title: The 5-HT5A receptor regulates excitability in the auditory startle circuit: functional implications for sensorimotor gating.
abstract: Here we applied behavioral testing, pharmacology, and in vivo electrophysiology to determine the function of the serotonin 5-HT5A receptor in goldfish startle plasticity and sensorimotor gating. In an initial series of behavioral experiments, we characterized the effects of a selective 5-HT5A antagonist, SB-699551 (3-cyclopentyl-N-[2-(dimethylamino)ethyl]-N-[(4'-{[(2-phenylethyl)amino]methyl}-4-biphenylyl)methyl]propanamide dihydrochloride), on prepulse inhibition of the acoustic startle response. Those experiments showed a dose-dependent decline in startle rates in prepulse conditions. Subsequent behavioral experiments showed that SB-699551 also reduced baseline startle rates (i.e., without prepulse). To determine the cellular mechanisms underlying these behaviors, we tested the effects of two distinct selective 5-HT5A antagonists, SB-699551 and A-843277 (N-(2,6-dimethoxybenzyl)-N'[4-(4-fluorophenyl)thiazol-2-yl]guanidine), on the intrinsic membrane properties and synaptic sound response of the Mauthner cell (M-cell), the decision-making neuron of the startle circuit. Auditory-evoked postsynaptic potentials recorded in the M-cell were similarly attenuated after treatment with either 5-HT5A antagonist (SB-699551, 26.41 ± 3.98% reduction; A-843277, 17.52 ± 6.24% reduction). This attenuation was produced by a tonic (intrinsic) reduction in M-cell input resistance, likely mediated by a Cl(-) conductance, that added to the extrinsic inhibition produced by an auditory prepulse. Interestingly, the effector mechanisms underlying neural prepulse inhibition itself were unaffected by antagonist treatment. In summary, these results provide an in vivo electrophysiological characterization of the 5-HT5A receptor and its behavioral relevance and provide a new perspective on the interaction of intrinsic and extrinsic modulatory mechanisms in startle plasticity and sensorimotor gating.
authors.affiliation: Graduate Center, City University of New York, New York, New York 10065, USA.
authors.forename: Paul C P
authors.initials: PC
authors.lastname: Curtin
authors.forename: Violeta
authors.initials: V
authors.lastname: Medan
authors.forename: Heike
authors.initials: H
authors.lastname: Neumeister
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Bronson
authors.forename: Thomas
authors.initials: T
authors.lastname: Preuss
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000162:Acoustics; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005072:Evoked Potentials, Auditory / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D006054:Goldfish; D006146:Guanidines / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011189:Potassium Chloride / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000378:metabolism*; D013216:Reflex, Startle / Q000502:physiology*; D055139:Sensory Gating / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001713:Biphenyl Compounds; D006146:Guanidines; C576531:N-(2,6-dimethoxybenzyl)-N'-(4-(4-fluorophenyl)thiazol-2-yl)guanidine; D011985:Receptors, Serotonin; C515421:SB-699551-A; D012702:Serotonin Antagonists; D013844:Thiazoles; C078730:serotonin 5 receptor; D011189:Potassium Chloride