ABSTRACT
Small molecules that increase the presynaptic function of aminergic cells may provide neuroprotection in Parkinson's disease (PD) as well as treatments for attention deficit hyperactivity disorder (ADHD) and depression. Model genetic organisms such as Drosophila melanogaster may enhance the detection of new drugs via modifier or 'enhancer/suppressor' screens, but this technique has not been applied to processes relevant to psychiatry. To identify new aminergic drugs in vivo, we used a mutation in the Drosophila vesicular monoamine transporter (dVMAT) as a sensitized genetic background and performed a suppressor screen. We fed dVMAT mutant larvae â¼ 1000 known drugs and quantitated rescue (suppression) of an amine-dependent locomotor deficit in the larva. To determine which drugs might specifically potentiate neurotransmitter release, we performed an additional secondary screen for drugs that require presynaptic amine storage to rescue larval locomotion. Using additional larval locomotion and adult fertility assays, we validated that at least one compound previously used clinically as an antineoplastic agent potentiates the presynaptic function of aminergic circuits. We suggest that structurally similar agents might be used to development treatments for PD, depression and ADHD, and that modifier screens in Drosophila provide a new strategy to screen for neuropsychiatric drugs. More generally, our findings demonstrate the power of physiologically based screens for identifying bioactive agents for select neurotransmitter systems.
Subject(s)
Antiparkinson Agents/pharmacology , Drosophila melanogaster , Drug Evaluation, Preclinical/methods , Vesicular Monoamine Transport Proteins/metabolism , Animals , Animals, Genetically Modified , Dacarbazine/pharmacology , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Female , Fertility/drug effects , Larva/drug effects , Larva/physiology , Locomotion/drug effects , Locomotion/physiology , Male , Mutation , Parkinson Disease/drug therapy , Pergolide/pharmacology , Synapses/drug effects , Vesicular Monoamine Transport Proteins/geneticsABSTRACT
Background: Hearing loss following spinal anaesthesia is a known yet uncommonly reported complication. This study was aimed at determining the incidence and type of hearing loss (HL) following spinal anaesthesia (SA) and the relationship with the size of spinal needle. Methods: A prospective study of patients scheduled for spinal anaesthesia for surgery at the Operating room and Otorhinolaryngology department in a tertiary centre was undertaken. The audiometry was done and the pre- and post - anaesthesia results were compared.Results: Ninety - four ears of 47 patients; 16 males and 31 females; age range between 21 and 63 years (mean + SD= 41+5) were included. The duration of anaesthesia was between 90 and 150 minutes (mean + SD= 116+9). HL was seen in 9 ears of 7 patients (15) and tinnitus in 14 ears. The preoperative and postoperative BC PTA were 10 - 45dB (mean + SD= 26+ 5) and 25 - 65dB (mean + SD=38+5) respectively; (P= 0.02) while the preoperative and postoperative AC PTA in the early frequency range (0-100Hz) were between 5 - 45dB (mean + SD= 20+ 5) and 25 - 50dB (mean + SD=25+7) respectively; (P= 0.08). There was significant difference in the mean BC PTA between those who had procedure less than 1 hour; 37.2dB and those greater than 1 hour 38.4dB; (P=0.004). According to the Quincke needle sizes; the mean BC PTA among those who had 26G and 27G were 37.4dB and 38.1dB respectively (P=0.2). Conclusion: HL complicating SA is significant and associated with duration of procedure thus should be included in informed consent for medico-legal and ethical reasons and measures must be taken to avoid the leak of cerebrospinal fluid
