Critical role of the embryonic mid–hindbrain organizer in the behavioral response to amphetamine and methylphenidate

• Published in: Neuroscience Vol. 163; no. 4; pp. 1012 - 1023
• Main Authors: Tilleman, H, Kofman, O, Nashelsky, L, Livneh, U, Roz, N, Sillaber, I, Biegon, A, Rehavi, M, Brodski, C
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 10.11.2009; Elsevier
• Subjects: Amphetamine - administration & dosage; Amphetamine - pharmacology; Animals; Biological and medical sciences; Brain - drug effects; Brain - physiology; Central Nervous System Stimulants - administration & dosage; Central Nervous System Stimulants - pharmacology; dopamine; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins - metabolism; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; hyperactivity; isthmic organizer; Male; Medical sciences; Methylphenidate - administration & dosage; Methylphenidate - pharmacology; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Motor Activity - drug effects; Motor Activity - physiology; Neurology; Neurons - drug effects; Neurons - physiology; Neuropharmacology; Otx2; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; psychostimulants; Rhombencephalon - drug effects; Rhombencephalon - physiology; serotonin; Serotonin - metabolism; Serotonin Plasma Membrane Transport Proteins - metabolism; Vertebrates: nervous system and sense organs; psychostimulants; EPM; hyperactivity; elevated plus maze; FLU; serotonin; fluoxetine; MHO; Otx2; WT; HPLC; isthmic organizer; methylphenidate; MP; caudate putamen; noradrenaline transporter; amphetamine; mid-hindbrain organizer; CPu; high performance liquid chromatography; dopamine transporter; DAT; AMPH; dopaminergic; NET; wild-type; dopamine; DA; Embryo; Dopamine; CNS stimulant; Serotonin; Psychotropic; Catecholamine; Neurotransmitter; Amfetamine; Behavior; Methylphenidate
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2009.07.040

Abstract The embryonic mid–hindbrain organizer, which is composed of a transient cell population in the brainstem, controls the development of dopaminergic and serotonergic neurons. Different genes determining the position and activity of this embryonic structure have been implicated in dopamine- and serotonin-associated disorders. Mouse mutants with a caudally shifted mid–hindbrain organizer, are hyperactive, show increased numbers of dopaminergic neurons and a reduction in serotonergic cells. In the present study we used these mutants to gain insights into the genetic and developmental mechanisms underlying motor activity and the response to psychostimulants. To this end, we studied the motor activity of these animals after exposure to methylphenidate and amphetamine and characterized their dopaminergic and serotonergic innervation. Saline-treated mutants showed increased locomotion, more stereotypic behavior and a decrease in rearing compared to wild-type mice. This baseline level of activity was similar to behaviors observed in wild-type animals treated with high doses of psychostimulants. In mutants methylphenidate (5 or 30 mg/kg) or amphetamine (2 or 4 mg/kg) did not further increase activity or even caused a decrease of locomotor activity, in contrast to wild-type mice. Fluoxetine (5 or 10 mg/kg) reduced hyperactivity of mutants to levels observed in wild-types. Transmitter measurements, dopamine and serotonin transporter binding assays and autoradiography, indicated a subtle increase in striatal dopaminergic innervation and a marked general decrease of serotonergic innervation in mutants. Taken together, our data suggest that mice with an aberrantly positioned mid–hindbrain organizer show altered sensitivity to psychostimulants and that an increase of serotonergic neurotransmission reverses their hyperactivity. We conclude that the mid–hindbrain organizer, by orchestrating the formation of dopaminergic and serotonergic neurons, is an essential developmental parameter of locomotor activity and psychostimulant response.