Modulation of dialysate levels of dopamine, noradrenaline, and serotonin (5-HT) in the frontal cortex of freely-moving rats by (-)-pindolol alone and in association with 5-HT reuptake inhibitors: comparative roles of beta-adrenergic, 5-HT1A, and 5-HT1B receptors.
(-)-Pindolol, which possesses significant affinity for 5-HT1A, 5-HT1B, and beta 1/2-adrenergic receptors (AR)s, dose-dependently increased extracellular levels of dopamine (DA) and noradrenaline (NAD) versus 5-HT, in dialysates of the frontal cortex (FCX), but not accumbens and striatum, of freely-moving rats. In distinction, the preferential beta 1-AR antagonist, betaxolol, and the preferential beta 2-AR antagonist, ICI118,551, did not increase basal levels of DA, NAD, or 5-HT. Further, they both dose-dependently and markedly blunted the influence of (-)-pindolol upon DA and NAD levels. The selective 5-HT1A receptor antagonist, WAY100,635, slightly attenuated the (-)-pindolol-induced increase in DA and NAD levels, while the selective 5-HT1B antagonist, SB224,289, was ineffective. These data suggest that (-)-pindolol facilitates frontocortical dopaminergic (and adrenergic) transmission primarily by activation of beta 1/2-ARs and, to a lesser degree, by stimulation of 5-HT1A receptors, whereas 5-HT1B receptors are not involved. (-)-Pindolol potentiated the increase in FCX levels of 5-HT elicited by the 5-HT reuptake inhibitors, fluoxetine and duloxetine, and also enhanced their ability to elevate FCX levels of DA--though not of NAD. In contrast to (-)-pindolol, betaxolol and ICI118,551 did not affect the actions of fluoxetine, whereas both WAY100,635 and SB224,289 potentiated the increase in levels of 5-HT--but not DA or NAD levels--elicited by fluoxetine. In conclusion, (-)-pindolol modulates, both alone and together with 5-HT reuptake inhibitors, dopaminergic, adrenergic, and serotonergic transmission in the FCX via a complex pattern of actions at beta 1/2-ARs, 5-HT1A, and 5-HT1B receptors. These findings have important implications for clinical studies of the influence of (-)-pindolol upon the actions of antidepressant agents.
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betaxolol ICI118,551 fluoxetine WAY100,635 SB224,289 5-HT DA NAD fluoxetine (-)-pindolol (-)-Pindolol 5-HT dopamine DA (-)-pindolol noradrenaline NAD 5-HT betaxolol ICI118,551 DA (-)-Pindolol NAD 5-HT (-)-pindolol DA NAD WAY100,635 (-)-pindolol DA NAD SB224,289 5-HT (-)-pindolol (-)-pindolol 5-HT dopamine noradrenaline serotonin 5-HT 5-HT1B (AR)s beta 1/2-ARs 5-HT 5-HT1A 5-HT1B beta 1-AR beta 2-AR 5-HT1A 5-HT1A 5-HT1B 5-HT1B beta 1/2-adrenergic receptors beta 1/2-ARs fluoxetine 5-HT1A 5-HT1A, 5-HT1B duloxetine DA NAD (-)-pindolol