Cortical 3α-hydroxy-5α-pregnan-20-one levels after acute administration of Δ9-tetrahydrocannabinol, cocaine and morphine

Grobin, A. Chistina; VanDoren, Margaret J.; Porrino, Linda J.; Morrow, A. Leslie

doi:10.1007/s00213-004-2084-3

Cited by 28 publications

(22 citation statements)

References 73 publications

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“…Further, these findings suggest that physiological and/or interoceptive effects of cocaine may involve stress-induced increases in corticosteroids and progestins and that administration of P may dampen some of the psychotropic effects of cocaine by attenuating stress-induced activation of neuroendocrine responses. It is important to note that it has also been reported that cocaine has no effect on 3α,5α-THP levels (Grobin et al, 2005).…”

Section: Progestins and Response To Drugs Of Abusementioning

confidence: 92%

“…Administration of various drugs of abuse has also been demonstrated to enhance production of 3α,5α-THP. For example, systemic administration of delta9-tetrahydrocannabinol can increase cortical levels of 3α,5α-THP (Grobin et al, 2005). High, but not lower, dosages of morphine also enhance cortical levels of 3α,5α-THP (Grobin et al, 2005) and 3α,5α-THP administration amplifies the release of dopamine in the nucleus accumbens in response to morphine (Rouge-Pont et al, 2002).…”

Section: Progestins Stress Hpa Functionmentioning

confidence: 99%

“…For example, systemic administration of delta9-tetrahydrocannabinol can increase cortical levels of 3α,5α-THP (Grobin et al, 2005). High, but not lower, dosages of morphine also enhance cortical levels of 3α,5α-THP (Grobin et al, 2005) and 3α,5α-THP administration amplifies the release of dopamine in the nucleus accumbens in response to morphine (Rouge-Pont et al, 2002). Ethanol administration increases plasma and cortical concentrations of 3α,5α-THP (Barbaccia et al, 1999;Hirani et al, 2002;Janis et al, 1998;Morrow et al, 1999;VanDoren et al, 2000).…”

Section: Progestins Stress Hpa Functionmentioning

confidence: 99%

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

Frye

2007

Pharmacology Biochemistry and Behavior

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Progesterone (pregn-4-ene-3,20-dione; P) and its metabolite 5α-pregnan-3α-ol-20-one (3α,5α-THP) are secreted by ovaries, adrenals, and glial cells. 3α,5α-THP in the midbrain ventral tegmental area mediates sexual receptivity of rodents through its actions at GABA A , NMDA, and/ or D 1 receptors. The extent to which 3α,5α-THP may influence anti-anxiety/anti-stress effects, conditioning and/or reward through these substrates and/or by altering hypothalamic pituitary adrenal axis function is discussed. Biosynthesis of 3α,5α-THP occurs in responses to mating and may underlie some of the rewarding aspects of sexual behavior. Recent findings from our laboratory which demonstrate that progestins can enhance approach to novel stimuli, conditioning, and reinforcement are reviewed. How progestins' effects on these processes may underlie response to drugs of abuse is considered and new findings which demonstrate interactions between progestins and cocaine are presented.

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Section: Progestins and Response To Drugs Of Abusementioning

confidence: 92%

Section: Progestins Stress Hpa Functionmentioning

confidence: 99%

Section: Progestins Stress Hpa Functionmentioning

confidence: 99%

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

Frye

2007

Pharmacology Biochemistry and Behavior

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“…In humans, examination stress (Droogleever Fortuyn et al, 2004) and performance stress (Girdler et al, 2006) were also accompanied by significant elevations in circulating levels of THP in both sexes, although ethnic differences have been reported (Girdler et al, 2006). Recent studies also suggest that drugs such as alcohol (VanDoren et al, 2000), morphine and δ-9-tetrahydrocannabinol (Grobin et al, 2005) increase circulating THP levels as a long-term response to intake of these drugs. Thus, stress may represent an additional mechanism by which neurosteroid levels can be altered over time, irrespective of gender.…”

Section: Stress and Addictive Drugsmentioning

confidence: 99%

Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

Smith

Shen

Gong

et al. 2007

Pharmacology & Therapeutics

214

197

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Neurosteroids, such as the progesterone metabolite 3α-OH-5α[β]-pregnan-20-one (THP or [allo] pregnanolone), function as potent positive modulators of the GABA A receptor (GABAR) when acutely administered. However, fluctuations in the circulating levels of this steroid at puberty, across endogenous ovarian cycles, during pregnancy or following chronic stress produce periods of prolonged exposure and withdrawal, where changes in GABAR subunit composition may occur as compensatory responses to sustained levels of inhibition. A number of laboratories have demonstrated that both chronic administration of THP as well as its withdrawal transiently increase expression of the α4 subunit of the GABAR in several areas of the central nervous system (CNS) as well as in in vitro neuronal systems. Receptors containing this subunit are insensitive to benzodiazepine (BDZ) modulation and display faster deactivation kinetics, which studies suggest underlie hyperexcitability states. Similar increases in α4 expression are triggered by withdrawal from other GABA-modulatory compounds, such as ethanol and BDZ, suggesting a common mechanism. Other studies have reported puberty or estrous cycle-associated increases in δ-GABAR, the most sensitive target of these steroids which underlies a tonic inhibitory current. In the studies reported here, the effect of steroids on inhibition, which influence anxiety state and seizure susceptibility, depend not only on the subunit composition of the receptor but also on the direction of Cl -current generated by these target receptors. The effect of neurosteroids on GABAR function thus results in behavioral outcomes relevant for pubertal mood swings, premenstrual dysphoric disorder and catamenial epilepsy, which are due to fluctuations in endogenous steroids.

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“…The neurosteroid pregnenolone has been shown to enhance memory when given intrathecally (Flood, et al, 1992,Flood, et al, 1995,Mathis, et al, 1994,Mayo, et al, 1993,Robel, et al, 1995. In rodent models of alcohol intoxication, one mechanism through which alcohol elicits its effects is through increased synthesis of allopregnanolone in the brain (Brot, et al, 1997,Caldeira, et al, 2004,Finn, et al, 2004,Finn, et al, 2003,Follesa, et al, 2004,Grobin, et al, 2005,Janis, et al, 1998,VanDoren, et al, 2000. Finally, the neurosteroid allopregnanolone has been implicated in a severe form of premenstrual disorder, called premenstrual dysphoric disorder (Backstrom, et al, 2003,Bernardi, et al, 2004,Bicikova, et al, 1998,Bixo, et al, 1997,Epperson, et al, 2002,Friedman, et al, 1993,Girdler, et al, 2001,Monteleone, et al, 2000,Rapkin, et al, 1997,Schmidt, et al, 1994,Smith, et al, 1998.…”

Section: Introductionmentioning

confidence: 99%

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Mellon

Gong

Schonemann

2008

Brain Research Reviews

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The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3ß HSD, as well as those that expressed 3α HSD and 5α reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of lifespan, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABA A receptors may play a role. We treated NP-C mice with a synthetic GABA A neurosteroid, ganaxolone (3α-hydroxy-3β-methyl-5α -pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABA A receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.

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Cortical 3α-hydroxy-5α-pregnan-20-one levels after acute administration of Δ9-tetrahydrocannabinol, cocaine and morphine

Abstract: Some, but not all, drugs of abuse produce increases in cortical allopregnanolone levels. In addition, increases in plasma steroid precursor levels do not always translate into increases in brain allopregnanolone levels.

Cited by 28 publications

References 73 publications

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

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

Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

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