Infusions of allopregnanolone into the hippocampus and amygdala, but not into the nucleus accumbens and medial prefrontal cortex, produce antidepressant effects on the learned helplessness rats

Abstract

Patients with depression showed a decrease in plasma and cerebrospinal fluid allopregnanolone (ALLO). But antidepressants increased the contents of ALLO in the rat brain. We examined the antidepressant-like effects of infusion of ALLO into the cerebral ventricle, hippocampus, amygdala, nucleus accumbens, or prefrontal cortex of learned helplessness (LH) rats (an animal model of depression). Of these regions, infusions of ALLO into the cerebral ventricle, the CA3 region of hippocampus, or the central region of amygdala exerted antidepressant-like effects. Infusion of ALLO into the hippocampal CA3 region or the central amygdala did not produce memory deficits or locomotor activation in the passive avoidance and open field tests. It is well documented that ALLO exerts its effects through GABA receptors. Therefore, we examined the antagonistic effects of flumazenil (a GABA receptor antagonist) on the antidepressant-like effects of ALLO. Coinfusion of flumazenil with ALLO into the hippocampal CA3 region, but not into the central amygdala, blocked the antidepressant-like effects of ALLO. However, coinfusion of (+)MK801 (an NMDA receptor antagonist), but not cycloheximide (a protein synthesis inhibitor), blocked the antidepressant-like effects of ALLO in the central amygdala. These results suggest that ALLO exerts antidepressant-like effects in the CA3 region of hippocampus through the GABA system and in the central region of amygdala, dependently on the activation of the glutamatergic mechanisms.

Allopregnanolone regulates neurogenesis and depressive/anxiety-like behaviour in a social isolation rodent model of chronic stress

“…This suggests that metabolism of progesterone to ALLO may be involved in improved performance in the Forced Swim Test. Our results are also in agreement with recent work by Shirayama and colleagues (Shirayama et al, 2011) who showed that infusions of ALLO into the CA3 of the hippocampus or the amygdala for four days were capable of rescuing a learned helplessness phenotype in rats. The lack of difference in line crossings and rearing motions observed between treatment groups in the Open Field test also indicates that the administered dose of ALLO does not have a noticeable sedative effect.…”

Peripheral interleukin-6 promotes resilience versus susceptibility to inescapable electric stress

“…Stress paradigm (LH model) LH paradigm was performed as reported previously (4,10,11). To create the LH paradigm, rats are initially exposed to uncontrollable stress.…”

The neurosteroids allopregnanolone and dehydroepiandrosterone modulate resting-state amygdala connectivity

“…It had been reported that progesterone administration (which in turn increases allopregnanolone levels) modulates amygdala responsivity to emotional faces (van Wingen, et al, 2007), and increases functional connectivity between amygdala and dorsal medial prefrontal cortex (dmPFC) (van Wingen, et al, 2008). Allopregnanolone modulates GABA(A) receptor-mediated inhibitory postsynaptic currents in the central nucleus of the amygdala (Wang, et al, 2007), and microinfusions of allopregnanolone directly into the amygdala produce anxiolytic (Engin and Treit, 2007) and antidepressant (Shirayama, et al, 2011) effects. The anxiolytic and antidepressant effects of DHEA may be mediated by the amygdala as well.…”