Kappa opiate receptor agonists: effects on behavior and on brain function and structure in rhesus monkeys

In the present study several drugs that are predominantly agonists of kappa receptors were tested in rhesus monkeys prepared with deep and surface brain electrodes. The administration of two benzomorphan derivatives and of ethylketocyclazocine induced acute behavioral effects resembling catatonia concomitant with generalized spike and slow-wave electroencephalographic activity at widespread brain sites, that lasted for about 1 hr. After administration of one to three doses of these agonists (the benzomorphan derivatives to five monkeys and the ethylketocyclazocine to two monkeys), chronic recording changes developed, characterized by continuous high-amplitude spiking activity focal at the anterior septal region and periaqueductal gray of the mesencephalon. They increased in intensity with the passage of time, the monkeys having been followed as long as 5 months without further drug administration. Light microscopy and electron microscopy showed no structural abnormalities in the monkey brains at the sites of altered recordings, although occasional dendritic atrophy was noted at all cortical and subcortical brain sites examined. Chronic recording changes did not develop in a monkey that received U-50,488H on eight occasions. And none of the electrode-implanted monkeys that served as controls (having received no kappa agonists) developed recording changes. The sites affected by the active kappa agonists were those at which abnormal activity has been correlated with psychotic behavior. The ability of the kappa agonists to induce a lasting physiologic change without corresponding structural change at those focal sites implicated in schizophrenia may prove a useful probe in further investigations into the cause of schizophrenia and its ultimate treatment.