. In control rats, the administration of the potent and selective 5-HT 1A receptor antagonist WAY 100,635 ((N-{2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide trihydroxychloride) (100 mg/kg, i.v.) did not modify the spontaneous firing activity of 5-HT neurons, but in NE-lesioned rats using either 6-OHDA or DSP-4, WAY 100,635 produced a mean firing increase of 80 and 69%, respectively. When desipramine and D-amphetamine were used in control rats to prevent alterations in the availability of NE in the dorsal raphe, again WAY 100,635 produced a significant disinhibition of the firing of 5-HT neurons (83 and 53%, respectively). These data support the notion that the NE system tonically activates the firing activity of 5-HT neurons. When the fluctuations of the function of NE neurons normally produced by WAY 100,635 were prevented, a tonic activation of 5-HT 1A autoreceptors by endogenous 5-HT was unmasked.

Transcriptional regulation of the 5-HT1Areceptor: implications for mental illness

“…The 5-HT 1A autoreceptor was then shown to mediate 5-HT auto-inhibition [7,12]. A consistent observation has been that reduction or ablation of 5-HT 1A autoreceptors leads to increased 5-HT neurotransmission [13][14][15][16][17], while over-expression of 5-HT 1A autoreceptors reduces 5-HT neurotransmission [18][19][20]. While 5-HT 1A antagonists do not greatly affect basal firing, they consistently reverse inhibition of firing by 5-HT 1A agonist or specific reuptake inhibitor (SSRI) treatment, suggesting that the basal level of 5-HT under recording conditions may be insufficient to see effects.…”

Nicotine Alters Limbic Function in Adolescent Rat by a 5-HT1A Receptor Mechanism

“…The selective 5-HT1A-R antagonist, WAY 100 635 (0, 40, or 400 mg/kg), was co-administered intravenously with nicotine or saline. These doses were selected because they do not modify spontaneous firing of 5-HT neurons or basal locomotor activity (Carey et al, 2001;Haddjeri et al, 2004). The selective nAChR antagonists, DHbE (2 mg/kg) and MLA (1 mg/kg), were administered intravenously 5 min before daily nicotine pretreatment.…”

Activation of 5-HT1Areceptors in medullary raphé disrupts sleep and decreases shivering during cooling in the conscious piglet

“…In addition, WAY-100635 has been described as a "silent" 5-HT 1A antagonist, a term that has been used to distinguish true antagonists from partial agonists (23,24). Although a few studies have shown effects of WAY-100635 alone on behavior (56) and 5-HT neuronal firing rate (29,30) when microinjected into the dorsal raphé, the role of intrinsic 5-HT 1A agonists in the tonic control of medullary raphé 5-HT neuronal firing rate remains unclear.…”