Antipsychotic drugs up‐regulate tryptophan hydroxylase in ADF neurons of Caenorhabditis elegans: Role of calcium‐calmodulin‐dependent protein kinase II and transient receptor potential vanilloid channel

Abstract

Antipsychotic drugs produce acute behavioral effects through antagonism of dopamine and serotonin receptors, and long-term adaptive responses that are not well understood. The goal of the study presented here was to use Caenorhabditis elegans to investigate the molecular mechanism or mechanisms that contribute to adaptive responses produced by antipsychotic drugs. First-generation antipsychotics, trifluoperazine and fluphenazine, and second-generation drugs, clozapine and olanzapine, increased the expression of tryptophan hydroxylase-1::green fluorescent protein (TPH-1::GFP) and serotonin in the ADF neurons of C. elegans. This response was absent or diminished in mutant strains lacking the transient receptor potential vanilloid channel (TRPV; osm-9) or calcium/calmodulin-dependent protein kinase II (CaMKII; unc-43). The role of calcium signaling was further implicated by the finding that a selective antagonist of calmodulin and a calcineurin inhibitor also enhanced TPH-1::GFP expression. The ADF neurons modulate foraging behavior (turns/reversals off food) through serotonin production. We found that short-term exposure to the antipsychotic drugs altered the frequency of turns/reversals off food. This response was mediated through dopamine and serotonin receptors and was abolished in serotonin-deficient mutants (tph-1) and strains lacking the SER-1 and MOD-1 serotonin receptors. Consistent with the increase in serotonin in the ADF neurons induced by the drugs, drug withdrawal after 24-hr treatment was accompanied by a rebound in the number of turns/reversals, which demonstrates behavioral adaptation in serotonergic systems. Characterization of the cellular, molecular, and behavioral adaptations to continuous exposure to antipsychotic drugs may provide insight into the long-term clinical effects of these medications.

Behavioral adaptation in C. elegans produced by antipsychotic drugs requires serotonin and is associated with calcium signaling and calcineurin inhibition

“…The increase in varicosities correlates with an increase in the accumulation of TPH-1 secondary to a decrease in protein turnover. However, the drugs may also stimulate TPH-1 gene expression (Donohoe et al, 2008). Regardless, these data show that antipsychotic drugs produce dynamic remodeling of serotonergic neurons including sites of neurotransmitter release.…”

“…At this time, the animals were washed off the plates with M9 buffer (containing 50 mM sodium azide) and were placed on microscope slides for fluorescence analysis. Total fluorescence in the NSM processes was measured as described elsewhere (Donohoe et al, 2008) and the number of varicosities (thickenings > 2 times the diameter of the process) was also determined. Digital photomicrographs were taken with a CoolSNAP monochrome camera attached to a Nikon Eclipse TE300 inverted microscope equipped with an epifluorescence attachment (including a green fluorescent protein filter), and Nomarski optics.…”

“…Antipsychotic drugs produce significant changes in C. elegans behavior, including egg-laying, locomotion and foraging (Weinshenker et al, 1995; Donohoe et al, 2006, 2008). The main goal of the present study was to take advantage of this model system to characterize the cellular and molecular response to antipsychotic drugs in relation to changes in feeding behavior (pharyngeal pumping) mediated via a well-defined neural circuit.…”

“…Antipsychotic drugs block serotonin receptors (Meltzer, 1999), and affect signaling pathways that regulate tryptophan hydroxylase (TPH) (Mockus and Vrana, 1998; Ninan et al, 2003; Estevez et al, 2004; Zhang et al, 2004; Donohoe et al, 2008), the rate-limiting enzyme in serotonin biosynthesis. Therefore, it would not be surprising if these drugs produced functional changes in serotonergic systems of C. elegans , which could alter behavior such as pharyngeal pumping.…”

Big ideas for small brains: what can psychiatry learn from worms, flies, bees and fish?

“…25 Furthermore, C. elegans show sensitivity and intoxication to different drugs such as alcohol, nicotine and certain antipsychotic drugs, display different forms of non-associative and associative learning, and present sleep-like states during the quiescence phase associated with the four molts. [26][27][28][29][30] The molecular and cellular mechanisms regulating these behaviors have revealed conserved features across species. For example, a worm model of nicotine addiction presenting acute and chronic behavioral responses that parallel those observed in mammals, has revealed a novel and important role of the conserved TRPC (transient receptor potential canonical) channels in modulating the activity of nicotinic acetylcholine receptors.…”