Lordosis of Rats Is Modified by Neurosteroidogenic Effects of Membrane Benzodiazepine Receptors in the Ventral Tegmental Area

Abstract

Progestins modulate lordosis through actions in the ventral tegmental area (VTA). Whether neurosteroidogenesis of 5α-pregnan-3α-ol-20-one (3α,5α-THP), involving mitochondrial benzodiazepine receptors (MBR), is important for lordosis was investigated. Ovariectomized (Ovx), hormone-primed rats (experiments 1, 3, 5, 6) and rats in behavioral estrus (experiments 2 and 4) were unilaterally infused via chronic guide cannula to the VTA with a MBR agonist, N,N-dihexyl-2-(4-fluorophenyl) indole-30-acetamide (FGIN 1–27) or antagonist 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboximide (PK-11195). Experiment 1: Estradiol benzoate (EB)-primed (25 µg) rats administered 0 or 25 µg progesterone (P₄) SC showed increased lordosis when infused with 5.0 µg FGIN 1–27 to the VTA; those administered 100 or 200 µg P₄ SC exhibited greater lordosis when infused with 2.5 or 5.0 µg FGIN, relative to saline-infused rats. Experiment 2: Rats, near the termination of behavioral estrus, infused with 2.5 or 5.0 µg of FGIN 1–27 to the VTA, showed increased lordosis compared to that seen following vehicle administration. Experiment 3: EB-primed rats administered 200 or 500 µg P₄ SC showed decreased lordosis when infused with 100, 200, or 400 ng PK-11195, relative to saline-infused rats. Experiment 4: Rats infused at the peak of behavioral estrus with 100, 200, or 400 ng PK-11195 to the VTA exhibited reduced lordosis compared to that seen following vehicle administration. Experiment 5: 3α,5α-THP (100 ng) infusions to the VTA reinstated lordosis of hormone-primed rats infused with PK-11195 (100 ng) to the VTA. Experiment 6: FGIN 1–27 (5.0 µg) and PK-11195 (100 ng) infusions aimed at the VTA respectively increased and decreased midbrain levels of 3α,5α-THP compared to vehicle. Notably, the specific effects observed with infusions to the VTA were not seen with infusions to the control site, the substantia nigra. These data suggest that neurosteroidogenesis involving MBRs in the VTA mediates lordosis of hormone-primed or behavioral estrous rats.

Membrane actions of progestins at dopamine type 1-like and GABAA receptors involve downstream signal transduction pathways

“…For example, mating rapidly increases in 3α5α-THP in the midbrain VTA and this is observed among intact, naturally-receptive rodents, as well as ovx, and/or adrenalectomized E 2 -primed rodents [32][33]. Increasing or decreasing neurosteroidogenesis of 3α5α-THP in the VTA with infusions of PBR ligands, respectively, enhances and attenuates lordosis of hormone-primed or naturally-receptive rodents [34][35]. Inhibiting P450scc activity in the midbrain VTA produces decrements in 3α5α-THP and lordosis [34][35].…”

“…Increasing or decreasing neurosteroidogenesis of 3α5α-THP in the VTA with infusions of PBR ligands, respectively, enhances and attenuates lordosis of hormone-primed or naturally-receptive rodents [34][35]. Inhibiting P450scc activity in the midbrain VTA produces decrements in 3α5α-THP and lordosis [34][35]. Thus, another source of 3α5α-THP in the midbrain VTA is from central biosynthesis.…”

Infusions of 3α,5α-THP to the VTA enhance exploratory, anti-anxiety, social, and sexual behavior and increase levels of 3α,5α-THP in midbrain, hippocampus, diencephalon, and cortex of female rats

“…In the VMH, E 2 and P 4 initiate lordosis through classical actions at intracellular progestin receptors (PRs). However, in the VTA, P 4 modulates the duration and intensity of lordosis responses following metabolism to, and/or de novo synthesis of, 5α-pregnan-3α-ol-20-one (3α,5α-THP) and its subsequent actions at GABA A , dopamine-like type 1, and/or NMDA receptors and subsequent downstream signal transduction processes [5][6][7][8][9][10][11][12]. By using lordosis as a bioassay, we have elucidated that these are some of the mechanisms by which 3α,5α-THP has actions in the VTA to mediate mating.…”

In the Ventral Tegmental Area, G-Proteins and cAMP Mediate the Neurosteroid 3α,5α-THP’s Actions at Dopamine Type 1 Receptors for Lordosis of Rats

“…Rather, P’s mechanisms, in the VTA, include formation of 5α-pregnan-3α-ol-20-one (3α,5α-THP) [8, 9]. Notably, blocking de novo synthesis of, or P’s metabolism to, 3α,5α-THP in the VTA reduces lordosis of E 2 +P-primed rodents [8, 9, 10, 11]. Thus, P’s actions for lordosis, in the VTA, are independent of PRs, occur at neuronal membranes, and involve 3α,5α-THP.…”