Attention deficit, hyperactive disorder (ADHD) is a childhood cognitive disorder characterized by inattentiveness and/or hyperactivity and impulsiveness. The most effective treatment for ADHD is chronic low dose administration of amphetamine (AMPH)-like stimulants such as methylphenidate. All of these agents have prominent effects on monoaminergic neurotransmission yet little is known regarding the specific mechanism(s) through which they exert their therapeutic action in ADHD. Almost all of our information concerning AMPH-like stimulants derives from drug abuse studies which employ doses far in excess of those used clinically. Furthermore, there are profound dose and drug-specific differences in AMPH-like stimulant actions on monoaminergic neurotransmission. The central tenet of the proposal is that it is inappropriate to postulate therapeutic mechanisms of action for AMPH-like stimulants on the basis of animal studies of drug abuse. Moreover, a better understanding of the therapeutic actions of these drugs is needed in order to develop pharmacological treatments that do not possess the negative properties of AMPH-like stimulants (e.g. unwanted behavioral side effects, long term toxicities, abuse potential). The goal of the proposed study is to develop methodologies for evaluating the effects of therapeutically-relevant doses of methylphenidate on: 1) catecholaminergic neurotrasmission, 2) the impact of acute and chronic low dose stimulants on sensory processing, sensory detection and attention, 3) the receptor mechanism involved in stimulant-induced alterations in sensory processing, sensory detection and attention, and 4) the long-term consequences of low dose stimulants on a variety of physiological and behavioral processes in developing animals. The major techniques to be employed here include gas chromotography for determining plasma levels of methylphenidate, microdialysis for determining plasma levels of methylphenidate, microdialysis for determining catecholamine levels in specified brain regions, EEG and EMG for identifying behavioral states of arousal, multi-channel many neuron recording in cerebral cortex, thalamus and locus coeruleus for characterizing patterns of neural discharge in awake behaving rats, and computer based analysis of many neuron spike train data. These studies will fill a significant gap in our understanding of therapeutic actions of AMPH-like stimulants in ADHD.
| Devilbiss, David M; Berridge, Craig W (2008) Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness. Biol Psychiatry 64:626-35 |
