Receptor Crosstalk: Characterization of Mice Deficient in Dopamine D1 and Adenosine A2A Receptors

Abstract

Here we report the development of D 1 A 2A receptor knockout mice to investigate whether interactions between dopamine D 1 and adenosine A 2A receptors participate in reward-related behavior. The combined deletion of D 1 and A 2A receptors resulted in mice with decreased weight and appetitive processes, reduced rearing and exploratory behaviors, increased anxiety, and a significantly poorer performance on the rotarod, compared to wild-type littermates. D 1 A 2A receptor knockout mice shared phenotypic similarities with mice deficient in D 1 receptors, while also paralleling behavioral deficits seen in A 2A receptor knockout mice, indicating individual components of the behavioral phenotype of the D 1 A 2A receptor knockout attributable to the loss of both receptors. In contrast, ethanol and saccharin preference in D 1 A 2A receptor knockout mice were distinctly different from that observed in derivative D 1 or A 2A receptordeficient mice. Compared to wild types, preference and consumption of ethanol were decreased in D 1 A 2A receptor knockout mice, the reduction in ethanol consumption greater even than that seen in D 1 receptor-deficient mice. Preference and consumption of saccharin were also reduced in D 1 A 2A receptor knockout mice, whereas saccharin preference was similar in wild-type, D 1 , and A 2A receptor knockout mice. These data suggest an interaction of D 1 and A 2A receptors in the reinforcement processes underlying the intake of rewarding substances, whereby the A 2A receptor seems involved in goal-directed behavior and the motor functions underlying the expression of such behaviors, and the D 1 receptor is confirmed as essential in mediating motivational processes related to the repeated intake of novel substances and drugs.

A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement vs Opiate-Seeking Behavior

“…A functional hypodopaminergic state exists in A 2A knockout mice (Dassesse et al, 2001) and two studies have demonstrated increased expression of D 1 and D 2 mRNA in the striatum of these mice (Dassesse et al, 2001;Short et al, 2006b), a finding consistent with models of decreased dopaminergic function (Fang et al, 1997;Smith et al, 1997). A decreased dopaminergic state would be in line with decreased reward in A 2A receptor knockout mice.…”

“…For example, the adenosine A 2A receptor agonist CGS 21680 induces catalepsy and this is counteracted by administration of the D 2 antagonist BHT-920 (Ferre et al, 1991b). In addition to direct interactions with the dopamine D 2 receptor, A 2A receptors have been shown to interact indirectly with dopamine D 1 receptors to regulate D 1 -mediated behavioral and cellular effects (Pollack and Fink, 1996;Pinna et al, 1996;Svenningsson et al, 1998;Short et al, 2006b).…”

“…Adenosine, via A 2A receptors, modulates behaviors associated with acute and chronic exposure to cannabinoids (Soria et al, 2004), psychostimulants (Chen et al, 2000;Soria et al, 2006), nicotine , and alcohol (Arolfo et al, 2004;Short et al, 2006b). The bulk of evidence to date concerning adenosine involvement in opiate reward centers on opiate withdrawal.…”

Central PGE2exhibits anxiolytic-like activity via EP1and EP4receptors in a manner dependent on serotonin 5-HT1A, dopamine D1and GABAAreceptors

“…The anxiolytic-like activity of PGE 2 is associated with the activation of serotonin 5-HT 1A , dopamine D 1 and GABA A receptors Next, we investigated mediators associated with the anxiolyticlike activity of PGE 2 . Serotonin 5-HT 1A , dopamine D 1 and GABA A receptors are known to be involved in anxiolytic-like activity in animals and humans [21,[23][24][25]; thus, we investigated whether these receptors were involved in the anxiolytic-like activity of PGE 2 using antagonists for them.…”

Electroconvulsive therapy: a novel hypothesis for the involvement of purinergic signalling

“…ADO is also thought to interact with other potent mood regulators: the psychotomimetic phencyclidine and alcohol [10]. ADO and dopamine receptors share an extensive co-localisation within the forebrain regions implicated in mood and motivational processes, and there is considerable evidence that A 2A receptor activation is able to influence dopaminergic function [36] and hence mediate goal-directed behaviour [37]. There is attenuation of psychostimulantinduced behavioural responses in mice lacking A 2A receptors [38].…”