GABAergic regulation of locomotion before and during an ethanol exposure in Drosophila melanogaster

Daack, Calvin W.; Yeh, Derek; Busch, Marc; Kliethermes, Christopher L.

doi:10.1016/j.bbr.2021.113369

Cited by 4 publications

(4 citation statements)

References 59 publications

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“…GAD65-KO showed higher open-field locomotor activity at baseline, and the locomotion stimulant effect of EtOH facilitated their basic locomotor activity. This result could be evidenced by previous studies showing that systemic administration of agonists for GABA receptors reduces the EtOH-induced locomotor stimulant response [53], whereas systemic administration of antagonists for GABA receptors enhances the locomotor stimulant response [45,54,55]. Thus, GABAergic inhibition participates in the suppression of EtOH-induced alteration of locomotor activity and motor coordination [6,8,28].…”

Section: Discussionmentioning

confidence: 68%

GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing

2023

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γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter and its concentrations in the brain could be associated with EtOH-induced impairment of motor coordination. GABA is synthesized by two isoforms of glutamate decarboxylase (GAD): GAD65 and GAD67. Mice deficient in GAD65 (GAD65-KO) can grow up to adulthood, and show that GABA concentration in their adult brains was 50–75% that of wild-type C57BL/6 mice (WT). Although a previous study showed that there was no difference in recovery from the motor-incoordination effect of acute intraperitoneally administered injections of 2.0 g/kg EtOH between WT and GAD65-KO, the sensitivity of GAD65-KO to acute EtOH-induced ataxia has not been fully understood. Here, we sought to determine whether motor coordination and spontaneous firing of cerebellar Purkinje cells (PCs) in GAD65-KO are more sensitive to the effect of EtOH than in WT. Motor performance in WT and GAD65-KO was examined by rotarod and open-field tests following acute administration of EtOH at lower-doses, 0.8, 1.2 and 1.6 g/kg. In a rotarod test, there was no significant difference between WT and GAD65-KO in terms of baseline motor coordination. However, only the KO mice showed a significant decrease in rotarod performance of 1.2 g/kg EtOH. In the open-field test, GAD65-KO showed a significant increase in locomotor activity after 1.2 and 1.6 g/kg EtOH injections, but not WT. In in vitro studies of cerebellar slices, the firing rate of PCs was increased by 50 mM EtOH in GAD65-KO compared with WT, whereas no difference was observed in the effect of EtOH at more than 100 mM between the genotypes. Taken together, GAD65-KO are more susceptible to the effect of acute EtOH exposure on motor coordination and PC firing than WT. This different sensitivity could be attributed to the basal low GABA concentration in the brain of GAD65-KO.

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Section: Discussionmentioning

confidence: 68%

GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing

2023

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“…This increase in GABA signaling is known to contribute to the sedative effects of ethanol [80,81]. Drosophila ionotropic GABA A receptor, with resistance to dieldrin (RDL), contributes to ethanol-induced locomotor stimulation, and the metabotropic GABA B receptor has been shown to influence alcohol sensitivity and tolerance [82][83][84][85]. Dzitoyeva and colleagues showed that the administration of GABA B agonist prior to ethanol exposure prevented the development of rapid ethanol tolerance and decreased ethanol sensitivity, and GABA B antagonist increased resistance to the motor-impairing effect of alcohol in flies.…”

Section: Gabamentioning

confidence: 99%

Synaptic Mechanisms of Ethanol Tolerance and Neuroplasticity: Insights from Invertebrate Models

Bhandari,

Seguin,

Rothenfluh

2024

IJMS

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Alcohol tolerance is a neuroadaptive response that leads to a reduction in the effects of alcohol caused by previous exposure. Tolerance plays a critical role in the development of alcohol use disorder (AUD) because it leads to the escalation of drinking and dependence. Understanding the molecular mechanisms underlying alcohol tolerance is therefore important for the development of effective therapeutics and for understanding addiction in general. This review explores the molecular basis of alcohol tolerance in invertebrate models, Drosophila and C. elegans, focusing on synaptic transmission. Both organisms exhibit biphasic responses to ethanol and develop tolerance similar to that of mammals. Furthermore, the availability of several genetic tools makes them a great candidate to study the molecular basis of ethanol response. Studies in invertebrate models show that tolerance involves conserved changes in the neurotransmitter systems, ion channels, and synaptic proteins. These neuroadaptive changes lead to a change in neuronal excitability, most likely to compensate for the enhanced inhibition by ethanol.

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“…These findings establish a connection between GABAergic neurotransmission and the mammalian reward system and alcohol intake. Similarly, in fruit flies, male locomotion after ethanol intake was shown to depend on the GABAergic system [133]. An additional link has been made between the GABAergic system and the basolateral amygdala (BLA), where deletion of the δ GABA A receptor subunit in parvalbumin (PV) interneurons increased ethanol intake in males but not in females [134].…”

Section: Experience Induces Dimorphic Behavioural Outputs In Rodentsmentioning

confidence: 99%

Environmental experiences shape sexually dimorphic neuronal circuits and behaviour

2023

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Dimorphic traits, shaped by both natural and sexual selection, ensure optimal fitness and survival of the organism. This includes neuronal circuits that are largely affected by different experiences and environmental conditions. Recent evidence suggests that sexual dimorphism of neuronal circuits extends to different levels such as neuronal activity, connectivity and molecular topography that manifest in response to various experiences, including chemical exposures, starvation and stress. In this review, we propose some common principles that govern experience‐dependent sexually dimorphic circuits in both vertebrate and invertebrate organisms. While sexually dimorphic neuronal circuits are predetermined, they have to maintain a certain level of fluidity to be adaptive to different experiences. The first layer of dimorphism is at the level of the neuronal circuit, which appears to be dictated by sex‐biased transcription factors. This could subsequently lead to differences in the second layer of regulation namely connectivity and synaptic properties. The third regulator of experience‐dependent responses is the receptor level, where dimorphic expression patterns determine the primary sensory encoding. We also highlight missing pieces in this field and propose future directions that can shed light onto novel aspects of sexual dimorphism with potential benefits to sex‐specific therapeutic approaches. Thus, sexual identity and experience simultaneously determine behaviours that ultimately result in the maximal survival success.

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GABAergic regulation of locomotion before and during an ethanol exposure in Drosophila melanogaster

Cited by 4 publications

References 59 publications

GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing

GAD65 deficient mice are susceptible to ethanol-induced impairment of motor coordination and facilitation of cerebellar neuronal firing

Synaptic Mechanisms of Ethanol Tolerance and Neuroplasticity: Insights from Invertebrate Models

Environmental experiences shape sexually dimorphic neuronal circuits and behaviour

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