Overexpression of the Drosophila vesicular monoamine transporter increases motor activity and courtship but decreases the behavioral response to cocaine

Abstract

Aminergic signaling pathways have been implicated in a variety of neuropsychiatric illnesses, but the mechanisms by which these pathways influence complex behavior remain obscure. Vesicular monoamine transporters (VMATs) have been shown to regulate the amount of monoamine neurotransmitter that is stored and released from synaptic vesicles in mammalian systems, and an increase in their expression has been observed in bipolar patients. The model organism Drosophila melanogaster provides a powerful, but underutilized genetic system for studying how dopamine (DA) and serotonin (5HT) may influence behavior. We show that a Drosophila isoform of VMAT (DVMAT-A) is expressed in both dopaminergic and serotonergic neurons in the adult Drosophila brain. Overexpression of DVMAT-A in these cells potentiates stereotypic grooming behaviors and locomotion and can be reversed by reserpine, which blocks DVMAT activity, and haloperidol, a DA receptor antagonist. We also observe a prolongation of courtship behavior, a decrease in successful mating and a decrease in fertility, suggesting a role for aminergic circuits in the modulation of sexual behaviors. Finally, we find that DMVAT-A overexpression decreases the fly's sensitivity to cocaine, suggesting that the synaptic machinery responsible for this behavior may be downregulated. DVMAT transgenes may be targeted to additional neuronal pathways using standard Drosophila techniques, and our results provide a novel paradigm to study the mechanisms by which monoamines regulate complex behaviors relevant to neuropsychiatric illness.

Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

“…5). This enhanced transmitter release and locomotion suggest elevated dopamine neurotransmission in these mice, a finding reflected in previous work on the overexpression of the Drosophila vesicular monoamine transporter (DVMAT-A) (31)(32)(33). Together with previous findings demonstrating reduced dopamine release and locomotion in VMAT2-deficient animals, the results from the VMAT2-HI mice suggest that there is a gene dosage-dependent regulation of vesicular capacity and dopamine output (21,41,42).…”

“…Although the detrimental effects of reduced VMAT2 function are recognized, our understanding of the potential benefits of increased VMAT2 function in vivo has been limited to a Drosophila model (31)(32)(33). Thus, we generated VMAT2-overexpressing mice using a bacterial artificial chromosome (BAC) to determine whether increased vesicular packaging could provide an elevation of monoamine output in a mammalian system.…”

Dispensable, Redundant, Complementary, and Cooperative Roles of Dopamine, Octopamine, and Serotonin inDrosophila melanogaster

“…For all other experiments WT controls were Canton-S (CS). The dVMAT null, homozygous for the loss-of-function allele (dVMAT P1 ), and the UAS-DVMAT transgene have been previously described (Oh et al 2003;Chang et al 2006;Romero-Calderon et al 2008;Simon et al 2009). Note that the UAS-DVMAT transgene used here encodes the neuronal isoform of DVMAT (DVMAT-A); a distinct RNA splice variant of dVMAT (DVMAT-B) is expressed only in a small subset of glia in the visual system and is unlikely to be relevant to the behaviors discussed here (Greer et al 2005;Romero-Calderon et al 2008).…”

“…In Drosophila, molecular-genetic and pharmacologic analyses have demonstrated the importance of DA in sleep, arousal, light perception, circadian entrainment, feeding, and aversive conditioning (Schwaerzel et al 2003;Andretic et al 2005;Kume et al 2005;Neckameyer and Weinstein 2005;Chang et al 2006;Draper et al 2007;Bayersdorfer et al 2010;Hirsh et al 2010;Riemensperger et al 2011); of 5-HT in aggression, place memory, circadian rhythms, and sleep (Yuan et al 2005(Yuan et al , 2006Sitaraman et al 2008;Alekseyenko et al 2010); and of OA in sleep, locomotion, female fertility, aggression, place memory, and the fly's response to environmental stressors (Hirashima et al 2000;Lee et al 2003;Fox et al 2006;Hardie et al 2007;Crocker and Sehgal 2008;Zhou et al 2008;Crocker et al 2010;Sitaraman et al 2010). However, as in mammals, the relative importance of each aminergic system for particular behaviors and their potential interplay remain unclear.…”

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

“…The Drosophila VMAT gene contains two splice variants, dVMAT-A and -B, where dVMAT-A is expressed in all dopaminergic, serotonergic, and octopaminergic neurons and functions similarly to mammalian VMAT2 (19,20). To assess the potential for 1-octen-3-ol to exert dopaminergic toxicity through disruption of dopamine handling in vivo, we first exposed two loss-of-function mutant lines for dVMAT-A, l(2)SH0459/+ and Delta14/+, to 0.5 ppm of 1-octen-3-ol (21).…”