Electrophysiological responses of serotoninergic dorsal raphe neurons to 5‐HT_1A and 5‐HT_1B agonists

Abstract

A direct comparison was made of the effects of serotonin 5 -H T 1~ and 5-H T~B selective compounds on the spontaneous firing rate of dorsal raphe serotoninergic neurons in chloral-hydrate-anesthetized rats. Following intravenous administration, the ~-H T~A selective compounds ipsapirone (TVX Q 7821) and LY 165163 potently inhibited single-unit activity in a dose-dependent manner whereas the ~-H T~B selective compounds, m-chlorophenylpiperaine (mCPP) and trifluoromethylphenylpiperazine (TFMPP), displayed only weak or irregular actions. Low microiontophoretic currents of ipsapirone and LY 165163 were also effective in suppressing spontaneous firing; dose-response relationships for the ~-H T~A compounds were indistinguishable from that of 5-HT itself. In contrast, dorsal raphe neurons were only weakly responsive to microiontophoretic application of mCPP and TFMPP dose-response relationships for the ~-H T~B compounds were significantly displaced from that of 5-HT. In intracellular studies, ipsapirone and LY 165163, when added to the media bathing brain slices, mimicked the actions of 5-HT in hyperpolarizing dorsal raphe cell membranes and decreasing input resistance; however, the maximal effects of the 5-Efl"l'~ compounds on these membrane properties exceeded those of 5-HT. In summary, dorsal raphe 5-HT neurons appear highly responsive to 5-H T 1~, but not to ~-H T~B compounds; these findings are discussed with regard to the 5-HT receptor subtypes as candidates for the somatodendritic autoreceptor of dorsal raphe Ipsapirone, LY 165163, mCPP, TFMPP neurons.

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…Both pre-and postsynaptic 5-HT 1A Rs are coupled to various members of the G i/o protein family. They are expressed on serotonergic neurons in the raphe, where they exert autoinhibitory function, and various other brain areas involved in fear and anxiety [54,55]. Mechanisms underlying the anxiolytic effects of 5-HT 1A R activation are complex, varying between both brain region, and pre-versus postsynaptic locus, and are not fully established [56].…”

Differential Occupancy of Somatodendritic and Postsynaptic 5HT1A Receptors by Pindolol A Dose-Occupancy Study with [11C]WAY 100635 and Positron Emission Tomography in Humans

“…In general, pre-synaptic receptors are more "agonist" sensitive compared to post synaptic receptors (Meller et al 1990;Jolas et al 1995). A number of drugs act as full agonists in the DRN but as partial agonists in the hippocampus (such as buspirone or ipsapirone); or as partial agonists in the DRN and as antagonists in the hippocampus (such as (Andrade and Nicoll 1987;Sprouse and Aghajanian 1987;Sinton and Fallon 1988;Sprouse and Aghajanian 1988;Hjorth and Sharp 1990;Greuel and Glaser 1992;Fabre et al 1997). Importantly, these pharmacological differences are detected in functional assays in vivo, rather than in binding studies.…”

Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression

“…The state mimicking hopelessness and despair stems from the diminished release of serotonin (5-HT) from raphe nuclei into the terminals [2]. In turn, the compromised serotonergic transmission is due to the functional upregulation of presynaptic serotonin type 1A (5-HT1A) receptors [3], which normally control 5-HT release from raphe nuclei on a negative feedback basis [4][5][6]. Finally, the upregulation of 5-HT1A autoreceptors is driven by the dysregulation of the hypothalamo-pituitaryadrenocortical (HPA) axis [1,7], which (dysregulation) by itself represents a neuroendocrine hallmark of chronic stress [8].…”