Antagonizing effects of a novel antipsychotic quinolinone derivative (OPC-14597) on dopaminergic inhibition of neuronal activities in the nucleus accumbens.

Abstract 1. 1. The effects of a newly synthesized quinolinone derivative, 7-{4-[4-(2,3-dichlorophenlyl)-1-piperazinyl]butyloxy}-3,4-dihydro-2-(1 H )-quinolinone (OPC-14597), an antipsychotic drug, on neuronal activities of the nucleus accumbens (Acc) were investigated in rats anesthetized with chloral hydrate using a microiontophoretic method. 2. 2. Spikes elicited by stimulation of the parafascicular nucleus (Pf) of the thalamus were extracellularly recorded in the Acc neuron of chloral hydrate-anesthetized adult Wistar rats using a glass microelectrode attached along a seven-barreled micropipette, each of which was filled with dopamine, OPC-14597, SKF 38393 (D1 receptor agonist), quinpirole (D2 receptor agonist) and 2M NaCl. The drugs were microiontophoretically applied to the target neurons recorded. 3. 3. Effects of the drugs on the Acc neurons activated monosynaptically by stimulation of the Pf were examined. Spikes elicited by Pf stimulation were inhibited by iontophoretic application of dopamine, SKF 38393 and quinpirole in a dose-dependent manner. 4. 4. Microiontophoretic application of OPC-14597 alone affected the spikes elicited by the Pf stimulation in none of 26 neurons tested. However, the dopamine-, SKF 38393- and quinpirole-induced inhibition of the spike generation in the Acc neurons was antagonized during simultaneous application of OPC-14597. 5. 5. The firing induced by iontophoretically applied glutamate was inhibited by dopamine, SKF 38393 and quinpirole, but not by OPC-14597. However, the dopamine-, SKF 38393- and quinpirole-induced inhibition of the glutamate-induced firing was also antagonized during simultaneous application of OPC-14597 in a dose-dependent manner in all neurons tested. 6. 6. These findings suggest that OPC-14597 blocks dopaminergic inhibition of the Acc neurons receiving input from the Pf by acting on both D1 and D2 receptors located on the neurons.