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.