507 Holtzman rats received
injections, through chemitrodes chronically implanted into the basolateral amygdala, of 0.2-1 microliter of sterile isotonic
solution containing nanomolar quantities of
cholinergic muscarinic agonists and/or antagonists. The bulk of the injected
solution diffused only a short distance as judged by autoradiography. Once daily
injections of 2.7 nmoles of
carbamylcholine, an initially subconvulsive dose, kindled the progressive development of epileptic
seizures similar to those seen in electrical amygdaloid kindling. This response was dependent on dose and on interstimulus interval, and once established persisted at least 8 weeks without further stimulation. Spontaneous
seizures were observed in some fully kindled animals. No kindling-specific changes were seen by light microscopy.
Muscarine (3 nmol) and the active (+), but not the inactive (-), isomer of
acetyl-beta-methylcholine also kindled
seizures. The action of (+)-
acetyl-beta-methylcholine was potentiated by the
cholinesterase inhibitor physostigmine. The
muscarinic antagonists atropine and quinuclidinyl benzylate (QNB) blocked kindling by
carbamylcholine or
muscarine.
Atropine, QBN and
scopolamine greatly reduced agonist-induced
seizures in previously kindled rats. Highly significant transfer effects were observed between
muscarinic agonists, i.e.
muscarine-kindled rats had widespread
seizures on their first
carbamylcholine exposure and vice versa. Kindled animals had a lowered seizure threshold for
muscarinic agonists.
Dibutyryl cyclic GMP produced
seizures but no kindling. Those results demonstrate that in this model the stimulation of a group of
muscarinic cholinergic synapses is both necessary and sufficient to induce a kindled state characterized by both evoked and spontaneous
seizures, and support the view that
epilepsy can be acquired and expressed transsynaptically.