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The role of the adenosine A2A receptor in NAc dopamine release and morphine reward
Adenosine A2A receptors show restricted localisation to the dopamine rich areas of the brain, such as the nucleus accumbens (NAc), which has implications for the reward circuitry of addiction. Adenosine A2A receptor knockout mice show alterations in addictive behaviours, including reduced cocaine self administration, the a bolition of cannabinoid reward, i ncreased signs of morphine withdrawal, an increase in functional activity of MOP receptors and a reduction in dopamine D 2 function in the ventral tegmental area (Berrendero et al, 2003; Bailey et al, 2004; Soria et al, 2004, 2006; Al-Hasani et al, 2006). The aim of this study was to investigate further addictive responses to morphine , using male CD1 wildtype and adenosine A2A receptor knockout mice, aged 8-12 weeks. We studied morphine-induced conditioned place preference (CPP) at doses of 5 and 10mg/kg (s.c). Microdialysis was used to measure in vivo dopamine release in freely moving mice, during the acute administration of morphine and cocaine (20 mg/kg, s.c). Locomotor activity was also recorded during these studies. Although the CPP experiments were repeated under various conditions and doses of morphine (5 and 10mg/kg), neither the wildtype or the adenosine A2A receptor knockout mice showed any reliable increase in their preference for the morphine-paired chamber after conditioning. There was, however, an increase in locomotor activity induced by morphine (10mg/kg) in both genotypes (two-way ANOVA, P<0.05 for treatment effect, n=9-11). No detectable dopamine release was found in the NAc following acute treatment with morphine (20mg/kg). Dopamine was released in the NAc in response to cocaine (20mg/kg) and this was significantly lower in the knockout mice than in the wildtype (P<0.05, Duncan’s post-hoc test n=5-7). Cocaine also caused an increase in locomotor activity in both genotypes, with the increase in small local movements being greater in the wildtype than in the adenosine A 2A receptor knockout mice, while the increase in ambulatory distance travelled was greater in the adenosine A 2A receptor knockout mice than in the wildtype mice (P<0.05, Duncan’s post-hoc test, n=5-7). In conclusion, no reliable morphine conditioning was found in CD1 mice and there was no detectable morphine-induced DA release in the NAc. However, morphine did increase locomotor activity. There was robust cocaine-induced dopamine release in the NAc, which was also accompanied by an increase in locomotor activity and these responses were altered in adenosine A2A receptor knockout mice. These findings suggest that CD1 mice are insensitive to the rewarding effects of morphine.
Al-Hasani R, et al (2006) http://www.pa2online.org/abstracts/Vol4Issue2abst035P.pdf |
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