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| 115P London, UK Pharmacology 2016 |
The effect of metergoline on D amphetamine induced depression of visual activity in the Superior Colliculus
Introduction The use of psychostimulants for efficacious treatment of attention deficit hyperactivity disorder (ADHD) has been criticised based on the vulnerability of the ADHD population to both medication diversion and medication abuse (1). There is a need to develop new non-addictive ADHD interventions, where the first step is to elucidate the mechanism of action of current psychostimulant medication. Potential therapeutic targets of psychostimulants include the superficial layers of the superior colliculus (SC). D-amphetamine depresses visual responses in the superficial SC in vivo (2), which in-vitro evidence has shown to be reversed following local application of a serotonin (5-HT) antagonist (3). The present study aims to investigate whether D-amphetamine depression of SC visual responses in vivo is mediated by 5-HT.
Methods Hooded lister rats (control n = 8; experimental n = 8) were anaesthetised with a split-dose injection of urethane (ethyl carbonate as a 25% aqueous solution; 5ml/kg IV). Cannulation surgery was performed on the left femoral vein to allow for the later injection of metergoline (3.0mg/ml in 60% Dimethyl sulfoxide (DMSO) 40% distilled water; experimental group) or 60% DMSO (control group). Unilateral craniometry was performed to expose the cortex overlaying the right SC. A microelectrode and coupled microinjector loaded with D-amphetamine (10mg/ml in 0.1 ml/kg 0.9% saline) was lowed through the cortex overlaying the SC until the SC was encountered. Pre-drug baseline visual response to 150 whole field light flashes (contralateral to SC electrode) was obtained (0.5hz, 10ms duration, 2s stimulus separation). Response to 150 whole field light flashes were then recorded following local injection of 1µl D-amphetamine and again following systemic IV injection of 0.7:1mg/kg metergoline.
Results D-amphetamine application resulted in a dose dependent depression of the peak amplitude of visual activity for both groups. The depression was reversed following the introduction of metergoline (pre-amphetamine activity compared to post metergoline: t=0.643; p=0.266) but not by the introduction of DMSO (pre-amphetamine activity compared to post DMSO: t=5.539; p<0.001).
Conclusion Collicular response to visual stimuli was depressed following local introduction of D-amphetamine. This depression was reversed to pre-drug levels following the systemic antagonism of 5-HT. Future studies will assess more selective 5-HT antagonists to elucidate if a focus on 5-HT drugs may be a useful route to developing non addictive alternative therapies for ADHD.
References 1. Greydanus et al., (2007). Dis Mon 53: 70-131 2. Gowan et al., (2008) J.Neural Transm 115: 377-387 3. Dommett et al., (2009) Neuroscience 164: 1369-1376