Caffeine induces behavioural sensitization and overexpression of cocaine-regulated and amphetamine-regulated transcript peptides in mice.

This study examined whether repeated administration of caffeine would induce behavioural sensitization and overexpression of cocaine-regulated and amphetamine-regulated transcript (CART) peptides in mice. The involvement of dopaminergic receptors and adenosine receptors in caffeine-induced behavioural sensitization and CART overexpression was studied. The relevance of D₁R and D₂R, and A₁R and A(2A)R in the overexpression of CART peptides in mouse striatum was also evaluated. Repeated administration of caffeine induced behavioural sensitization in mice. Significant increases in CART mRNA levels were observed on day 3 and peaked at day 5 of caffeine administration, and then decreased gradually. Higher proportions of CART⁺ cells were observed in the dorsolateral and ventrolateral part of the caudate putamen than in the nucleus accumbens shell and core. The behavioural sensitization induced by caffeine was inhibited by dopaminergic receptor antagonists and adenosine receptor agonists. D₁R and D₂R, and cyclic AMP (cAMP)/protein kinase A (PKA)/phospho-cAMP response element-binding protein (pCREB) signalling were activated by caffeine, but A₁R and A(2A)R were inhibited. Overexpression of caffeine-induced CART peptides and pCREB activity were blocked by N-cyclopentyladenosine (CPA, an A₁R agonist) and 4-[2-[[6-amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (CGS 21680, an A(2A)R agonist), but not by R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390, a D₁R antagonist) or raclopride (a D₂R antagonist). Caffeine-induced overexpression of CART peptides was associated with the inhibition of A₁R and A(2A)R, and the activation of cAMP/PKA/pCREB signalling. Moreover, the A(2A)R-D₂R heterodimer might be involved in the overexpression of CART peptides induced by caffeine.