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.
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.
Shirayama
Yukihiko
Y
Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan. shirayama@rapid.ocn.ne.jp
Muneoka
Katsumasa
K
Fukumoto
Makoto
M
Tadokoro
Shigenori
S
Fukami
Goro
G
Hashimoto
Kenji
K
Iyo
Masaomi
M
D000679:Amygdala / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D056654:CA3 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology; D003863:Depression / Q000188:drug therapy; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D004338:Drug Combinations; D005442:Flumazenil / Q000008:administration & dosage; D018756:GABA Antagonists / Q000008:administration & dosage; D006380:Helplessness, Learned; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects; D011280:Pregnanolone / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects*
D000928:Antidepressive Agents; D004338:Drug Combinations; D018756:GABA Antagonists; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D005442:Flumazenil; D016291:Dizocilpine Maleate; D011280:Pregnanolone