Activation Of Serotonin 1A Receptors Research Articles

Effects of serotonin through serotonin 1A and serotonin 4 receptors on inhibition in the guinea-pig dentate gyrus in vitro

The role of serotonin 1A and serotonin 4 receptors in the modulation of synaptic inhibition in the dentate gyrus of guinea-pig hippocampal slices was studied. The effects of serotonin (5-hydroxytryptamine) on hilar neurons and on inhibitory postsynaptic potentials in granule cells were compared using intracellular recording in the presence of glutamatergic receptor antagonists. On the basis of electrophysiological properties hilar neurons were classified as type I neurons (presumably inhibitory) and type II neurons (presumably excitatory). Serotonin hyperpolarized a proportion of type I hilar neurons (60%) and decreased their input resistance through activation of a K +-conductance. This effect was mediated by serotonin 1A receptors since it was mimicked by the selective serotonin 1A receptor agonist (±)-8-hydroxy-dipropylaminotetralin hydrobromide and blocked by the selective serotonin 1A receptor antagonist (+) WAY 100135. In some type I hilar neurons (40%) neither serotonin nor (±)-8-hydroxy-dipropylaminotetralin hydrobromide induced a membrane hyperpolarization. Instead, serotonin induced an excitatory response, depolarizing the cells and blocking the slow afterhyperpolarization. Similar effects were seen in all hilar neurons after blockade of serotonin 1A receptors. They were mimicked by the serotonin 4 receptor agonist zacopride. Serotonin induced either decreases or increases in the frequency of spontaneous GABA A receptor-mediated inhibitory postsynaptic potentials in granule cells via activation of serotonin 1A and of serotonin 4 receptors, respectively. 4-aminopyridine-evoked GABA B receptor-mediated inhibitory postsynaptic potentials were inhibited by serotonin via activation of serotonin 1A receptors. However, after blockade of serotonin 1A receptors, serotonin increased the frequency of GABA B-inhibitory postsynaptic potentials through the activation of serotonin 4 receptors. We conclude that a proportion of inhibitory neurons in the dentate area does not express serotonin 1A receptors and is excited by serotonin. Other inhibitory neurons express serotonin 1A receptors and are inhibited by serotonin.

Immunocytochemical studies of the 5-HT1A receptor in ventral medullary neurons that project to the intermediolateral cell column and contain serotonin or tyrosine hydroxylase immunoreactivity

Activation of serotonin-1A receptors (5-HT(1A)R) in the medulla oblongata lowers sympathetic nerve discharge and blood pressure. Binding sites for 5-HT(1A)R ligands are present in ventral medullary nuclei [e.g., rostral ventrolateral medulla (RVLM), raphe pallidus (RPa), and parapyramidal region (PPR)] that project to sympathetic preganglionic neurons in the intermediolateral cell column (IML). However, the projections and the neurochemical contents of the ventral medullary neurons that are likely to be involved in the hypotensive actions of 5-HT(1A) agonists are unclear. Using a sheep antibody to a fragment of the third intracellular loop of the 5-HT(1A)R, we localized 5-HT(1A)R immunoreactivity (ir) to IML-projecting neurons that were retrogradely labeled with rhodamine beads injected into the IML of adult male rats. The percentages of IML-projecting neurons containing 5-HT(1A)R-ir were 49% in RPa, 34% in PPR, and 44% in RVLM. Using multiple-immunofluorescence labeling, we also demonstrated 5-HT(1A)R-ir in serotonergic (5-HT) and in catecholaminergic (tyrosine hydroxylase; TH-ir) neurons of the ventral medulla. The percentages of 5-HT-ir neurons containing 5-HT(1A)R-ir were 28% in RPa, 18% in PPR, and 31% in raphe obscurus. In addition, 5-HT(1A)R-ir was present in 14% of TH-ir neurons of the RVLM. Moreover, some IML-projecting neurons in the PPR and RPa were doubly immunolabeled for 5-HT(1A)R-ir and 5-HT, and some IML-projecting neurons in the RVLM were doubly immunolabeled for 5-HT(1A)R-ir and TH-ir. These data provide anatomical evidence for the presence of 5-HT(1A)R on serotonergic and catecholaminergic bulbospinal neurons and for their potential role in directly modifying the activity of these ventral medullary neurons.

Serotonin1A receptor activation by flesinoxan in humans: Body Temperature and Neuroendocrine Responses

The effects of the selective 5-HT1A receptor agonist flesinoxan on neuroendocrine function, temperature, and behavior were assessed in male healthy volunteers using a double-blind, placebo-controlled crossover design. Flesinoxan (7 and 14 micrograms/kg), administered intravenously in 11 healthy volunteers, elicited a dose-related decrease in body temperature and increases in growth hormone, adrenocorticotropic hormone (ACTH), cortisol, and prolactin plasma levels. In a second independent study, 12 healthy volunteers were pretreated sequentially, at one-week intervals, with either the 5-HT1A antagonist pindolol (30 mg, PO), the nonselective 5-HT1/2 antagonist methysergide (4 mg, PO), or placebo, prior to being administered flesinoxan (1 mg, IV). The growth hormone response to flesinoxan was blocked by pindolol but not by methysergide, whereas the prolactin response was blocked by methysergide but not by pindolol. The ACTH and cortisol responses to flesinoxan were potentiated by methysergide. The flesinoxan-induced hypothermia was attenuated by both methysergide and pindolol, although the latter effects did not reach statistical significance. The present results suggest that the growth hormone response and the hypothermic response to the intravenous infusion of flesinoxan may serve as a valid index of 5-HT1A receptor function in humans.

Activation of serotonin 1A receptors inhibits midbrain periaqueductal gray neurons of the rat

The midbrain periaqueductal gray (PAG) is involved in a variety of functions including pain modulation, vocalization, autonomic control, fear and anxiety. This area contains serotonin receptors, particularl 5-HT 1A that are known to play a role in the above functions The goals of this study were to characterize the effects of 8-OH-DPAT, a selective 5-HT 1A agonist, on the firing characteristics and membrane properties of PAG neurons. Both in vivo and in vitro preparations were used. The effects of 8-OH-DPAT on baseline activity of 91 neurons were tested in the in vivo preparation. In 50/91 cells, 8-OH-DPAT produced a decrease in the firing rate that ranged between 21 and 98% (mean±S.E.M. decrease of49±1.9%). This inhibitory effect was dose dependent and could be blocked by spiperone. In 10/91 cells, 8-OH-DPAT produced an increase in the firing rate that range between 13 and 290%, with mean increase of83±7.4%. The baseline fate of the remaining 31 cells was not affected by 8-OH-DPAT. In the PAG slice preparation, the effects of 8-OH-DPAT on synaptic and membrane properties of 17 PAG neurons were tested using whole-cell voltage clamp-recording procedures. In 14 cells, application of 8-OH-DPAT produced hyperpolarization that ranged between 6 and 21 mV, with mean of8.4±2.0mV. This hyperpolarization was associated with a decrease in membrane impedance that ranged between 8 and 45%, with mean decrease of21.6±4.5%. The remaining three neurons did not respond to 8-OH-DPAT. Under voltage clamp conditions and in the presence of TTX, application of 8-OH-DPAT produced a reversal potential that ranged between −70 and −90 mV, with mean of−80±2.68mV. In conclusion: (1) 8-OH-DPAT has a strong influence on neurons in all regions of the PAG in particular on cells located in the dorsal PAG; (2) in both in vivo and in vitro preparations, the 5-HT 1A-mediated response of PAG neurons in inhibitory; and (3) the inhibitory effect of 5-HT 1A is associated with hyperpolarization of the cell membrane that is likely due to an increase in K conductance.

Serotonin 1A facilitation of frog motoneuron responses to afferent stimuli and to N-methyl- d-aspartate

The effects of serotonin and excitatory amino acids on motoneurons were examined by sucrose gap recordings from the ventral root of the isolated, hemisected frog spinal cord superfused with magnesium-free, carbonate-buffered Ringer solution. Low concentrations of serotonin (0.1 μM) and the serotonin 1A agonist8-hydroxy-2-( n-dipropylamino)tetralin (8-OH-DPAT; 0.01 μM) significantly increased the duration and amplitude of the polysynaptic components of ventral root potentials produced by dorsal root stimulation. The facilitations of the ventral root potentials were blocked by the serotonin 1A antagonist spiroxatrine, but were unaffected by the serotonin 2 antagonist ketanserin or the serotonin 3 antagonist 1αH,3α,5αH-tropan-3-yl-3,-dichlorobenzoate (MDL 72222). The actions of 0.1 μM serotonin on motoneuron depolarizations evoked by the putative excitatory amino acid transmitters l-glutamate and l-aspartate were quite variable, but in the presence of ketanserin (20 μM), small consistent increases in amino acid-induced motoneuron depolarizations were observed. 8-OH-DPAT significantly enhanced motoneuron depolarizations elicited by the selective excitatory amino acid agonist N-methyl- d-aspartate in both normal and tetrodotoxin-containing Ringer solution. Quisqualate-induced motoneuron depolarizations were also facilitated by 8-OH-DPAT in normal Ringer solution, but these increases were eliminated by addition of either tetrodotoxin or the N-methyl- d-aspartate antagonist d(−)-2-amino-5-phosphonovalerate to the Ringer superfusate. Kainate-depolarizations were not altered by low concentrations of serotonin or 8-OH-DPAT. Prior exposure of the cord to spiperone, but not ketanserin or MDL 72222 blocked the enhancement of N-methyl- d-aspartate-induced motoneuron depolarizations by 8-OH-DPAT. In the presence of saturating concentrations of glycine, 8-OH-DPAT facilitated N-methyl- d-aspartate responses. Increases in extracellular potassium activity, measured with ion-selective microelectrodes inserted in the intermediate gray matter, evoked by repetitive stimulation of myelinated afferent fibers in the sciatic nerve and by application of N-methyl- d-aspartate were significantly enhanced by 8-OH-DPAT. These findings are compatible with the notion that serotonergic activation of serotonin 1A receptors plays a role in regulating the responsiveness of frog spinal motoneurons to excitatory afferent inputs and to N-methyl- d-aspartate-mediated synaptic transmission.

Serotonin-1A receptor activation in hippocampal CA1 neurons by 8-hydroxy-2-(di- n-propylamino)tetralin, 5-methoxytryptamine and 5-hydroxytryptamine

Serotonin (5-HT) usually induced a slow hyperpolarization lasting several minutes on first drop-application onto CA1 neurons. Subsequent applications always caused a briefer (<2 min) hyperpolarization, usually followed by a depolarization. 8-Hydroxy-2(di- n-propylamino)tetralin, a 5-HT 1A receptor agonist, and 5-methoxytryptamine, a 5-HT 1 receptor agonist, produced only the long-lasting hyperpolarization. The application of 5-HT agonists caused a persistent prolongation of the post-spike train afterhyperpolarization. These observations suggest that the long-lasting hyperpolarization produced by 5-HT may be mediated by the activation of the 5-HT 1A receptor subtype.

Experimental studies on the neurocardiovascular effects of urapidil.

The major purpose of our study was to determine whether urapidil acts in the central nervous system (CNS) to lower arterial blood pressure. Once demonstrating a CNS antihypertensive action of urapidil we further set out to determine: (1) the relative role of a CNS antihypertensive action to the total antihypertensive effect of urapidil; (2) the brain site of action for the antihypertensive effect of urapidil; and, (3) the receptor mechanism whereby urapidil acts in the CNS to lower arterial blood pressure. Studies were conducted in chloralose-anaesthetised cats, and arterial blood pressure and heart rate were monitored. Drugs were administered intravenously (IV), into the cerebral ventricles (ICV), topically by application to the ventral surface of the medulla and by microinjection into specific nuclei. Receptor binding studies were also conducted using rat cerebral cortex homogenates. We found that injection of urapidil into the fourth ventricle decreased arterial pressure. Local application of urapidil to the ventral medullary surface also decreased arterial blood pressure. Microinjection of urapidil into one of the nuclei associated with the ventral surface of the medulla, the rostral part of the nucleus reticularis lateralis (rLRN), produced a similar degree of antihypertensive effect. The effect of urapidil was not altered by alpha 1-receptor blockade. Instead, the urapidil effect resembled that produced by drugs that stimulate serotonin (5-hydroxytryptamine)-1A receptors (B695-40 and 8-OH-DPAT). Furthermore, urapidil was found to have the highest potency for binding to serotonin-1A receptor sites (as compared to alpha 1- and alpha 2-receptor sites). Urapidil administered IV was shown to lower arterial blood pressure in part by blocking peripheral alpha 1-adrenoceptors but also, in high doses, by acting in the CNS to decrease central sympathetic outflow. These data indicate that urapidil is a unique drug, possessing both peripheral and CNS actions which contribute to its antihypertensive effect. Urapidil may also be unique in that its central action may involve activation of serotonin-1A receptors.