title: Molecular mechanisms of tolerance to and withdrawal of GABA(A) receptor modulators.
abstract: Here, we summarize recent data pertaining to the effects of GABA(A) receptor modulators on the receptor gene expression in order to elucidate the molecular mechanisms behind tolerance and dependence induced by these drugs. Drug selectivity and intrinsic activity seems to be important to evidence at the molecular level the GABA(A) receptor tolerance. On the contrary, we suggested that all drug tested are equally potentially prone to induce dependence. Our results demonstrate that long-lasting exposure of GABA(A) receptors to endogenous steroids, benzodiazepines and ethanol, as well as their withdrawal, induce marked effects on receptor structure and function. These results suggest the possible synergic action between endogenous steroids and these drugs in modulating the functional activity of specific neuronal populations. We report here that endogenous steroids may play a crucial role in the action of ethanol on dopaminergic neurons.
authors.affiliation: Department of Experimental Biology "Bernardo Loddo,", Center of Excellence for the Neurobiology of Dependence, University of Cagliari, 09123, Italy. biggio@unica.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Biggio
authors.forename: Laura
authors.initials: L
authors.lastname: Dazzi
authors.forename: Francesca
authors.initials: F
authors.lastname: Biggio
authors.forename: Luisa
authors.initials: L
authors.lastname: Mancuso
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Talani
authors.forename: Fabio
authors.initials: F
authors.lastname: Busonero
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mostallino
authors.forename: Enrico
authors.initials: E
authors.lastname: Sanna
authors.forename: Paolo
authors.initials: P
authors.lastname: Follesa
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001569:Benzodiazepines / Q000494:pharmacology; D002457:Cell Extracts / Q000494:pharmacology; D002462:Cell Membrane; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance / Q000235:genetics*; D004563:Electrochemistry; D000431:Ethanol / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D015151:Immunoblotting; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D017551:Microdialysis; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013256:Steroids / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013995:Time; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D002457:Cell Extracts; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D013256:Steroids; D001569:Benzodiazepines; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D014446:Tyrosine 3-Monooxygenase