The phenomenon of contingent tolerance to carbamazepine (CBZ) during amygdala-kindled seizure development was discovered by Dr. Weiss of the Section on Psychobiology. We have begun autoradiographic studies of various receptors to investigate the biochemical mechanism of this contingent tolerance to CBZ. The assays have been performed in a pilot study. The following neurotransmitter receptors were assayed. 1) Glutamate NMDA subtype with [3H]MK-801. 2) GABA-A with [3H]muscimol and [35S]TBPS. 3) Central-type benzodiazepine with [3H]Ro-15-1788. 4) Peripheral-type benzodiazepine with [3H] Ro 5-4864. 5) Adenosine A1 and A2a subtypes with [3H]cyclohexyladenosine and [3H]CGS-21680, respectively. No changes in striatal adenosine A2a receptor binding were observed. Likewise, no changes in the hippocampus were observed for adenosine A1 or NMDA receptors. [3H]Ro 5-4864 was not a suitable ligand for autoradiographic analysis of peripheral-type benzodiazepine receptors. However, the data have confirmed that GABA- A receptors and central-type benzodiazepine receptors show increased binding in the dentate gyrus of the hippocampus with electrical kindling of the amygdala. We extend those findings by showing that [ 35 S]TBPS binding is also increased in the dentate gyrus with kindling. Interestingly, in rats made tolerant to CBZ (contingent tolerance), GABA- A receptor binding was decreased toward control levels as compared with non-tolerant kindled rats, while central-type benzodiazepine receptor and TBPS binding did not differ between tolerant and non-tolerant rats. This finding suggests that the mechanism of contingent tolerance to CBZ involves a decrease in GABA- A receptor function without involvement of the benzodiazepine site. This biochemical correlate of GABA- A receptor changes with contingent tolerance to CBZ in the amygdala kindling paradigm is the primary focus of ongoing research.
