The purinergic P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2 ' 4'-disulphonic acid prevents both the acute locomotor effects of amphetamine and the behavioural sensitization caused by repeated amphetamine injections in rats

Repeated administration of amphetamine-like psychostimulants produce a prog ressive and long-lasting hypersensitivity to their behavioural effects know n as behavioural sensitization,(10) Previous studies have shown that admini stration of the purinergic P2 receptor agonist 2-methylthio ATP into the nu cleus accumbens of rats raises the extracellular level of dopamine(14) acco mpanied with enhanced locomotion(12) in a similar manner. Furthermore, the quantitative EEG after application of 2-methylthio ATP or amphetamine was c haracterized by an elevation of the alpha1-power.(13,20) However, purinergi c P2 receptor antagonists decreased the basal level of dopamine in the NAc and in addition prevented the effects of 2-methylthio ATP.(12,14) The purpo se of the present study was to investigate, whether endogenous ATP acting v ia purinergic P2 receptors is involved in the process of amphetamine-induce d sensitization. Rats were treated systemically for five successive days wi th d-amphetamine (1.5 mg/kg) and tested in an open field with respect to th eir locomotor response. The enhanced locomotor activity after the first inj ection of amphetamine,vas diminished by the previous intracerebroventricula r application of the purinergic P2 receptor antagonist pyridoxalphosphate-6 -azophenyl-2'4'-disulphonic acid (PPADS; 0.6 nmol) (P < 0.05). The challeng e with a lower dose of amphetamine (0.75 mg/kg) produced an increased locom otion in comparison to the response after the first amphetamine application indicating the expression of a behavioural sensitization. Pretreatment wit h PPADS prior to each amphetamine administration prevented the increase of locomotor activity after the challenge with amphetamine (P < 0.05). In summ ary, the present study demonstrates that PPADS blocks both the acute locomo tor effects of amphetamine and the development of behavioural sensitization to the psychostimulant. We suggest that the activation of purinergic P2 re ceptors by endogenous ATP is necessary for the expression of these effects. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.