Cholecystokinin modulates cocaine -evoked dopamine release via CCK-A and CCK-B receptors in rat striatum.
Item
-
Title
-
Cholecystokinin modulates cocaine -evoked dopamine release via CCK-A and CCK-B receptors in rat striatum.
-
Identifier
-
AAI3063855
-
identifier
-
3063855
-
Creator
-
Loonam, Thomas Michael.
-
Contributor
-
Adviser: Jesus A. Angulo
-
Date
-
2002
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Biology, Neuroscience
-
Abstract
-
The dopamine system has been the focus of much research during the past 30 years, mainly because alterations in dopamine transmission are involved, directly or indirectly in several brain dysfunctions. Cocaine has been well established as an indirect dopamine agonist by means of binding to the dopamine transporter (DAT) and blocking synaptic dopamine from being transported into the terminal. Using in vivo microdialysis, we assessed the effects of three treatment paradigms (acute, chronic, and early withdrawal) on cocaine-evoked extracellular dopamine in the rat caudate-putamen. Repeated administration of cocaine (10 mg/kg i.p., once daily) produces a progressive augmentation in extracellular dopamine concentration. However, when daily cocaine administration was discontinued for 3 days, animals in early withdrawal displayed a decrease in extracellular dopamine in response to a cocaine challenge compared to a cocaine challenge administered in naive and chronically treated animals. The development of tolerance to cocaine-induced elevations in extracellular dopamine during early withdrawal was shown not to be a result of an increase in DAT sites as shown with receptor autoradiography. As a result of the anatomical distribution of the neuropeptide cholecystokinin (CCK) within the striatal dopaminergic system, we investigated a possible role for CCK in the development of tolerance in cocaine-evoked extracellular dopamine. By perfusing CCK-8S, CCK-A receptor antagonist L-364, 769, and CCK-B receptor antagonist L-369,293 directly into the caudate-putamen via the microdialysis probe, we assessed these effects on cocaine-evoked dopamine release. Both L-364,769 and L-369,293 elevated and CCK-8S further decreased cocaine-evoked extracellular dopamine levels, respectively. Interestingly, in naive animals, L-364,769 blocked cocaine-evoked elevations and L-369,293 increased cocaine-evoked elevations in extracellular dopamine levels. In chronically treated animals, both L-364,769 and L-369,293 elevated, while CCK-8S slightly decreased dopamine levels. Receptor autoradiography demonstrated a significant increase in binding for CCK receptors in early withdrawal animals compared to naive and chronic groups, supporting the neurochemical data obtained above. It is concluded that CCK appears to play a significant modulatory role, via both CCK-A and CCK-B receptors, in the development of tolerance in extracellular dopamine to the effects of daily cocaine administration, and also in cocaine-evoked extracellular dopamine concentrations in naive and chronically treated animals.
-
Type
-
dissertation
-
Source
-
PQT Legacy CUNY.xlsx
-
degree
-
Ph.D.
