Determination of in vivo dopamine D3 receptor selectivity for agonists and antagonists utilizing induction of yawning and hypothermia in rats

Abstract

Accurate assessment of in vivo selectivity for preferential D3 agonists and antagonists has been slowed by the absence of behaviors specifically mediated by the D3 receptor as well as the relative lack of agonists and antagonists highly selective for the D3 receptor. We have previously demonstrated that the induction of yawning behavior by D2/D3 agonists is mediated by an agonist activity at the D3 receptor while the inhibition of yawning at higher doses results from a concomitant D2 agonist activity (Collins et al., 2005). In addition to the induction of yawning behavior, all D2/D3 agonists produce significant decreases in core body temperature, an effect that has been shown to be mediated by their D2 agonist activity (Chaperon et al., 2003). We have compared several dopaminergic agonists with a wide range of in vitro D3 selectivity, including; PD-128907, quinelorane, pramipexole, 7-OH-DPAT, quinpirole, apomorphine and sumanirole with respect to their ability to induce yawning behavior and hypothermia. In addition, the D2 antagonist, L-741626, and the D3 antagonists, U99194 and PG01037 have been used to pharmacologically validate the specific involvement of the D3 and D2 receptor in yawning and hypothermia respectively. Therefore, the induction and, at higher doses, suppression of yawning in conjunction with hypothermia allows the inference of an in vivo selectivity ratio for D3 compared to D2 receptor activity. Using this analysis, pramipexole is the most selective of the agonists tested, while apomorphine is the least. Supported by USPHS grants DA00254 and F013771 through NIDA.