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. 2015 Mar 10:5:8902.
doi: 10.1038/srep08902.

Paliperidone and aripiprazole differentially affect the strength of calcium-secretion coupling in female pituitary lactotrophs

Marek Kucka  1 , Melanija Tomić  1 , Ivana Bjelobaba  1 , Stanko S Stojilkovic  1 , Dejan B Budimirovic  2
Affiliations

Paliperidone and aripiprazole differentially affect the strength of calcium-secretion coupling in female pituitary lactotrophs

Marek Kucka et al. Sci Rep. .

Abstract

Hyperprolactinemia is a common adverse in vivo effect of antipsychotic medications that are used in the treatment of patients with schizophrenia. Here, we compared the effects of two atypical antipsychotics, paliperidone and aripiprazole, on cAMP/calcium signaling and prolactin release in female rat pituitary lactotrophs in vitro. Dopamine inhibited spontaneous cAMP/calcium signaling and prolactin release. In the presence of dopamine, paliperidone rescued cAMP/calcium signaling and prolactin release in a concentration-dependent manner, whereas aripiprazole was only partially effective. In the absence of dopamine, paliperidone stimulated cAMP/calcium signaling and prolactin release, whereas aripiprazole inhibited signaling and secretion more potently but less effectively than dopamine. Forskolin-stimulated cAMP production was facilitated by paliperidone and inhibited by aripiprazole, although the latter was not as effective as dopamine. None of the compounds affected prolactin transcript activity, intracellular prolactin accumulation, or growth hormone secretion. These data indicate that paliperidone has dual hyperprolactinemic actions in lactotrophs i) by preserving the coupling of spontaneous electrical activity and prolactin secretion in the presence of dopamine and ii) by inhibiting intrinsic dopamine receptor activity in the absence of dopamine, leading to enhanced calcium signaling and secretion. In contrast, aripiprazole acts on prolactin secretion by attenuating, but not abolishing, calcium-secretion coupling.

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Figures

Figure 1
Figure 1. Concentration-dependent effect of dopamine (DA), aripiprazole (ARI), and paliperidone (PAL) on prolactin (PRL), growth hormone (GH), and cyclic AMP (cAMP) release and intracellular content in pituitary cells in static cultures.
(a and b) Both ARI and DA inhibited PRL (a) and cAMP (b) release, whereas PAL had no obvious effects on either. Notice that 1 μM ARI was less effective than 1 μM DA in inhibiting PRL and cAMP release. (c) No effect of DA, ARI, or PAL application on GH secretion. (d) A highly significant correlation between cAMP and PRL release in DA-treated cells (open circles) and the lack of significant correlation between these parameters in ARI-treated cells (open squares). (e) No effect of DA, ARI, or PAL on intracellular PRL content. (f) ARI and DA decreased intracellular cAMP content in a concentration dependent manner, whereas PAL increased it at higher concentrations. (g) The lack of a 2 h and 6 h treatment with 1 μM ARI and 1 μM PAL on PRL gene (Prl) expression, shown as relative to the expression of the housekeeping gene Gapdh (100%). (h) A highly significant correlation between intracellular cAMP content vs. released PRL in DA-treated cells and the lack of correlation between these parameters in ARI-treated cells. Correlation analysis shown in panels (d) and (h) was performed as described in the Methods, and data points are derived from panels (a), (b), and (f). *P < 0.01.
Figure 2
Figure 2. Concentration-dependent effect of ARI and PAL on the released and intracellular content of PRL and cAMP in the presence of 1 μM DA in rat pituitary cells in static cultures.
(a and b) ARI partially and PAL completely blocked DA-induced inhibition of PRL (a) and cAMP (b) release. (c and d) Intracellular content of PRL (c) was not affected by DA, ARI or PAL, whereas intracellular accumulation of cAMP (d) was partially rescued by ARI and almost completely by PAL. In this and the following figures, horizontal lines on the top of each panel indicate the duration of treatment. Dotted horizontal lines indicate basal values in the presence (bottom) and absence (top) of DA.
Figure 3
Figure 3. Concentration-dependent response effect of ARI and PAL on PRL release in perifused pituitary cells.
(a) ARI inhibited PRL release in all concentrations tested (0.1, 0.5 and 1 μM) and the subsequent application of 1 μM DA further down-regulated hormone release. (b) PAL alone slightly increased PRL release and blocked the inhibitory effect of 1 μM DA on hormone release in a concentration dependent manner; PAL was used at concentrations of 0, 0.1, 0.5, and 1 μM, as indicated. (c) ARI inhibited PRL secretion to comparable levels as DA, whereas DA was unable to inhibit PRL release in the presence of PAL (closed circles); PAL was able to reverse DA inhibitory action with a transient overshot (open circles). All drugs were applied at a 1 μM concentration. The vertical dotted line indicates the moment of switch in drug application as indicated above the line.
Figure 4
Figure 4. The effect of ARI and PAL on cAMP release in perifused rat pituitary cells.
(a) PAL increased cAMP release (20–80 min application) compared to the baseline levels (0–20 min). The washout of PAL was accompanied with a gradual but incomplete return of cAMP release to basal levels during the 20 min washout period. Basal indicates cAMP release in untreated cells (open diamonds). (b) ARI (open squares) decreased cAMP release less effectively than DA (open circles). Applying DA to cells pre-treated with ARI further inhibited cAMP production. In contrast, PAL increased cAMP release from cells (closed circles). The addition of DA diminished this increase to basal levels only. Applying PAL to cells pretreated with DA diminished the inhibitory effect of DA on cAMP release (open circles). (c) Application of forskolin, an adenylyl cyclase activator, tremendously facilitated cAMP release (open diamonds). ARI decreased forskolin-stimulated cAMP release (open squares) in a similar fashion but less effectively than DA (open circles), whereas PAL increased forskolin-stimulated cAMP production (closed circles). All drugs were applied at a 1 μM concentration. The vertical dotted line indicates the moment of switch in drug application as indicated above the line.
Figure 5
Figure 5. The effect of DA, ARI, and PAL on calcium influx in single rat lactotrophs.
(a) Spontaneous calcium transients were blocked by ARI with no further effect of DA in 19 of 31 cells (bottom trace). In the residual cells, ARI did not abolish spontaneous calcium transients but nevertheless blocked DA-induced inhibition of calcium influx (top trace). (b) Once [Ca2+]i was inhibited by 1 μM DA, 1 μM ARI could not induce any further effect in 14 of 15 lactotrophs (upper trace). 1 μM PAL recovered spontaneous calcium transients previously blocked by DA in 9 of 10 cells (bottom trace). (c) When applied in 0.1 μM concentration, PAL gradually increased [Ca2+]i in a fraction of cells (12 of 48; top trace) and was ineffective in residual cells. In a fraction of non-responders (7 of 48), the subsequent application of 1 μM DA inhibited calcium transients (bottom trace). (d) When applied in 1 μM concentration, PAL rapidly increased [Ca2+]i in a fraction of cells (13 of 45; top trace) and was ineffective in residual cells (bottom trace). In all of these 45 cells, PAL blocked further effect of 1 μM DA. Arrows indicate the moment of drug application, and the subsequent compound was added without dilution of the first compound. Horizontal dotted lines in panels c and d indicate baseline [Ca2+]i.
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