Amphetamine (AMPH)-Iike psychostimulants, such as methylphenidate, are notorious for their abuse potential but also have considerable therapeutic value in treatment of attention deficit, hyperactive disorder (ADHD). These agents have prominent effects on monoaminergic neurotransmission yet little is known regarding the specific physiological mechanism(s) through which they exert their therapeutic action in ADHD. Instead, almost all of our information concerning AMPH-like stimulants derives from drug abuse studies that employ doses far in excess of those used clinically. Identification of the mechanisms underlying AMPH-Iike stimulant action are critical for future development of compounds that have greater efficacy, less toxicity, and lower abuse liability. Recent evidence links the therapeutic actions of methylphenidate to the locus cocruleus (LC) - norepinephrine (NE) system in the brain, yet there are still many unanswered questions regarding the basic output functions of this major monoaminergic pathway. For example, much is known about the effects of exogenous NE on postsynaptic cellular targets, but there have been few comprehensive studies of the impact of LC-mediated NE-release on the operation of cells, circuits and neural networks that receive LC efferent projections. With these considerations in mind the present proposal establishes three major goals. The first is to show that activation of the LC efferent pathway can exert NE-like modulatory actions on signal processing functions of individual thalamic and cortical sensory neurons. The second is to determine how extracellular levels of NE fluctuate within sensory networks as a function of LC output. The third is to determine how low dose methylphenidate affects LC-mediated modulation of thalamic and cortical sensory neuron responses to synaptic input. These studies will use the rat trigeminal somatosensory system as a model and will employ microdialysis and HPLC-EC detection methods for NE, multi-channel, multi-neuron recording procedures in awake and anesthetized rats, tactile and electrical stimulation of the trigeminal somatosensory pathway, and electrical and chemical activation of the LC efferent path. By characterizing the effect of LC output on sensory neuron response properties and by clarifying the relationship between LC discharge and NE release in sensory pathways, it will be possible to begin predicting how signal processing through sensory networks are altered under conditions, such as arousal and sustained attention, where output from the LC efferent system is increased. This work will not only fill a large gap between the results of direct NE application studies and predictions of LC efferent actions but will also provide a solid framework for evaluating the effects of AMPH-Iike stimulants in sensory circuit operations and ADHD treatment.
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