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The effects of GR127935, a putative 5-HT1D receptor antagonist, on brain 5-HT metabolism, extracellular 5-HT concentration and behaviour in the guinea pig. 1995

P H Hutson, and L J Bristow, and J R Cunningham, and J E Hogg, and J Longmore, and F Murray, and D Pearce, and Z Razzaque, and K Saywell, and M D Tricklebank
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, U.K.

Studies of neurotransmitter release in guinea pig and human brain indicate that the 5-HT terminal autoreceptor is the 5-HT1D subtype and that it regulates the depolarization evoked release of 5-HT. Thus, blockade of the terminal 5-HT autoreceptor should enhance 5-HT release in vivo. In the present study, we have used the recently described, selective and potent 5-HT1D receptor antagonist, GR127935, to determine if blockade of the terminal 5-HT autoreceptor enhanced 5-HT neurotransmission in the guinea pig. Neurochemical studies showed that GR127935 (0.1, 0.3 and 1.0 mg/kg i.p.) significantly increased 5-HT metabolism in forebrain regions but not in the raphe nucleus of the guinea pig. However, using in vivo dialysis, GR127935 did not significantly increase cortical 5-HT efflux when given either systemically (1 and 5 mg/kg i.p.) or by infusion via the probe directly into the cortex (10, 33 and 100 microM). Fast cyclic voltammetry studies in the guinea pig dorsal raphe slice in vitro failed to observe any significant effects of GR127935 (0.01-1 microM) on electrically evoked 5-HT release. Behavioural studies in the guinea pig were also unable to demonstrate any effects of GR127935 (0.1-3.0 mg/kg i.p.) per se or in combination with the 5-HT precursor 5-hydroxytryptophan. Taken together, results from the present neurochemical and behavioral studies in the guinea pig provide little substantial evidence that blockade of the terminal 5-HT autoreceptor following the acute administration of GR127935 increased brain 5-HT neurotransmission in vivo.

UI MeSH Term Description Entries
D008297 Male Males
D008719 Methiothepin A serotonin receptor antagonist in the CENTRAL NERVOUS SYSTEM used as an antipsychotic. Metitepine,Methiothepin Maleate,Methiothepine,Maleate, Methiothepin
D009435 Synaptic Transmission The communication from a NEURON to a target (neuron, muscle, or secretory cell) across a SYNAPSE. In chemical synaptic transmission, the presynaptic neuron releases a NEUROTRANSMITTER that diffuses across the synaptic cleft and binds to specific synaptic receptors, activating them. The activated receptors modulate specific ion channels and/or second-messenger systems in the postsynaptic cell. In electrical synaptic transmission, electrical signals are communicated as an ionic current flow across ELECTRICAL SYNAPSES. Neural Transmission,Neurotransmission,Transmission, Neural,Transmission, Synaptic
D010069 Oxadiazoles Compounds containing five-membered heteroaromatic rings containing two carbons, two nitrogens, and one oxygen atom which exist in various regioisomeric forms. Oxadiazole
D010879 Piperazines Compounds that are derived from PIPERAZINE.
D011903 Raphe Nuclei Collections of small neurons centrally scattered among many fibers from the level of the TROCHLEAR NUCLEUS in the midbrain to the hypoglossal area in the MEDULLA OBLONGATA. Caudal Linear Nucleus of the Raphe,Interfascicular Nucleus,Nucleus Incertus,Rostral Linear Nucleus of Raphe,Rostral Linear Nucleus of the Raphe,Superior Central Nucleus,Central Nucleus, Superior,Incertus, Nucleus,Nuclei, Raphe,Nucleus, Interfascicular,Nucleus, Raphe,Nucleus, Superior Central,Raphe Nucleus
D001921 Brain The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM. Encephalon
D004409 Dyskinesia, Drug-Induced Abnormal movements, including HYPERKINESIS; HYPOKINESIA; TREMOR; and DYSTONIA, associated with the use of certain medications or drugs. Muscles of the face, trunk, neck, and extremities are most commonly affected. Tardive dyskinesia refers to abnormal hyperkinetic movements of the muscles of the face, tongue, and neck associated with the use of neuroleptic agents (see ANTIPSYCHOTIC AGENTS). (Adams et al., Principles of Neurology, 6th ed, p1199) Dyskinesia, Medication-Induced,Medication-Induced Dyskinesia,Drug-Induced Dyskinesia,Drug-Induced Dyskinesias,Dyskinesia, Drug Induced,Dyskinesia, Medication Induced,Dyskinesias, Drug-Induced,Dyskinesias, Medication-Induced,Medication Induced Dyskinesia,Medication-Induced Dyskinesias
D004558 Electric Stimulation Use of electric potential or currents to elicit biological responses. Stimulation, Electric,Electrical Stimulation,Electric Stimulations,Electrical Stimulations,Stimulation, Electrical,Stimulations, Electric,Stimulations, Electrical
D005473 Fluoxetine The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often has a more acceptable side-effects profile than traditional antidepressants. Fluoxetin,Fluoxetine Hydrochloride,Lilly-110140,N-Methyl-gamma-(4-(trifluoromethyl)phenoxy)benzenepropanamine,Prozac,Sarafem,Lilly 110140,Lilly110140

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