Our progress in the three years of this grant shows that microdialysis can be used in behaving animals to monitor dopamine (DA), serotonin (SER), and their metabolites during body weight changes, self-stimulation or injection of drugs. Drugs of abuse were injected systemically and locally, showing that part of the systemic effect of addictive stimulants is an action on presynaptic DA and SER terminals. Experiments were completed for publication showing increased extracellular DA with amphetamine, cocaine, phencyclidine, and nicotine. Systemic haloperidol to block DA receptors caused an acute rise in extracellular DA, but after chronic treatment, DA decreased in the striatum and prefrontal cortex. A nicotinic antagonist blocked nicotine-induced dopamine release in the NAC. Direct infusion of amphetamine by reverse dialysis gave effects like local bolus injection, suggesting that reverse dialysis could be used for self-infusion. In vitro tests showed that a peptide could also pass through the dialysis membrane. This progress suggests the feasibility of local self- infusion of amphetamine or peptides and block with selective receptor antagonists during ongoing measurement of neurotransmitters by microdialysis in the NAC and PFC. In Year 1 we propose to continue development of microdialysis applied to freely moving animals. Microdialysis will be used to measure extracellular DA and SER in the NAC during circadian activities, body weight changes, self-stimulation, and self- infusion of amphetamine. Anatomical specificity will be tested by simultaneous microdialysis in the prefrontal cortex. In Year 2 we will study the effect of locally infused peptides, CCK, neurotensin and met-enkephalin, using microdialysis to simultaneously apply the compound and measure the monoamine response. Repeated samples will be taken to measure the time course and dose-response effects of the peptides. In Year 3 we propose to study the effect of active peptides on amphetamine self-infusion and to test self-infusion of peptides alone. Year 4 will be devoted to blocking the effects of manoamines and peptides. Year 5 is for testing the effect of body weight changes on self-infusion and for assaying the release of peptides by high performance capillary electrophoresis. The uniqueness of this proposal lies in the use of in vivo microdialysis to monitor mesolimbic DA and SER output during ongoing behavior such as local amphetamine self-administration. This research will help clarify the function of selected peptides in modulating the mesolimbic DA system and their role in stimulant addiction. The significance lies (a) in discovering if rats self- titrate their extracellular DA or SER, (b) in finding the role of peptides in controlling the mesolimbic reward system, and (c) in the further development of microdialysis as a means of understanding and screening drugs of abuse.
Showing the most recent 10 out of 21 publications
