title: Caffeine regulates frontocorticostriatal dopamine transporter density and improves attention and cognitive deficits in an animal model of attention deficit hyperactivity disorder.
abstract: Attention deficit hyperactivity disorder (ADHD) likely involves dopaminergic dysfunction in the frontal cortex and striatum, resulting in cognitive and motor abnormalities. Since both adenosine and dopamine modulation systems are tightly intertwined, we tested if caffeine (a non-selective adenosine receptor antagonist) attenuated the behavioral and neurochemical changes in adolescent spontaneously hypertensive rats (SHR, a validated ADHD animal model) compared to their control strain (Wistar Kyoto rats, WKY). SHR were hyperactive and had poorer performance in the attentional set-shifting and Y-maze paradigms and also displayed increased dopamine transporter (DAT) density and increased dopamine uptake in frontocortical and striatal terminals compared with WKY rats. Chronic caffeine treatment was devoid of effects in WKY rats while it improved memory and attention deficits and also normalized dopaminergic function in SHR. Additionally, we provide the first direct demonstration for the presence of adenosine A2A receptors (A2AR) in frontocortical nerve terminals, whose density was increased in SHR. These findings underscore the potential for caffeine treatment to normalize frontocortical dopaminergic function and to abrogate attention and cognitive changes characteristic of ADHD.
authors.affiliation: Department of Pharmacology, Biological Science Center, Federal University of Santa Catarina, Florianopolis, Brazil. pablopandolfo@gmail.com
authors.forename: Pablo
authors.initials: P
authors.lastname: Pandolfo
authors.forename: Nuno J
authors.initials: NJ
authors.lastname: Machado
authors.forename: Attila
authors.initials: A
authors.lastname: Köfalvi
authors.forename: Reinaldo N
authors.initials: RN
authors.lastname: Takahashi
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects / Q000502:physiology; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000188:drug therapy / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D002110:Caffeine