Molecular mechanisms of tolerance to and withdrawal of GABA(A) receptor modulators.
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.
Biggio
Giovanni
G
Department of Experimental Biology "Bernardo Loddo,", Center of Excellence for the Neurobiology of Dependence, University of Cagliari, 09123, Italy. biggio@unica.it
Dazzi
Laura
L
Biggio
Francesca
F
Mancuso
Luisa
L
Talani
Giuseppe
G
Busonero
Fabio
F
Mostallino
Maria Cristina
MC
Sanna
Enrico
E
Follesa
Paolo
P
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
D002457:Cell Extracts; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D013256:Steroids; D001569:Benzodiazepines; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D014446:Tyrosine 3-Monooxygenase