title: Comparing Pharmacological Modulation of Sensory Gating in Healthy Humans and Rats: The Effects of Reboxetine and Haloperidol.
abstract: Sensory gating is the brain's ability to filter out irrelevant information before it reaches high levels of conscious processing. In the current study we aimed to investigate the involvement of the noradrenergic and dopaminergic neurotransmitter systems in sensory gating. Furthermore, we investigated cross-species reliability by comparing effects in both healthy humans and rats, while keeping all experimental conditions as similar as possible between the species. The design of the human experiment (n=21) was a double-blind, placebo-controlled, cross-over study where sensory gating was assessed following a dose of either reboxetine (8 mg), haloperidol (2 mg), their combination or placebo at four separate visits. Similarly in the animal experiment sensory gating was assessed in rats, (n=22) following a dose of reboxetine (2 mg/kg), haloperidol (0.08 mg/kg), their combination or placebo. The sensory gating paradigms in both experiments were identical. In humans, we found significantly reduced P50 suppression following separate administration of reboxetine or haloperidol, while their combined administration did not reach statistical significance compared with placebo. In the rats, we found a similar significant reduction of sensory gating (N40) following treatment with haloperidol and the combination of haloperidol and reboxetine, but not with separate reboxetine treatment, compared with placebo. Our study indicates that even when experimental conditions are kept as similar as possible, direct human to rat cross-species translation of pharmacological effects on sensory gating is challenging, which calls for more focussed research in this important translational area.
authors.affiliation: Synaptic Transmission 1, H. Lundbeck A/S, Valby, Denmark.|Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS). Center for Neuropsychiatric Schizophrenia Research (CNSR), Copenhagen University Hospital, Psychiatric Center Glostrup, Glostrup, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Witten
authors.affiliation: Synaptic Transmission 1, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Jesper Frank
authors.initials: JF
authors.lastname: Bastlund
authors.affiliation: Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS). Center for Neuropsychiatric Schizophrenia Research (CNSR), Copenhagen University Hospital, Psychiatric Center Glostrup, Glostrup, Denmark.
authors.forename: Birte Y
authors.initials: BY
authors.lastname: Glenthøj
authors.affiliation: Discovery DMPK, H. Lundbeck A/S, Copenhagen-Valby, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Medical Affairs-Addiction Disorders, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Björn
authors.initials: B
authors.lastname: Steiniger-Brach
authors.affiliation: Synaptic Transmission 1, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
authors.affiliation: Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS). Center for Neuropsychiatric Schizophrenia Research (CNSR), Copenhagen University Hospital, Psychiatric Center Glostrup, Glostrup, Denmark.|Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bob
authors.initials: B
authors.lastname: Oranje
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage*; D000328:Adult; D000818:Animals; D001307:Auditory Perception / Q000187:drug effects / Q000502:physiology; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D018592:Cross-Over Studies; D018492:Dopamine Antagonists / Q000008:administration & dosage*; D004311:Double-Blind Method; D005072:Evoked Potentials, Auditory / Q000187:drug effects / Q000502:physiology; D006220:Haloperidol / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D009025:Morpholines / Q000008:administration & dosage*; D051381:Rats; D000077593:Reboxetine; D055139:Sensory Gating / Q000187:drug effects* / Q000502:physiology*; D013045:Species Specificity; D055815:Young Adult
chemical_list: D018759:Adrenergic Uptake Inhibitors; D018492:Dopamine Antagonists; D009025:Morpholines; D000077593:Reboxetine; D006220:Haloperidol