Epileptogenesis reduces the sensitivity of presynaptic gamma-aminobutyric acidB receptors on glutamatergic afferents in the amygdala.
Intracellular recordings were obtained from the basolateral amygdala in in vitro rat brain slice preparations to examine whether gamma-aminobutyric acid (GABA)B receptors are altered after in vivo kindling-induced epileptogenesis. Stimulating the stria terminalis evoked excitatory (EPSPs) and inhibitory (IPSPs) postsynaptic potentials in control neurons, and epileptiform bursting or enhanced EPSPs, but no IPSPs, in neurons from animals, 4 to 8 weeks after the last kindled seizure. Baclofen (0.1 nM-100 microM) depressed EPSPs in control and kindled basolateral amygdala neurons, but the EC50 appeared to be shifted 100-fold from 5 nM in control to 500 nM in kindled neurons. Further analysis suggested a high-affinity component may be affected in kind led neurons. The absence of IPSPs in kindled neurons could not account for this shift, because effects of baclofen on EPSP amplitude were reduced in kindled animals even when GABAA receptors were blocked with bicuculline methiodide (30 microM) and postsynpatic GABAB receptors with intracellular guanosine 5'-O-3-thiotriphosphate (10 mM); 6-cyano-2,3-dihydroxy-7-nitroquinoxaline (10 microM) was also present to block bicuculline methiodide-induced bursting. Membrane responses to exogenously applied N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid were not affected by baclofen. Baclofen also hyperpolarized basolateral amygdala neurons and reduced membrane input resistance with an EC50 of 1 microM in control and kindled neurons. Post- but not presynaptic effects of baclofen were blocked by 2-hydroxy-saclofen (100 microM) and pertussis toxin pretreatment. In conclusion, kindling-induced epileptogenesis reduces the sensitivity of presynaptic GABAB receptors, an effect which may contribute to the enhancement of excitatory transmission in kindled animals. Furthermore, different pharmacological properties of pre- and postsynaptic receptors in the amygdala suggest two distinct populations of GABAB receptors whose long-lasting responses to kindling-induced seizures are different.
Asprodini
E K
EK
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston.
Rainnie
D G
DG
Shinnick-Gallagher
P
P
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001921:Brain / Q000187:drug effects*; D004827:Epilepsy / Q000378:metabolism*; D005071:Evoked Potentials / Q000187:drug effects; D007696:Kindling, Neurologic; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013570:Synaptic Membranes / Q000187:drug effects
D011963:Receptors, GABA-A; D001418:Baclofen