Altered neuronal responsiveness to biogenic amines in rat cerebral cortex after serotonin denervation or depletion

To further investigate monoaminergic mechanisms in cerebral cortex, responsiveness of cortical neurons to microiontophoretic applications of serotonin (5-HT), dopamine (DA) or noradrenaline (NA) was examined in the frontoparietal region of control, 5,7-dihydroxytryptamine (5,7-DHT)- and p-chlorophenylalanine (PCPA)-treated rats anesthetized with urethane. As a rule, 100 nA applications of either one of these biogenic amines induced marked slowing or total interruption of 'spontaneous' firing overlasting the 30 s period of ejection. Given the large amounts of monoamines ejected, it could be inferred that such microiontophoretic applications produced a maximal activation of receptors. In control rats, the responses to 5-HT, DA and NA were of approximately equal duration (approximately equal to 5 min). Two to 4 weeks after denervation with 5,7-DHT, most neurons (75%) exhibited greatly prolonged responses to 5-HT (approximately equal to 14 min), and marked depressions of firing could be induced by small ejection currents (approximately equal to 2 nA) having little or no effect in the controls. In addition, 85% of the units supersensitive to 5-HT showed considerably shortened responses to DA and NA (approximately equal to 1 min). After 2-14 days of depletion with PCPA, there was no change in the responsiveness to 5-HT in spite of a 91% lowering of cortical 5-HT content equivalent to that measured after denervation. Nevertheless, responsiveness to DA and NA was again diminished in a majority (80%) of the units tested. In control or PCPA-treated rats, acute administration of the 5-HT re-uptake blocker fluoxetine increased the duration of depressions induced by 100 nA applications of 5-HT but did not enhance responsiveness to low ejection currents. This suggested that, after 5-HT denervation, the suppression of re-uptake was mainly responsible for the prolongation of 5-HT responses ('presynaptic' component of supersensitivity), whereas a modification of 5-HT receptors accounted for the greater efficacy of small doses of 5-HT ('postsynaptic' component). Responsiveness to the microiontophoretic application of phenylephrine (PHE), a noradrenergic a-agonist, was comparable with that to NA in PCPA- and 5,7-DHT-treated as well as in control rats. Therefore, the hyposensitivity to DA and NA appeared indicative of a desensitization of catecholamine receptors caused by the absence of 5-HT. Such a desensitization may be viewed as an adaptive change resulting from an increased release of endogenous DA and NA. This interpretation would in turn imply that, normally, 5-HT regulates catecholamine release in the neocortex.