Blockade of FG 7142 kindling by anticonvulsants acting at sites distant from the benzodiazepine receptor

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Repeated administration of beta-carboline FG 7142 induces chemical kindling, a process of developing seizure sensitivity.
• This phenomenon is hypothesized to involve alterations in benzodiazepine (BZ)/GABA receptor function.

Purpose of the Study:

• To investigate the role of BZ receptor ligands and various anticonvulsant drugs in blocking the expression and development of FG 7142-induced kindling in mice.
• To explore the mechanisms underlying FG 7142 chemical kindling.

Main Methods:

• Mice were administered FG 7142 (40 mg/kg, i.p.) daily to induce kindling.
• The ability of BZ receptor agonists (clonazepam, ZK 93,423, CL 218,872), antagonists (flumazenil, ZK 93,426), and anticonvulsants (sodium valproate, ethosuximide, MK 801, 2-chloradenosine) to block convulsions and kindling development was assessed.
• Phenytoin and carbamazepine served as ineffective controls.

Main Results:

• BZ receptor agonists and antagonists, along with sodium valproate and ethosuximide, effectively blocked FG 7142-induced convulsions in kindled mice.
• MK 801 and 2-chloradenosine also demonstrated effectiveness in blocking convulsions.
• All tested substances, when given with repeated FG 7142, prevented or significantly reduced kindling development, except for phenytoin and carbamazepine.
• MK 801 and 2-chloradenosine's ability to prevent kindling suggests mechanisms beyond direct BZ receptor interaction.

Conclusions:

• While BZ receptor ligands can block FG 7142-induced seizures, they are not solely responsible for inducing kindling.
• The development of FG 7142 kindling likely involves secondary changes in neuronal pathways distinct from BZ/GABA receptors.
• This study highlights the complex neurobiological underpinnings of chemical kindling and identifies potential therapeutic targets.