Selective dopamine D4 receptor agonist (A-412997) improves cognitive performance and stimulates motor activity without influencing reward-related behaviour in rat.
Current therapies for attention deficit hyperactivity disorder comprise psychostimulants, which block the dopamine transporter and/or stimulate the release of dopamine, leading to a global elevation in extrasynaptic dopamine. These drugs are, however, associated with a series of unwanted side effects such as insomnia, anorexia, headache, stomach problems and potential drug abuse. Recent evidence suggests that the dopamine D4 receptor may represent a selective dopamine target that could mediate cognitive as well as striatal motor processes. In this study we compare the effects of a selective D4 receptor agonist, A-412997, with methylphenidate or amphetamine in preclinical models of efficacy versus abuse liability. Both methylphenidate and A-412997 improved a temporally induced deficit in the rat novel object recognition task at doses 10-fold lower than those stimulating activity. In both cases, procognitive doses were associated with elevated extracellular levels of dopamine and acetylcholine in the medial prefrontal cortex. In contrast to amphetamine, A-412997 did not mediate reward-related behaviour in the conditioned place preference paradigm, a preclinical rodent test used to assess potential abuse liability. Collectively, these data suggest that selective activation of the D4 receptor may represent a target for the treatment of attention deficit hyperactivity disorder without the potential drug abuse liability associated with current psychostimulant therapies.
Woolley
Marie L
ML
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline plc, New Frontiers Science Park, Harlow, Essex, UK. marie.2.woolley-roberts@gsk.com
Waters
Kerry A
KA
Reavill
Charlie
C
Bull
Sharlene
S
Lacroix
Laurent P
LP
Martyn
Abbe J
AJ
Hutcheson
Daniel M
DM
Valerio
Enzo
E
Bate
Simon
S
Jones
Declan N C
DN
Dawson
Lee A
LA
D000081:Acetamides / Q000494:pharmacology*; D000109:Acetylcholine / Q000378:metabolism; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D045604:Extracellular Fluid / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy; D008774:Methylphenidate / Q000494:pharmacology; D017551:Microdialysis / Q000379:methods; D009043:Motor Activity / Q000187:drug effects*; D010364:Pattern Recognition, Visual / Q000187:drug effects; D010775:Photic Stimulation; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050638:Receptors, Dopamine D4 / Q000819:agonists*; D012201:Reward
C506999:2-(3',4',5',6'-tetrahydro-2'H-(2,4') bipyridinyl-1'-yl)-N-m-tolyl-acetamide; D000081:Acetamides; D018491:Dopamine Agonists; D011725:Pyridines; D050638:Receptors, Dopamine D4; D008774:Methylphenidate; D000661:Amphetamine; D000109:Acetylcholine; D004298:Dopamine