Neurosteroids modulate compulsive and persistent behavior in rodents: implications for obsessive-compulsive disorder.
Neurosteroids are reported to modulate GABAergic and glutamatergic pathways that then influence serotonin and dopamine, the neurotransmitters implicated in pathophysiology of obsessive-compulsive disorder (OCD). Fluoxetine, a selective serotonin reuptake inhibitor clinically used in OCD is reported to increase the levels of neurosteroids like allopregnanolone, whereas OCD patients exhibit higher plasma levels of dehydroepiandrosterone 3-sulphate (DHEAS), a neuroactive steroid having opposite effects to that of allopregnanolone. Hence, it was contemplated that neurosteroids may influence obsessive-compulsive behavior. To test this possibility we studied the influence of various neurosteroids on two behavioral models of OCD, namely marble-burying behavior in mice and 8-OH-DPAT induced disruption of spontaneous alternation behavior (SAB) in rats. The results revealed that allopregnanolone (1 microg/mouse, i.c.v) and progesterone (20mg/kg, s.c.) reduced the marble-burying behavior in mice, whereas dehydroisoandrosterone 3-sulphate (DHAS) (5mg/kg, i.p.) exacerbated the same. The effects of allopregnanolone were comparable to that of fluoxetine (10mg/kg, i.p.). In view of the report that restraint stress increases the levels of allopregnanolone and isolation stress decreases the same, we studied the effect of these stressors on marble-burying behavior; wherein it was found to be less in restraint stress exposed mice, and higher in socially isolated mice. Restrain stress-induced attenuation of marble-burying behavior was blocked by finasteride, a neurosteroid biosynthesis blocker. In rat model of SAB disruption, acute and chronic treatment with allopregnanolone (1 microg/mouse, i.c.v.) reduced 8-OH-DPAT-induced persistent behavior, whereas treatment with DHAS (5mg/kg, i.p.) had an opposite effect. In conclusion, the studies indicate that neurosteroids can modulate obsessive-compulsive behavior in a bidirectional manner, and could serve as an effective target in the management of OCD.
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Umathe
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University Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Mahatma Jyotiba Fuley Shaikshanik Parisar, Amravati Road, Nagpur, MS 440 033, India. umathesn@hotmail.com
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Vaghasiya
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Jain
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Dixit
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D007276:Injections, Intraventricular / Q000379:methods; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009771:Obsessive-Compulsive Disorder / Q000097:blood* / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D011280:Pregnanolone / Q000097:blood* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012934:Social Isolation / Q000523:psychology; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D019314:Dehydroepiandrosterone Sulfate; D005473:Fluoxetine; D011280:Pregnanolone; D017367:Selective Serotonin Reuptake Inhibitors