Sensorimotor gating is disrupted by acute but not chronic systemic exposure to caffeine in mice

Rationale

Caffeine is a psychostimulant drug that blocks adenosine A₁ and A_2A receptors (A₁Rs and A_2ARs). However, its ability to disrupt early sensory gating as indexed by prepulse inhibition (PPI), which is consistently disrupted by other psychostimulant agents, has never been convincingly demonstrated.

Objectives

To compare the impact of caffeine on PPI expression in C57BL/6 mice by two dose-response experiments differing in terms of chronicity, regimen, and route of administration. To study separately the acute effect of selective antagonists against A₁R or A_2AR.

Methods

Caffeine (10, 30, 100 mg/kg, intraperitoneal (i.p.)) was either administered shortly before testing or via caffeinated drinking water (0.3, 1.0, 2 g/l) in home cages over 3 weeks. Two separate dose-response studies tested the acute effect of the selective A₁R antagonist, 1,3 dipropyl-8 cyclopentyl xanthine (DPCPX), and the selective A_2AR antagonist, 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] (SCH 58261) (0.2, 1.0, 5.0 mg/kg, i.p.). The two drugs were combined in a final experiment to identify their potential synergistic interaction.

Results

While the two lower acute doses of caffeine attenuated PPI, the highest dose potentiated PPI. By contrast, chronic caffeine exposure did not affect PPI. Neither DPCPX nor SCH 58261 altered PPI, and no synergism was observed when the two drugs were combined.

Conclusions

This is the first demonstration that acute caffeine disrupts PPI, but the relative contribution of A₁R and A_2AR blockade remains unclear, and possible non-adenosinergic mechanisms cannot be ruled out. The null effect under chronic caffeine exposure might involve the development of tolerance, but the precise receptor subtypes involved also warrant further investigation.