Progestins influence motivation, reward, conditioning, stress, and/or response to drugs of abuse

Frye, Cheryl A.

doi:10.1016/j.pbb.2006.07.033

Cited by 92 publications

(98 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Oral administration of P 4 has also been reported to have similar effects on men and women [18,73,74]. As well, we have found that cocaine administration enhances corticosterone in rats, and pre-treatment with P 4 can moderately attenuate this [23]. 3α,5α-THP may have effects to reduce reinforcing effects of drugs and this may be due, in part, to its ability to dampen stress reactivity.…”

Section: Discussionsupporting

confidence: 65%

Exploratory, anti-anxiety, social, and sexual behaviors of rats in behavioral estrus is attenuated with inhibition of 3α,5α-THP formation in the midbrain ventral tegmental area

Frye¹,

Paris²,

Rhodes³

2008

Behavioural Brain Research

Self Cite

View full text Add to dashboard Cite

The progesterone (P 4 ) metabolite and neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP) acts in the midbrain ventral tegmental area (VTA) to modulate lordosis of female rats. 3α,5α-THP also mediates exploratory, affective, and social behaviors; whether actions of 3α,5α-THP in the VTA mediate these behaviors is of interest. To elucidate the role of the VTA in mediating exploratory, affective, and social behaviors, the present study examined effects of inhibiting 3α,5α-THP formation in the VTA. Rats received intra-VTA infusions of either PK11195 (400 ng/μl, which inhibits de novo 3α,5α-THP production), indomethacin (10 μg/μl, which blocks metabolism of P 4 to 3α,5α-THP), PK11195 and indomethacin together, or β-cyclodextrin vehicle and tested on a battery of anxiety (open field and elevated plus maze), social (partner preference and social interaction), and sexual (paced mating) tasks. Compared to rats infused with vehicle to the VTA, rats infused with inhibitor(s) demonstrated significant reductions in central entries in the open field, time on open arms of an elevated plus maze, time spent interacting with a conspecific, initiation and intensity of lordosis, sexual solicitations, and midbrain 3α,5α-THP levels. These findings suggest that actions of 3α,5α-THP in the VTA are important for mediating aspects of exploration, anxiety, and social behavior related to mating.

show abstract

Section: Discussionsupporting

confidence: 65%

Exploratory, anti-anxiety, social, and sexual behaviors of rats in behavioral estrus is attenuated with inhibition of 3α,5α-THP formation in the midbrain ventral tegmental area

Frye¹,

Paris²,

Rhodes³

2008

Behavioural Brain Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Rats with natural elevations in progestogens have decreased anxiety-and depressive-like behavior and this effect is mimicked by P 4 administration to ovx rats or mice (Frye et al 2000(Frye et al , 2006aFrye and Rhodes 2006;Frye and Walf 2002;MartinezMota et al 1999;Rodriguez-Landa et al 2007). Attenuating metabolism of P 4 to 3α,5α-THP in a 5α-reductase knockout model, or with a 5α-reductase inhibitor administered systemically or to the hippocampus/amygdala, increases anxiety-like and depressive-like behavior in rodents with natural elevations in P 4 or those administered P 4 (Frye andWalf 2002, 2004;Rhodes and Frye 2001;Walf et al 2006). These data, in addition to the present findings that P 4 administration decreased depressive-like behavior in wildtype and APPswe+PSEN1Δ9 mice, suggest that P 4 and its metabolites may have beneficial effects on affective behavior in a healthy as well as a compromised system.…”

Section: Discussionmentioning

confidence: 99%

“…Progestogens are trophic factors with a wide variety of functional effects throughout the lifespan (reviewed in Frye 2007). In the brain, P 4 is converted by the 5α-reductase enzyme to dihydroprogesterone (DHP), which is then converted to 3α,5α-THP by the 3α-hydroxysteroid dehydrogenase enzyme.…”

Section: Introductionmentioning

confidence: 99%

Progesterone reduces depression-like behavior in a murine model of Alzheimer’s Disease

Frye

Walf

2009

AGE

Self Cite

View full text Add to dashboard Cite

Although anxiety and depression are not the core symptoms of Alzheimer's Disease (AD), there are changes observed in mood in those with AD, as well as in the aging population. Anxiety and depression may be influenced by progesterone P 4 and/or its neuroactive metabolites, dihydroprogesterone (DHP) and 5α-pregnan-3α-ol-20-one (3α,5α-THP). To begin to investigate progestogens' role in AD, a double transgenic mouse model of early-onset familial AD that cooverexpresses mutant forms of amyloid precursor protein (APPswe) and presenilin 1 Δ exon 9 mutation was utilized. As such, the effects of long-term (from 6 to 12 months of age) administration of P 4 to ovariectomized (ovx) wildtype and APPswe+PSEN1Δe9 mice for changes in affective behavior was investigated. APPswe+PSEN1Δ9 mutant mice had increased anxiety-like (i.e., increased emergence latencies, decreased time spent on the open quadrants of the elevated zero maze) and increased depressive-like behavior (i.e., increased time spent immobile) than did wildtype mice. Compared to vehicle-administration, P 4 administration (which produced physiological circulating P 4 , DHP, and 3α,5α-THP levels, particularly in the wildtype mice) decreased depressant-like behavior in the forced swim test. These effects occurred independent of changes in general motor behavior/coordination, pain threshold, and plasma corticosterone levels. Thus, the APPswe+PSEN1Δ9 mutation alters affective behavior, and P 4 treatment reversed depressive-like behavior.

show abstract

“…For example, 3α5α-THP's effects to prolong the opening of GBR chloride channels in vitro can be inhibited with antagonists of G-proteins, protein kinase C (PKC), or cAMP-dependent protein kinase [49]. Further, systemic administration of P 4 increases levels of cAMP in the prefrontal cortex in a 3α5α-THP-and GBR-dependent manner [32][33]50]. Thus, together these data suggest that activity of signal transduction factors may underlie \functioning of progestins at downstream targets, such as GBRs and D 1…”

Section: The Role Of Signal Transduction Cascades For Progestins' Actmentioning

confidence: 99%

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

Frye

Walf

2008

Steroids

View full text Add to dashboard Cite

In the ventral tegmental area (VTA), progestins facilitate lordosis via rapid actions at membrane dopamine Type 1-like (D 1 ) and/or GABA A receptors (GBRs), rather than via cognate, intracellular progestin receptors. Downstream signal transduction pathways involved in these effects were investigated using lordosis as a bioassay. If progestins' actions at D 1 and/or GBRs in the VTA require activation of G-proteins, adenylyl cyclase, cyclic AMP-dependent protein kinase A (PKA), phospholipase C (PLC), and/or PKC, then pharmacologically blocking these pathways would be expected to attenuate progestin-facilitated lordosis and its enhancement by D 1 and GBR activity. Ovariectomized, estradiol-primed rats were infused first with vehicle or signal transduction inhibitor, and second with vehicle, a D 1 or GBR agonist, and then with vehicle or progestins to the VTA. Rats were tested for lordosis following infusions. Results indicated that initiation of G-proteins, adenylyl cyclase, PKA, PLC, or PKC in the VTA is required for rapid effects of progestins through D 1 and/ or GBRs to facilitate lordosis. As well, progestins' actions at n-methyl-d-aspartate receptors (NMDARs) may modulate activity at D 1 and/or GBRs and mitogen activated protein kinase may be a common signaling pathway. Findings from a microarray study demonstrated that there was upregulation of genes associated with steroid metabolism, GBRs, D 1 , NMDARs and signal transduction factors in the midbrain VTA of naturally-receptive mated compared to non-mated rats. Thus, in the VTA, progestins have rapid membrane-mediated actions via D 1 , GBRs, NMDARs and their downstream signal transduction pathways.

show abstract

Progestins influence motivation, reward, conditioning, stress, and/or response to drugs of abuse

Cited by 92 publications

References 120 publications

Exploratory, anti-anxiety, social, and sexual behaviors of rats in behavioral estrus is attenuated with inhibition of 3α,5α-THP formation in the midbrain ventral tegmental area

Exploratory, anti-anxiety, social, and sexual behaviors of rats in behavioral estrus is attenuated with inhibition of 3α,5α-THP formation in the midbrain ventral tegmental area

Progesterone reduces depression-like behavior in a murine model of Alzheimer’s Disease

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

Contact Info

Product

Resources

About