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

Abstract

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.

Neuropeptide CART prevents memory loss attributed to withdrawal of nicotine following chronic treatment in mice

“…) and caffeine (Hu et al . ). In the present study, CART gene expression changed following chronic nicotine withdrawal (8 and 24‐hour timepoints).…”

Decreased Caffeine-Induced Locomotor Activity via Microinjection of CART Peptide into the Nucleus Accumbens Is Linked to Inhibition of the pCaMKIIa-D3R Interaction

“…It was previously found that CREB activity in the NAc shell is important for the activity of psychostimulants [ 35 – 37 ]. After caffeine administration, CART peptides are more highly expressed in the NAc shell than in the NAc core [ 15 , 29 ]. The NAc shell is reported to have a major role in the integration of brain reward mechanisms and the functions of core structures that are engaged in motor-associated outputs [ 38 ].…”

“…In turn, CART peptides can regulate locomotor activity via dopamine receptor and cAMP/PKA/pCREB signaling pathway activities. Our previous report showed that cocaine- and caffeine-induced sensitization was expressed on the 5 th day of administration and that CREB phosphorylation and CART peptide expression peaked on the 5 th day [ 28 , 29 ]. In the present study, we examined the effects of CART peptides on locomotor activity and CREB phosphorylation on the 5 th day of caffeine administration.…”

CART Peptides and Drugs of Abuse: A Review of Recent Progress

“…Hu et al [ 40 ] tested whether repeated CAFF administration would cause behavioral sensitization and an increased expression of CART. It did produce behavioral sensitization, and CART levels did increase and peaked at day 5 and then declined.…”