Adenosine and dopamine receptors interact in the CNS to modulate behaviour, including sensorimotor gating. Prepulse inhibition (PPI) has been suggested to be an operational measure of sensorimotor gating. PPI and startle habituation are disrupted in patients with schizophrenia. In experimental animals, both parameters are modulated by dopaminergic and adenosine receptor agonists and antagonists. In the present study, we measured PPI and startle habituation in mice that lack functional adenosine A(2A) receptors. Startle amplitudes, startle habituation and PPI were significantly reduced in mice homozygous null for the adenosine A(2A) receptor (A(2A)(-/-)). In addition, differential effects of amphetamine and MK-801 on startle amplitude, startle habituation and PPI were observed between A(2A)(-/-) and wildtype controls. These data support the involvement of adenosine A(2A) receptors in regulation of PPI and startle habituation.