Neural bases for addictive properties of benzodiazepines.
Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behaviour. The neural basis for the addictive nature of benzodiazepines, however, remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA(A) (gamma-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on alpha1-containing GABA(A) receptors expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell-type-specific expression of alpha1-containing GABA(A) receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing alpha1 may be devoid of addiction liability.
Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland.
Kelly R
KR
Tan
Matthew
M
Brown
Gwenaël
G
Labouèbe
Cédric
C
Yvon
Cyril
C
Creton
Jean-Marc
JM
Fritschy
Uwe
U
Rudolph
Christian
C
Lüscher
D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D016739:Behavior, Addictive / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004553:Electric Conductivity; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D008954:Models, Biological; D009020:Morphine / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009928:Organ Specificity; D018091:Receptors, AMPA / Q000378:metabolism; D011963:Receptors, GABA-A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C546241:Gabra1 protein, mouse; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D008874:Midazolam; D004298:Dopamine