Hyperalgesia, low-anxiety, and impairment of avoidance learning in neonatal caffeine-treated rats.
BACKGROUND
The nonselective adenosine receptor antagonist caffeine is used clinically to treat apnea in preterm infants. The brain developmental stage of preterm infants is usually at a period of rapid brain growth, referred as brain growth spurt, which occurs during early postnatal life in rats and is highly sensitive to central nervous system (CNS) acting drugs.


OBJECTIVE
The aim of this work was to study whether caffeine treatment during brain growth spurt produces long-term effects on the adenosine receptor-regulated behaviors including nociception, anxiety, learning, and memory.


METHODS
Neonatal male and female Sprague-Dawley rats were administered either deionized water or caffeine (15-20 mg kg(-1) day(-1)) through gavage (0.05 ml/10 g) over postnatal days (PN) 2-6. The hot-plate test, elevated plus-maze, dark-light transition test, and step-through inhibitory avoidance learning task were examined in juvenile rats. Furthermore, the responses to adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA)-induced hypothermia and A(2A) receptor agonist CGS21680-induced locomotor depression were also compared.


RESULTS
Caffeine-treated rats showed hyperalgesia in hot-plate test, less anxiety than controls in the elevated plus-maze and dark-light transition, and impairment in step-through avoidance learning test. Moreover, the responses to CPA-induced hypothermia and CGS21680-induced locomotor depression were enhanced in caffeine-treated rats.


CONCLUSIONS
These results indicate that caffeine exposure during brain growth spurt alters the adenosine receptor-regulated behaviors and the responsiveness to adenosine agonists, suggesting the risk of adenosine receptor-related behavioral dysfunction may exist in preterm newborns treated for apnea with caffeine.
Pan
Hong-Zhen
HZ
Institute of Pharmacology and Toxicology, Tzu Chi University, 701, section 3, Chung-Yang Road, Hualien 970, Taiwan.
Chen
Hwei-Hsien
HH
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000378:metabolism / Q000517:prevention & control*; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001833:Body Temperature Regulation / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D002110:Caffeine / Q000633:toxicity*; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D005260:Female; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008568:Memory / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010627:Phenethylamines / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013997:Time Factors
D000697:Central Nervous System Stimulants; D010627:Phenethylamines; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D002110:Caffeine; C048599:N(6)-cyclopentyladenosine; D000241:Adenosine