Dopamine D3 receptor ligands show place conditioning effect but do not influence cocaine-induced place preference

Abstract

The importance of dopamine D3 receptors in reward related processes, especially in cocaine addiction, has been investigated extensively. However, in the reported studies a combination of different experimental conditions and different ligands have been used which renders the interpretation and comparison of the diverse results extremely difficult. Here, we report one comparative study investigating a wide range of dopamine D3 receptor ligands in one model of cocaine abuse: the place conditioning paradigm in rats. Of the antagonists tested, the moderately D3 selective nafadotride and the more selective SB-277011 did not produce any place conditioning effect while U-99194A caused place-preference. The most D3 selective agonist PD-128907, the less selective 7-OH-DPAT and the moderately selective partial agonist BP-897 all caused significant place aversion. None of the compounds influenced the cocaine-induced place preference. Results suggest the D3-preferring agonists could affect the reward mechanisms of the brain, however, modulation of D3 receptor function does not appear to be a significant mechanism for modifying the place conditioning effect of cocaine.

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

“…However, in other studies, U-99194A has been shown to support CPP (Kling-Petersen et al, 1995;Gyertyán and Gál, 2003). On the other hand, numerous convergent studies indicated that distinct to BP 897, D 3 R full agonists shared with D 1 /D 2 nonselective and D 2 selective agonists the capacity to establish CPP (Hoffman and Beninger, 1988;Papp, 1988;Mallet and Beninger, 1994;Kling-Petersen et al, 1995;Khroyan et al, 1997), although some inconsistencies also exist in this respect (Rodríguez de Fonseca et al, 1995;Khroyan et al, 1997;Gyertyán and Gál, 2003). In fact, D 3 R-preferring agonists may exhibit biphasic effects on place conditioning.…”

“…In keeping with a study showing that BP 897 reduced the discriminative stimulus effect of cocaine in mice (Beardsley et al, 2001), the present results suggest that this D 3 R partial agonist attenuated the perception of the appetitive value of cocaine by rats. By contrast, Gyertyán and Gál (2003) reported no blockade of the establishment of cocaine (10 mg/kg) CPP by BP 897 (0.5-1 mg/kg). With regard to antagonists, SB-277011-A (1-10 mg/kg), injected at either the acquisition or the expression phase, abolished cocaine (15 mg/kg) CPP (Vorel et al, 2002), and the D 2-like R antagonist, haloperidol (0.03-0.1 mg/kg), impaired the expression of cocaine (10 mg/kg) CPP (Adams et al, 2001).…”

“…This result is in keeping with data from self-administration and drug discrimination studies, showing that BP 897 has no positive appetitive value and does not share the stimulus effects of psychostimulants (Pilla et al, 1999;Beardsley et al, 2001). On the contrary, a trend towards conditioned place avoidance (CPA) was observed, an effect also obtained at the same dose (1 mg/kg) by Gyertyán and Gál (2003), whereas, in mice, BP 897 was reported to induce neither CPP nor CPA (Francès et al, 2003). Preclamol, a partial agonist at D 2 autoreceptors, and the D 3 R antagonists, l-nafadotride (B10-fold selective for rat D 3 R over D 2 R, in vivo (Griffon et al, 1995)), U-99194A (B20-fold selective for D 3 R vs D 2 R expressed in CHO cells (Waters et al, 1993)), and SB-277011-A (4100-fold selective for rat D 3 R over D 2 R expressed in CHO cells (Reavill et al, 2000)), seem devoid of incentive properties (Chaperon and Thiébot, 1996;Kivastik et al, 1996;Boyce and Risinger, 2002;Vorel et al, 2002;Gyertyán and Gál, 2003).…”

“…With regard to antagonists, SB-277011-A (1-10 mg/kg), injected at either the acquisition or the expression phase, abolished cocaine (15 mg/kg) CPP (Vorel et al, 2002), and the D 2-like R antagonist, haloperidol (0.03-0.1 mg/kg), impaired the expression of cocaine (10 mg/kg) CPP (Adams et al, 2001). However, other studies reported no reduction of cocaine CPP by SB 277011-A (5-20 mg/kg), PNU 99194A (12-24 mg/ kg), and nafadotride (1 mg/kg), given at the conditioning phase (Gyertyán and Gál, 2003), raclopride (0.03-0.1 mg/kg, pretest) (Adams et al, 2001), and sulpiride (50-100 mg/kg, preconditioning or pretest) (Cervo and Samanin, 1995). Likewise, agonists may apparently exert variable effects.…”

“…Preclamol, a partial agonist at D 2 autoreceptors, and the D 3 R antagonists, l-nafadotride (B10-fold selective for rat D 3 R over D 2 R, in vivo (Griffon et al, 1995)), U-99194A (B20-fold selective for D 3 R vs D 2 R expressed in CHO cells (Waters et al, 1993)), and SB-277011-A (4100-fold selective for rat D 3 R over D 2 R expressed in CHO cells (Reavill et al, 2000)), seem devoid of incentive properties (Chaperon and Thiébot, 1996;Kivastik et al, 1996;Boyce and Risinger, 2002;Vorel et al, 2002;Gyertyán and Gál, 2003). However, in other studies, U-99194A has been shown to support CPP (Kling-Petersen et al, 1995;Gyertyán and Gál, 2003). On the other hand, numerous convergent studies indicated that distinct to BP 897, D 3 R full agonists shared with D 1 /D 2 nonselective and D 2 selective agonists the capacity to establish CPP (Hoffman and Beninger, 1988;Papp, 1988;Mallet and Beninger, 1994;Kling-Petersen et al, 1995;Khroyan et al, 1997), although some inconsistencies also exist in this respect (Rodríguez de Fonseca et al, 1995;Khroyan et al, 1997;Gyertyán and Gál, 2003).…”