Isolation rearing-induced reduction of brain 5α-reductase expression: relevance to dopaminergic impairments.
Isolation rearing (IR), a well-established rat model of early chronic psychosocial stress, engenders marked behavioral alterations related to changes of dopamine (DA) neurotransmission in cortical and subcortical brain regions. Stress-induced shifts in γ-aminobutyric acid (GABA)-ergic signaling have been implicated in the dysregulation of DA release. The neurosteroid 3α-hydroxy-5α-pregnan-20-one (allopregnanolone/AP), synthesized from progesterone by the action of the rate-limiting enzyme 5α-reductase (5AR), is a potent positive allosteric modulator of GABA(A) receptor function. Thus, alterations of 5AR activity/expression may impact upon DA neurotransmission. We studied the effects of IR on the 5AR expression/function and extracellular concentrations of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC). Immediately after weaning, male rats were subjected to either IR or social rearing (SR) conditions for 5-8 weeks. Compared to SR, IR rats exhibited significantly lower protein expression of 5AR isoforms (1 and 2) in both brain regions and reduced brain, but not plasma, content of AP and allotetrahydrodeoxycorticosterone, the 5α-reduced metabolite of deoxycorticosterone. IR-exposed rats also exhibited higher levels of DA and DOPAC in the NAcc shell, but not in mPFC, when compared to SR rats. The 5AR inhibitor finasteride (FIN, 100 mg/kg, i.p.) enhanced DA and DOPAC content in the NAcc shell of SR, but not IR rats. FIN, however, elicited equivalent increases in DA and DOPAC levels in the mPFC of both groups. These results show that IR induces changes in expression/activity of brain 5AR which, in a brain-region specific manner, may partially underlie the alterations in DA signaling induced by this manipulation. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90031, USA. bortolat@usc.edu
Marco
M
Bortolato
Paola
P
Devoto
Paola
P
Roncada
Roberto
R
Frau
Giovanna
G
Flore
Pierluigi
P
Saba
Giuseppa
G
Pistritto
Alessio
A
Soggiu
Salvatore
S
Pisanu
Agata
A
Zappala
Maria Serafina
MS
Ristaldi
Maria
M
Tattoli
Vincenzo
V
Cuomo
Francesco
F
Marrosu
Maria Luisa
ML
Barbaccia
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D042944:Cholestenone 5 alpha-Reductase / Q000096:biosynthesis*; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018120:Finasteride / Q000494:pharmacology; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D011280:Pregnanolone / Q000097:blood / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012934:Social Isolation
D058891:5-alpha Reductase Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D018120:Finasteride; D011280:Pregnanolone; D042944:Cholestenone 5 alpha-Reductase; D004298:Dopamine