Dopamine agonist pretreatment alters LSD's electrophysiological action from dopamine agonist to antagonist

LSD (50 μg/kg, i.v.) significantly depressed the discharge rate of dopamine-containing neurons in the substantia nigra of chloral hydrate anesthetized rats. However, when this same dose of LSD was administered to rats whose nigral cell discharge had been reduced 45% below baseline by d-amphetamine (mean dose = 1.45 mg/kg, i.v.), the discharge rate was significantly increased (typically returning to the pre-amphetamine baseline). A similar pattern was observed when LSD was administered to apomorphine-pretreated animals. Brom-LSD also produced these reversal effects. These effects of LSD resemble those of classical central dopamine antagonists such as haloperidol. We hypothesize that the shift in LSD's action from that of dopamine agonist to antagonist by prior dopamine agonist treatment may be mediated by a conformational shift in the state of the dopamine receptor.