Dopamine D3 receptor mutant and wild-type mice exhibit identical responses to putative D3 receptor-selective agonists and antagonists

Abstract

Previous studies using a variety of drugs with different affinities for the dopamine (DA) D3 receptor suggested that this receptor is involved in regulating motor activity and hypothermia. However, the in vivo selectivity of many of these compounds has been repeatedly questioned. To examine the precise roles of the DA D3 receptor in motor activity and hypothermic responses, we used mutant mice lacking the DA D3 receptor to evaluate the in vivo effects of several putative D3 receptor-selective agonists and antagonists. Using automated photocell activity chambers, we observed that the decreases in locomotor activity produced by putative D3 receptor-selective agonists as well as increases in locomotor activity produced by putative D3 receptor antagonists are identical in D3 receptor mutant and wild-type mice. In addition, the hypothermia produced by the putative D3 receptor-selective agonist PD 128907 is identical in both groups of mice. Based on these findings, we propose that D3 receptors are unlikely to be involved in these effects and we caution that the putative D3 ligands that have been used to reach conclusions regarding the functional roles of D3 receptors lack the necessary in vivo selectivity to support such conclusions.

Comparative, Topographically-Based Evaluation of Behavioural Phenotype and Specification of D1-Like:D2 Interactions in a Line of Incipient Congenic Mice with D2 Dopamine Receptor 'Knockout'

“…Though more detailed dose-response studies are needed, these findings pertain to the controversy as to whether among D 2 -like receptors it is the D 3 or D 2 receptor, or both, which mediates putative 'autoreceptor' or inhibitory postsynaptic functions (Levant 1997). Our finding here that the action of a low dose of RU 24213 to reduce specific topographies of behaviour is attenuated in D 2 knockouts, but unaltered in their D 3 counterparts (McNamara et al 2000), as noted recently by Boulay et al (1999a,b) using other D 2 -like agonists, implicates the D 2 receptor in these effects; these findings are complementary to other behavioural and electrophysiological data which attribute to the D 2 rather than the D 3 subtype a primary role as an 'autoreceptor' on DAergic neurones or as an inhibitory postsynaptic receptor (Mercuri et al 1997;L'hirondel et al 1998;Koeltzow et al 1998;Xu et al 1999). Yet, unlike the abolition of stereotyped sniffing and ponderous locomotion in D 2 knockouts, the topographies of grooming, rearing free, rearing seated, and total rearing were reduced by higher doses of RU 24213 in a manner that did not differ between the genotypes; whether this effect involves D 3 , some other DAergic receptor, or a nonDAergic site remains to be clarified.…”

7-OH-DPAT and PD 128907 Selectively Activate the D3 Dopamine Receptor in a Novel Environment

“…First, lack of availability of suitably well-characterized selective ligands has hampered pharmacological studies. In vitro selectivity of previously available agonists and antagonists has been limited (Pugsley et al, 1995;Levant, 1997), and conflicting data regarding in vivo selectivity of these compounds has further hampered their usefulness (Daly and Waddington, 1993;Ahlenius and Salmi, 1994;Levant et al, 1996;Bancroft et al, 1998;Xu et al, 1999;Boulay et al, 1999a, b). Secondly, descriptions of the behavioral phenotype of D3 receptor knockout mice have been variable, confounding clear determination of the behavioral role mediated by the D3 receptor (Depoortere, 1999;Boulay et al, 1999b;Waddington et al, 2001).…”

“…Bars represent mean 7 SEM of total crossovers for each treatment group during the first 30 min after drug administration. particular, studies in two different laboratories using DA receptor knockout mice suggested that neither 7-OH-DPAT nor PD 128907 inhibit locomotion through selective D3 receptor stimulation (Xu et al, 1999;Boulay et al, 1999b). Both laboratories observed a similar hypolocomotor response to PD 128907 or 7-OH-DPAT in WT and D3 receptor mutant mice , while the locomotor inhibitory effect was absent in D2 receptor mutant mice (Boulay et al, 1999a).…”

“…Both laboratories observed a similar hypolocomotor response to PD 128907 or 7-OH-DPAT in WT and D3 receptor mutant mice , while the locomotor inhibitory effect was absent in D2 receptor mutant mice (Boulay et al, 1999a). Although all but one of these studies (Xu et al, 1999) employed 7-OH-DPAT doses at least 10-fold higher than the 10 mg/kg dose inhibitory to rodent locomotion in other investigations (Daly and Waddington, 1993), these results were interpreted by both laboratories as suggesting that locomotor inhibitory effects of 7-OH-DPAT, previously thought to result from D3 activation (Svensson et al, 1994), are mediated through D2 autoreceptors or other receptors.…”

“…7 -7-Hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) preferential D3/D2 binding is between 5.2-and 78-fold, depending upon assay conditions (Levant, 1997), while (+)-PD 128907 has an approximately 18-fold greater affinity for cloned D3 vs D2L receptors, with weaker affinity for cloned D4 and no significant affinity for other receptors tested (Pugsley et al, 1995). Selectivity of these compounds for D3 vs D2 receptor in vivo, however, has been a topic of much controversy (Daly and Waddington, 1993;Ahlenius and Salmi, 1994;Pugsley et al, 1995;Levant et al, 1996;Bancroft et al, 1998;Xu et al, 1999;Boulay et al, 1999a, b). Here we describe studies evaluating the behavioral effects of 7-OH-DPAT and PD 128907 in WT mice under both novel and acclimated conditions.…”