Testosterone attenuates and the selective estrogen receptor modulator, raloxifene, potentiates amphetamine-induced locomotion in male rats.
Although sex steroids are known to modulate brain dopamine, it is still unclear how testosterone modifies locomotor behaviour controlled, at least in part, by striatal dopamine in adolescent males. Our previous work suggests that increasing testosterone during adolescence may bias midbrain neurons to synthesise more dopamine. We hypothesised that baseline and amphetamine-induced locomotion would differ in adult males depending on testosterone exposure during adolescence. We hypothesised that concomitant stimulation of estrogen receptor signaling, through a selective estrogen receptor modulator (SERM), raloxifene, can counter testosterone effects on locomotion. Male Sprague-Dawley rats at postnatal day 45 were gonadectomised (G) or sham-operated (S) prior to the typical adolescent testosterone increase. Gonadectomised rats were either given testosterone replacement (T) or blank implants (B) for six weeks and sham-operated (i.e. intact or endogenous testosterone group) were given blank implants. Subgroups of sham-operated, gonadectomised and gonadectomised/testosterone-replaced rats were treated with raloxifene (R, 5mg/kg) or vehicle (V), daily for the final four weeks. There were six groups (SBV, GBV, GTV, SBR, GBR, GTR). Saline and amphetamine-induced (1.25mg/kg) locomotion in the open field was measured at PND85. Gonadectomy increased amphetamine-induced locomotion compared to rats with endogenous or with exogenous testosterone. Raloxifene increased amphetamine-induced locomotion in rats with either endogenous or exogenous testosterone. Amphetamine-induced locomotion was negatively correlated with testosterone and this relationship was abolished by raloxifene. Lack of testosterone during adolescence potentiates and testosterone exposure during adolescence attenuates amphetamine-induced locomotion. Treatment with raloxifene appears to potentiate amphetamine-induced locomotion and to have an opposite effect to that of testosterone in male rats.
Schizophrenia Research Institute, Sydney, Australia; Schizophrenia Research Laboratory, Neuroscience Research Australia, Barker Street, Sydney, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Australia. Electronic address: t.purves-tyson@neura.edu.au.
Tertia D
TD
Purves-Tyson
Schizophrenia Research Laboratory, Neuroscience Research Australia, Barker Street, Sydney, Australia.
Danny
D
Boerrigter
Schizophrenia Research Institute, Sydney, Australia; Schizophrenia Research Laboratory, Neuroscience Research Australia, Barker Street, Sydney, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia.
Katherine
K
Allen
Schizophrenia Research Institute, Sydney, Australia; Schizophrenia Research Laboratory, Neuroscience Research Australia, Barker Street, Sydney, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia.
Katerina
K
Zavitsanou
Neuroscience Research Australia, Barker Street, Sydney, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Australia.
Tim
T
Karl
Schizophrenia Research Institute, Sydney, Australia; Schizophrenia Research Laboratory, Neuroscience Research Australia, Barker Street, Sydney, Australia; School of Medical Sciences, Faculty of Medicine, University of New South Wales, Australia.
Vanezha
V
Djunaidi
Discipline of Biomedical Science, School of Medical Sciences, Sydney Medical School, University of Sydney, Australia.
Kay L
KL
Double
ANZAC Research Institute, University of Sydney, Concord Hospital, Australia.
Reena
R
Desai
ANZAC Research Institute, University of Sydney, Concord Hospital, Australia.
David J
DJ
Handelsman
Schizophrenia Research Institute, Sydney, Australia; Schizophrenia Research Laboratory, Neuroscience Research Australia, Barker Street, Sydney, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia.
Cynthia Shannon
CS
Weickert
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D020849:Raloxifene Hydrochloride / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D012669:Seminal Vesicles / Q000033:anatomy & histology / Q000187:drug effects; D013739:Testosterone / Q000494:pharmacology*
D000697:Central Nervous System Stimulants; D020845:Selective Estrogen Receptor Modulators; D013739:Testosterone; D020849:Raloxifene Hydrochloride; D000661:Amphetamine; D004298:Dopamine
Adolescence; Androgen; Dopamine; Locomotion; Psychosis; Sex steroids; Testosterone