Using UAS-Gal4 designer receptors exclusively activated by designer drugs to elucidate nondopaminergic modulation of methamphetamine-induced locomotion in Drosophila.

Methamphetamine (METH) use disorder is a serious public health problem with no Food and Drug Administration-approved therapeutic drugs to aid recovery. METH's primary mechanism of action increases dopaminergic neurotransmission in brain regions implicated in reward. However, the serotonergic system is also involved in reward processing and dopamine modulation, thus drugs affecting the serotonin system may have therapeutic potential for treating METH use disorder. To use male and female UAS-Gal4 flies expressing designer receptors exclusively activated by designer drugs to investigate the contributions of nondopaminergic neurons on locomotor response to METH over multiple days, as measured by the Drosophila activity monitoring system. While METH increased locomotor activity in most flies, sex and strain also contribute to METH response, with males of most fly strains displaying significantly greater METH-induced locomotor activity than females. We found METH-induced locomotor activity to be highly modulated by serotonergic signaling and circadian regulators. The mushroom body, serotonin availability, 5-HT1A neurons, 5-HT7 neurons, drosophila insulin-like protein neurons, and pigment dispersing factor neurons modulate locomotor activity independent of METH response. The mushroom body, 5-HT7 neurons, and drosophila insulin-like protein neurons also modulate METH response. While all the neuron types investigated were shown to modulate locomotor activity in some way, 5-HT7 neurons appear to mediate METH-induced locomotor response most directly.