Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells

Abstract

Ergovaline inhibition of radioligand binding to the D2 dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 dopamine receptor activation.

Bioprotective Alkaloids of Grass-Fungal Endophyte Symbioses

“…Lolines may be involved in vasoconstriction and vascular thickening, and the site of action may be a-2-adrenergic, D, dopamine, or serotonergic receptors (Larson et al, 1995;Strickland et al, 1996). Also, a significant immunosuppressive effect has been noted in feeding studies in mice (Dew et al, 1990).…”

“…Often measured are altered neurotransmitter metabolism and reduced prolactin and melatonin levels in blood, indicating an endocrine effect and supporting a dopaminergic mechanism for toxicity. Larson et al (1995) demonstrated that ergovaline had high affinity for D, dopamine receptors. Also, ergovaline acted as an agonist for the vasoactive intestinal peptide, stimulating cyclic AMP production in cultured cells, and this response was mediated via the reaction with the D, dopamine receptors.…”

Ergovaline, an endophytic alkaloid. 1. Animal physiology and metabolism

“…The interaction of ergovaline with dopamine receptors is best represented by the suppression of circulating prolactin (Elsasser and Bolt 1987). In vitro studies (Strickland et al 1994;Larson et al 1995) have specifically shown that ergovaline is a D2 dopamine-receptor agonist. Specifically, Larson et al (1995) showed that when ergovaline binds D2 receptors, a second messenger response is triggered that is similar to that of dopamine.…”

Ergovaline, an endophytic alkaloid. 2. Intake and impact on animal production, with reference to New Zealand

“…(1) Decreased circulating prolactin concentration Ergot alkaloids, such as ergovaline, are D 2 dopamine-receptor agonists that result in a suppression of plasma prolactin concentration (Larson et al 1995). The USA fescue toxicosis literature has demonstrated that circulating prolactin concentration is a very sensitive, but variable, indicator of ergopeptide (ergovaline) modulation of the D 2 dopamine receptor (Oliver 1997).…”