In recent years a dramatic rise in use of methamphetamine (MA) has prompted a serious research effort toidentify the neurobiological substrates that underlie the development of MA addiction. Despite substantialprogress, an understanding of the neurochemical systems that mediate the motivational aspects of drugseekingremains incomplete. A key example is our lack of information on the role of acetylcholine (ACh)receptors in MA addiction. A large proportion of MA addicts also self-administer the cholinergic agonistnicotine by smoking but we have only a rudimentary understanding of the role nicotinic receptors might playon the maintenance of MA addiction. To expand this understanding, we need to know how MA-seekingaffects the release of ACh and conversely, how manipulations of the cholinergic system affect MA-seekingbehaviors. To accomplish the first goal we will use microdialysis to measure ACh in the nucleus accumbens,dorsolateral striatum, hippocampus and prefrontal cortex of B6D2F1 mice that are trained to press a lever toself-administer MA through chronically implanted ICV cannulae. The results from these mice will becompared to matched controls that will receive equal amounts of MA (or vehicle) in a yoked fashion. Thisproject will provide neurochemical data on structures relevant to drug-seeking for use in other components ofthis research center.
The second aim will be to study the induction of transcription factors (ITF's) incholinergic cells, identified by co-labeling for ChAT, and terminal fields after active and passive MAadministration inB6D2Fl mice and in mice selectively bred in Scientific Component 6 for differences in MAdrinking and MA-induced locomotor sensitization. In addition to regional changes in molecular signalingevents such as ITF levels, we will measure the effect of active and passive MA on the choline uptake andvesicular ACh transporters. Finally, a third set of experiments will study the impact of brain-site specificmicroinjections of nicotinic and muscarinic drugs on the reinstatement of MA-seeking behavior in response toa stressful stimulus. These studies will address the issue of 'stressor responsivity' and the findings will bedirectly relevant to work being done in the clinical and the behavioral genetic components of the center.
Showing the most recent 10 out of 143 publications
