Abstract
Agonists acting at benzodiazepine, γ-aminobutyric acidA, barbiturate and neurosteroid recognition sites were studied for their attenuation of separation-induced ultrasonic vocalizations (USV) in rat pups. The behavioral effects of the neuroactive steroid 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) were assessed when the drug was administered alone and in combination with agonists and antagonists acting at the γ-aminobutyric acidA receptor complex. At 7 days postpartum, male and female Long-Evans rat pups were separated from the dam and littermates, and placed on a 20°C surface for 2 min. Allopregnanolone (1–30 mg/kg s.c.), alprazolam (0.03–1 mg/kg s.c.), diazepam (0.1–3 mg/kg s.c.), muscimol (0.03–0.3 mg/kg s.c.) and pentobarbital (1–30 mg/kg s.c.) dose-dependently decreased USV. Pretreatment with flumazenil (0.1 mg/kg s.c.) antagonized alprazolam’s and diazepam’s USV-suppressive effects; bicuculline (2 mg/kg s.c.) reversed muscimol’s USV-suppressive effects. Allopregnanolone (3 mg/kg s.c.) produced a 4- to 7-fold leftward shift in alprazolam’s and diazepam’s USV-suppressive effects, and also produced a modest leftward shift in pentobarbital’s USV dose-effect function. Neither flumazenil, bicuculline, nor picrotoxin (1 mg/kg s.c.) altered allopregnanolone’s USV-suppressive effects. These results suggest that the USV-suppressive effects of the neurosteroid allopregnanolone are mediated at the γ-aminobutyric acidAreceptor complex, and are independent from a direct action on the benzodiazepine or γ-aminobutyric acidA recognition sites on this complex.
Footnotes
-
Send reprint requests to: Dr. K. A. Miczek, Tufts University, Research Building, 490 Boston Avenue, Medford, MA 02155.
-
↵1 This work was supported by United States Public Health Service Grants AA5122 and DA02632 (K.A.M.) and by research fellowship CNPQ 201736/92-6 (H.M.T.B.).
-
↵2 Animals used in these studies were maintained in accordance with the Tufts University Committee on Animal Care, and Guidelines of the Committee on the Care and Use of Laboratory Animal Resources, National Health Council (Department of Health, Education and Welfare, Publication No. (NIH) 85-23, revised 1983).
-
↵3 Current address: Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, Ann Arbor, MI 48109-0632.
-
↵4 Current address: Division of Pharmacology, Funcacao Faculdade Federal Ciencias Medicas, Porto Alegre, Brazil.
- Abbreviations:
- BZ
- benzodiazepine
- Cl
- 95% confidence interval
- ED50
- 50% effective dose
- GABA
- γ-aminobutyric acid
- USV
- ultrasonic vocalization
- allopregnanolone
- 3α-hydroxy-5α-pregnan-20-one
- THDOC
- 5β-pregnane-3α-21-diol-20-one
- Received July 23, 1996.
- Accepted March 24, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|