Altered expression of adenosine A1 and A2A receptors in the carotid body and nucleus tractus solitarius of adult male and female rats following neonatal caffeine treatment

Neonatal caffeine treatment (adenosine receptor antagonist, 15 mg/kg/day, between postnatal days 3 and 12) affects respiratory patterns in adult male but not female rats as shown by an increase in the respiratory frequency in the early phase of response to hypoxia and an increase in the tidal volume in the late phase of response. Here, we tested the hypothesis that these changes are correlated with modified expression of adenosine receptors in the chemoreflex pathway. Carotid bodies, nucleus tractus solitarii, and superior cervical ganglia were collected from 3-month-old male and female rats that were either naive (not manipulated during the neonatal period) or treated with caffeine (NCT) or water (NWT) between postnatal days 3 and 12 by gavage. Western blot analysis was used to assess the expression of adenosine A1 and A2A receptors and tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis. In male rats, there was a 37% increase in the level of A2A receptor and a 17% decrease in tyrosine hydroxylase in the carotid body of NCT (p < 0.001) as compared to NWT rats. In the nucleus tractus solitarius, we found a 13% and 19% decrease in A1 receptor expression in NWT and NCT rats (p < 0.01), respectively, compared to naive rats. In the superior cervical ganglion, there was no change in A1 receptor, A2A receptor, and tyrosine hydroxylase expression. In female rats, the only changes observed were decreases of 12% and 15% in A1 receptor levels in the nucleus tractus solitarius of NWT and NCT rats (p < 0.01), respectively, compared to naive rats. We conclude that NCT induces long-term changes in the adenosine receptor system. These changes may partially explain the modifications of the respiratory pattern induced by NCT in adults. The increased expression of the adenosine A2A receptor (specific to male rats), combined with the decreased tyrosine hydroxylase expression in the carotid body, suggests that NCT affects adenosine-dopamine interactions regulating chemosensory activity.