Neuroanatomical Localization of the Dopaminergic Modulation of Clock Speed

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DESCRIPTION (provided by applicant): The perception of time in the seconds to minutes range, interval timing, is fundamental to behavior. Alterations in temporal perception result from the acute and chronic administration of a variety of drugs, and such alterations may play a part in the use and abuse of these drugs. For instance, dopaminergic drugs of abuse, such as methamphetamine and cocaine, cause alterations in the perception of time, such that time feels as though it is passing more slowly. This effect has been associated with an increase in the speed of an internal clock used for timing and time perception. Understanding the psychological and neural mechanisms of interval timing, as well as the changes brought on by drug use, may provide important insights into the range of processes that underlie drug use. For instance, understanding where and how dopamine is altering the perception of time may allow development of specific treatment strategies. While previous work has suggested a role for cortico-striatal-thalamic loops in interval timing, the specific computations performed by these brain structures remain unknown. A recent model of interval timing has proposed that cortical activity serves as the source of a temporal signal that is integrated by the striatum in order to estimate time. As dopaminergic drugs can directly alter neural activity in both cortical and striatal regions, it remains unclear where in the brain these drugs are exerting their effects. The current proposal will determine the location(s) in which dopamine modulates the speed of the internal clock. Specifically, we propose to microinject pharmacological agents that will increase or decrease the activity of the primary dopaminergic nuclei of the midbrain, (i.e., the substantia nigra and/or ventral tegmental area), and investigate the effects of these alterations on interval timing. These effects will be evaluated by training subjects to respond at specific times for food reinforcement, and evaluating the change in response times following drug administration into specific brain regions. Following an assessment of the effects of acute administration, the impact of chronic infusion of pharmacological agents into these nuclei will be assessed, as previous work using chronic systemic administration has shown that organisms adapt to a continually altered perception of time. By evaluating where these adaptations to chronic alterations in clock speed occur, we will better understand whether timing processes follow similar adaptation patterns as drug reinforcement and locomotor behaviors. Drugs of abuse have been shown to alter the perception of time in both an acute and chronic fashion. Determining the neural locations of these changes in timing, as well as their adaptation following chronic use will provide important information regarding the array of neural changes involved in the use, abuse, and dependence of drugs.