Abstract
Interactions between adenosine A2A and dopamine D2 receptors are thought to be involved in morphine and cocaine-induced addictive responses. The aim of this thesis was to further investigate the involvement of the adenosine A2A receptor in morphine and cocaine addiction. Using electrophysiology, D2 receptor function was studied in ventral tegmental area dopamine cells in CD1 wildtype and A2A receptor knockout mice. Responses to the D2 receptor agonist, quinpirole, were significantly reduced in A2A receptor knockout mice.Conditioning, extinction and reinstatement to morphine or cocaine were studied in CD1 wildtype and A2A receptor knockout mice and C57BL/6 mice. Reliable conditioning to either morphine or cocaine could not be established in CD1 mice; however significant conditioning, extinction and reinstatement could be induced following morphine or cocaine treatment in C57BL/6 mice. No significant difference in the qualitative binding or functional activation of u-opioid receptors in the ventral tegmental area and substantia nigra of CD1 and C57BL/6 mice were observed. The dopaminergic profile was studied in the brains of the CD1 mice that responded or did not respond to cocaine-induced conditioning studies. There was no difference in dopamine transporter binding and dopamine D2 G-protein activity between responders and non-responders. Significantly lower levels of D1 and D2 receptor binding was observed in the caudate-putamen of responders. Chronic ‘binge’ cocaine administration was studied in wildtype and A2A receptor knockout mice. Data collection and sample analysis were compromised in these studies allowing only qualitative comparisons. The results obtained indicated that wildtype mice treated with cocaine for 14 days showed an increase in ambulatory activity as well as an increase in extracellular dopamine released from the nucleus accumbens. These findings confirm the importance of interactions between the adenosinergic and dopaminergic systems during addictive processes and also highlight the importance of strain differences when studying behavioural responses.