Protracted withdrawal from alcohol and drugs of abuse impairs long-term potentiation of intrinsic excitability in the juxtacapsular bed nucleus of the stria terminalis.
The juxtacapsular bed nucleus of the stria terminalis (jcBNST) is activated in response to basolateral amygdala (BLA) inputs through the stria terminalis and projects back to the anterior BLA and to the central nucleus of the amygdala. Here we show a form of long-term potentiation of the intrinsic excitability (LTP-IE) of jcBNST neurons in response to high-frequency stimulation of the stria terminalis. This LTP-IE, which was characterized by a decrease in the firing threshold and increased temporal fidelity of firing, was impaired during protracted withdrawal from self-administration of alcohol, cocaine, and heroin. Such impairment was graded and was more pronounced in rats that self-administered amounts of the drugs sufficient to maintain dependence. Dysregulation of the corticotropin-releasing factor (CRF) system has been implicated in manifestation of protracted withdrawal from dependent drug use. Administration of the selective corticotropin-releasing factor receptor 1 (CRF(1)) antagonist R121919 [2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylamino-pyrazolo[1,5-a]pyrimidine)], but not of the CRF(2) antagonist astressin(2)-B, normalized jcBNST LTP-IE in animals with a history of alcohol dependence; repeated, but not acute, administration of CRF itself produced a decreased jcBNST LTP-IE. Thus, changes in the intrinsic properties of jcBNST neurons mediated by chronic activation of the CRF system may contribute to the persistent emotional dysregulation associated with protracted withdrawal.
Francesconi
Walter
W
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California 92037, USA. wfranc@scripps.edu
Berton
Fulvia
F
Repunte-Canonigo
Vez
V
Hagihara
Kazuki
K
Thurbon
David
D
Lekic
Dusan
D
Specio
Sheila E
SE
Greenwell
Thomas N
TN
Chen
Scott A
SA
Rice
Kenner C
KC
Richardson
Heather N
HN
O'Dell
Laura E
LE
Zorrilla
Eric P
EP
Morales
Marisela
M
Koob
George F
GF
Sanna
Pietro Paolo
PP
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage* / Q000009:adverse effects; D000431:Ethanol / Q000008:administration & dosage* / Q000009:adverse effects; D003932:Heroin / Q000008:administration & dosage* / Q000009:adverse effects; D017774:Long-Term Potentiation / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D012686:Septal Nuclei / Q000187:drug effects / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D000431:Ethanol; D003932:Heroin; D003042:Cocaine