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

Abstract

The D3 dopamine receptor is expressed primarily in limbic brain areas, and appears to play an inhibitory role in rodent locomotor behavior. Evidence suggests a potential role for the D3 receptor in the pathology of neuropsychiatric disease. Progress in elucidating D3 receptor function has been hampered, however, by a lack of well-characterized, selective ligands and by conflicting information regarding the behavioral phenotype of D3 receptor knockout mice. Here, we describe studies evaluating the behavioral effects of ( 7 )-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) and PD 128907, two D3 receptor agonists whose in vivo selectivity has been a topic of considerable controversy. We demonstrate that both compounds inhibit locomotion under novel environmental conditions in wild-type (WT) mice, but are without measurable behavioral effect under identical conditions in D3 receptor knockout mice. Additionally, we demonstrate that at low, D3 selective doses, these compounds are without behavioral effect in both WT and D3 receptor knockout mice that have acclimated to the testing environment. These findings suggest that D3 receptor stimulation inhibits novelty-stimulated locomotion, and establish conditions for the use of 7-OH-DPAT and PD 128907 as D3 receptor agonists in vivo. Potential implications of these observations are discussed.

Effects of a Dopamine D3 Receptor Ligand, BP 897, on Acquisition and Expression of Food-, Morphine-, and Cocaine-induced Conditioned Place Preference, and Food-seeking Behavior in Rats

“…In fact, D 3 R-preferring agonists may exhibit biphasic effects on place conditioning. For instance, in the range of very low doses claimed to be D 3 -selective (Pritchard et al, 2003), 7-OH-DPAT supported CPA, whereas CPP occurred at larger doses (Chaperon and Thiébot, 1996). It has been proposed that these agonists induce CPA by activating inhibitory D 3 (or D 2 ) autoreceptors, thereby reducing DA outflow, and CPP when they also stimulate postsynaptic D 2 R (Chaperon and Thiébot, 1996).…”

Dose–response analysis of locomotor activity and stereotypy in dopamine D3 receptor mutant mice following acute amphetamine

“…The genetic backgrounds of both mutant and wild-type mice are C57BL/6 × 129Sv, and mice have subsequently been backcrossed for three generations with inbred C57BL/6 mice to reduce the number of 129Sv-linked genes to 12.5% (Silver, 1995). Adult (8-12 weeks) male mice used in the present study were genotyped by PCR using DNA extracted from tail clips, as previously described (Pritchard et al, 2003). Experimental animals were housed with same sex siblings with 4-5 animals per cage in SPF Murine Facilities maintained on a 12:12 light:dark cycle.…”

“…Horizontal locomotor activity was monitored with a 16 × 16 photo beam array (San Diego Instruments, San Diego, CA) located 1.25 cm above the floor of the enclosure, as previously described (Pritchard et al, 2003). An air evacuation fan in each enclosure provided constant air circulation and background noise.…”

“…All mice were first acclimated to the activity chamber for 1 h prior to injections, and locomotor activity was recorded for 3 h following drug administration. Locomotor activity is expressed as crossovers, defined as entry into any of the active zones of the chamber, as previously described (Pritchard et al, 2003). Mice were randomly distributed to each treatment group, with saline-and AMPH-treated mice run in parallel.…”

“…Dopaminergic signaling in these pathways is mediated by G protein-coupled receptors grouped into two subfamilies: D1-like (D1 and D5) and D2-like (D2, D3, and D4) (reviewed in Missale et al, 1998). Accumulating evidence from pharmacological studies suggest that D3R stimulation is inhibitory to spontaneous and psychostimulant-induced locomotion, in opposition to concurrent D1R-and D2R-mediated signaling (Carr et al, 2002;De Boer et al, 1997;Ekman et al, 1998;Kling-Petersen et al, 1995;Ouagazzal and Creese, 2000;Pritchard et al, 2003;Waters et al, 1993;Xu et al, 1997;Zhang et al, 2004). A clear understanding of D3R behavioral functions has been limited, however, by the limited selectivity of D3R agonists and antagonists.…”