The effects of GABA transporter inhibition on synaptophysin and synaptotagmin expression in diazepam tolerance.
BACKGROUND
In light of the differential interactions seen between benzodiazepine, GABA transporter (GAT) inhibition and drug tolerance, the locomotor effects of a GAT1-specific inhibitor (SKF89976A) following diazepam tolerance were analysed and compared with the concomitant expression of synaptic vesicle proteins implicated in synaptic plasticity.


METHODS
Male PVG/OlaHsd rats were chronically dosed with diazepam to produce tolerance, and the expression of mRNA for synaptophysin and synaptotagmin were analysed in the hippocampus by means of in situ hybridisation. The action of the GAT inhibitor SKF89976A on the expression of these mRNAs, and on open field behaviour was subsequently observed.


RESULTS
The results show an unexpected sedative effect of GAT-inhibition in diazepam-tolerant rats. The expression data show a significant effect of diazepam treatment on synaptophysin expression, which is reversible by SKF89976A treatment.


CONCLUSIONS
The increased synaptophysin expression in the hippocampus of diazepam-tolerant rats may indicate a role for modulation of transmitter release, synaptic plasticity and learning in pharmacological tolerance. The reversibility of this effect following acute GAT inhibition suggests a complicated relationship between the benzodiazepine-binding site and other synaptic GABA-binding sites. Furthermore, the sedative behavioural effect of the GAT inhibitor in diazepam-tolerant rats is an unusual observation with implications for the treatment of drug-tolerant individuals.
Schmitt
Ulrich
U
Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany.
Conner
Alex C
AC
Rapp
Simone
S
Kissling
Christian
C
Jennen-Steinmetz
Christine
C
Hünnerkopf
Regina
R
Coogan
Andrew N
AN
Thome
Johannes
J
D000818:Animals; D001665:Binding Sites; D003975:Diazepam / Q000378:metabolism* / Q000494:pharmacology; D004327:Drinking Behavior / Q000187:drug effects; D004361:Drug Tolerance / Q000502:physiology; D058805:GABA Uptake Inhibitors; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009557:Nipecotic Acids / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism / Q000502:physiology; D016708:Synaptophysin / Q000032:analysis / Q000096:biosynthesis*; D050857:Synaptotagmins / Q000032:analysis / Q000096:biosynthesis*
D058805:GABA Uptake Inhibitors; D009557:Nipecotic Acids; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D016708:Synaptophysin; D050857:Synaptotagmins; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid; D003975:Diazepam