Effects of the selective dopamine D3 receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice

Dopamine D3 Receptor Modulates Akt/mTOR and ERK1/2 Pathways Differently during the Reinstatement of Cocaine-Seeking Behavior Induced by Psychological versus Physiological Stress

“…It has been reported that SB-27011-A administration does not alter spontaneous or stimulant-induced locomotion in basal conditions [ 66 ]. Furthermore, other D3R-selective-antagonist administrations to mice at doses that inhibited drug-seeking behaviors and drug-induced hyperlocomotion have been reported to not modify locomotor activity of mice in the absence of the abused substance [ 25 , 67 , 68 , 69 ]. Similarly, we observed lower locomotor activity during the reinstatement test of tail-pinch-induced cocaine-CPP after the administration of SB-277011-A.…”

“…Thus, it is highly improbable that the decreased activity observed after SB-277011-A administration is be due to the antagonism of D2 receptors. As stated above, as opposed to D2 antagonists, SB-277011-A (up to 90 mg/kg, PO) and other selective D3R blockers failed to affect spontaneous locomotion [ 25 , 67 , 68 , 69 ] and did not provoke catalepsy [ 66 ] or sedation [ 72 ]. In agreement with this, Reavill et al [ 73 ] reported that this antagonist was non-cataleptogenic and did not raise plasma prolactin levels at doses up to 78 mg/kg of the antagonist.…”

Arrestin-3 agonism at D3 dopamine receptors defines a subclass of second generation antipsychotics that promotes drug tolerance

“…While more prevalent with first-generation antipsychotics, SGAs can also cause locomotor effects, including dystonia and parkinsonism in humans (Casey, 2006;Divac et al, 2014) and locomotor inhibition in mice (Hoffman and Donovan, 1995). While both effects are traditionally thought to be mediated through D2R binding (Divac et al, 2014;Tarsy et al, 2002), mounting evidence suggests that D3R may also be important for locomotion and the locomotor effects of SGAs (Accili et al, 1996;Banasikowski and Beninger, 2012;Botz-Zapp et al, 2021;Bristow et al, 1996;Gyertyán and Sághy, 2004;Kiss et al, 2021;Millan et al, 2004Millan et al, , 1997Segman et al, 1999;Steen et al, 1997;Svensson, 1994;Waters et al, 1993). Individual SGA have variable degrees of locomotor side effects.…”

Pharmacological and Physicochemical Properties Optimization for Dual-Target Dopamine D3 (D3R) and μ-Opioid (MOR) Receptor Ligands as Potentially Safer Analgesics

“…For example, recent drug candidates (±)-1 and ( R )-2 (Figure ), two highly selective D 3 R antagonists, both decrease oxycodone drug-seeking and self-administration without decreasing anti-nociception, and importantly, without affecting peripheral biometric cardiovascular parameters when administered alone or in the presence of oxycodone or cocaine. Also, (±)-1 decreases dose escalation of opioid self-administration in both male and female rats and reduces the acquisition of drug seeking behavior. − These data have supported the preclinical development of these and other related compounds for not only the treatment of OUD, but potential prevention of opioid dependence, if administered with a prescription opioid for pain management. ,, These observations have supported drug development campaigns toward combination treatments with opioid analgesics, or potentially with methadone or buprenorphine, to improve their efficacy in preventing relapse and minimizing the possibility of cardiovascular or other opioid-driven side effects. Furthermore, achieving D 3 R subtype selectivity over D 2 R may limit extrapyramidal side effects, locomotor impairments, and metabolic disorders, associated with D 2 R antagonism, − improving their tolerability and compliance in this patient population. …”

“…12−14 These data have supported the preclinical development of these and other related compounds for not only the treatment of OUD, but potential prevention of opioid dependence, if administered with a prescription opioid for pain management. 13,15,16 These observations have supported drug development campaigns toward combination treatments with opioid analgesics, or potentially with methadone or buprenorphine, to improve their efficacy in preventing relapse and minimizing the possibility of cardiovascular or other opioid-driven side effects. Furthermore, achieving D 3 R subtype selectivity over D 2 R may limit extrapyramidal side effects, locomotor impairments, and metabolic disorders, associated with D 2 R antagonism, 17−20 improving their tolerability and compliance in this patient population.…”