Neurosteroids allosterically modulate the ion pore of the NMDA receptor consisting of NR1/NR2B but not NR1/NR2A

Elfverson, Martin; Linde, Anna-Malin; Grevès, Pierre Le; Zhou, Qin; Nyberg, Fred; Johansson, Tobias

doi:10.1016/j.bbrc.2008.05.055

Cited by 15 publications

(7 citation statements)

References 20 publications

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“…An electrophysiological study has demonstrated that ALLO reduces GABA A receptormediated inhibitory postsynaptic currents in the central nucleus of the amygdala via an NMDA receptor-mediated mechanism (Wang et al, 2007). Although direct effects of ALLO on glutamatergic receptors have never been reported, other sulfated neurosteroids have modulatory effects on the NMDA receptors (Elfverson et al, 2008;Sedlacek et al, 2008). These support the assumption that GABA A receptor function is modulated by the NMDA receptor in the central amygdala.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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“…It has been demonstrated that some sulfated neurosteroids modulate NMDA receptor activity via a steroid modulatory domain on the NMDA receptor NR2B subunit [18,28]. The results suggest that the non sulfated neurosteroid allopregnanolone could interact with NMDA receptors modulating the release of LHRH.…”

Section: Discussionmentioning

confidence: 96%

Allopregnanolone induces LHRH and glutamate release through NMDA receptor modulation

et al. 2011

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LHRH release from hypothalamus is influenced by the neurotransmitter glutamate that acts, among others, on NMDA receptors present in LHRH neurons. On the other hand, the neurosteroid allopregnanolone can modulate the activity of specific neurotransmitter receptors and affect neurotransmitter release. We examined the role of allopregnanolone on in vitro LHRH and glutamate release from mediobasal hypothalamus and anterior preoptic area of ovariectomized rats with estrogen and progesterone replacement. Moreover, we evaluated whether the neurosteroid might act through modulation of NMDA receptors. Allopregnanolone induced an increase in LHRH release. This effect was reversed when the NMDA receptors were blocked by the NMDA antagonist 2-amino-7-phosphonoheptanoic acid (AP-7) indicating that this neurosteroid would interact with NMDA receptors. Moreover allopregnanolone induced an augment in K(+) evoked [(3)H]-glutamate release from mediobasal hypothalamus-anterior preoptic area explants and this effect was also reversed when NMDA receptors were blocked with AP-7. These results suggest an important physiologic function of allopregnanolone on the regulation of neuroendocrine function in female adult rats. Not only appears to be involved in enhancing LHRH release through modulation of NMDA receptors but also in the release of glutamate which is critical in the control of LHRH release.

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“…Because neurosteroids have been shown to modulate other receptors including the NMDA and sigma receptor (Elfverson et al , 2008; Maurice et al , 1999), these results cannot unequivocally implicate GABA A receptor modulation in the amnestic effects produced by pregnanolone. However, in a radioligand binding study by Prince and Simmonds (1993), pregnanolone potentiated 1 nM [3H] flunitrazepam binding at the GABA A receptor, with increases in binding ranging from 140-150% of control.…”

Section: Discussionmentioning

confidence: 96%

Effects of pregnanolone and flunitrazepam on the retention of response sequences in rats

Amato¹,

Moerschbaecher²,

Winsauer

2011

Pharmacology Biochemistry and Behavior

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With increasing interest in using neuroactive steroids therapeutically, greater understanding of the effects of these substances on learning and memory is needed. Neuroactive steroids have effects at both the NMDA and GABAA receptor complexes, and therefore, may have the capacity to alter memory processes. To specifically assess the effects of a neurosteroid on memory, male Long‐Evans rats responding under a retention procedure were administered pregnanolone (1 ‐ 18 mg/kg). During the procedure, a tandem response sequence was acquired and then retested after delays of 30 (n=12) or 180 (n=12) minutes. Responding during both sequence acquisition and retest was maintained under a second‐order fixed‐ratio (FR) 2 schedule of food reinforcement and incorrect responding (errors) produced a 5‐sec timeout. Retention of the sequence was quantified as percent savings in errors to criterion and the 180‐min delay interval alone produced a time‐dependent decrease in retention. Pregnanolone produced a dose‐dependent decrease in the response rate, accuracy, and percent savings. However, decreases in retention occured at doses lower than those that disrupted response rate and accuracy. These data indicate that the neurosteroid pregnanolone potently disrupts retention and that this effect may be an important consideration in the evaluation of neuroactive steroids as therapeutics. Supported by DA 019625

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Neurosteroids allosterically modulate the ion pore of the NMDA receptor consisting of NR1/NR2B but not NR1/NR2A

Cited by 15 publications

References 20 publications

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

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

Allopregnanolone induces LHRH and glutamate release through NMDA receptor modulation

Effects of pregnanolone and flunitrazepam on the retention of response sequences in rats

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