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Hyperalgesia, low-anxiety, and impairment of avoidance learning in neonatal caffeine-treated rats
Hong-Zhen Pan1, Hwei-Hsien Chen
1Institute of Pharmacology and Toxicology, Tzu Chi University, 701, section 3, Chung-Yang Road, Hualien 970, Taiwan.
Insights
Caffeine given to developing rats during a critical brain growth period caused long-term changes in pain, anxiety, and learning. These findings suggest potential risks for preterm infants treated with caffeine for apnea.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Caffeine, a nonselective adenosine receptor antagonist, treats apnea in preterm infants.
- The early postnatal period in rats mirrors human preterm infants' brain growth spurt, a sensitive developmental stage.
Purpose of the Study:
- To investigate long-term effects of caffeine exposure during the brain growth spurt on adenosine receptor-regulated behaviors.
- To assess impacts on nociception, anxiety, learning, and memory.
Main Methods:
- Neonatal Sprague-Dawley rats received caffeine or water via gavage (postnatal days 2-6).
- Behaviors (nociception, anxiety, learning) were tested in juvenile rats.
- Responses to adenosine receptor agonists were evaluated.
Main Results:
- Caffeine-exposed rats exhibited hyperalgesia and reduced anxiety.
- Impaired learning and memory were observed in caffeine-treated rats.
- Enhanced responses to adenosine A1 and A2A receptor agonists were noted.
Conclusions:
- Caffeine exposure during the brain growth spurt alters adenosine receptor-mediated behaviors.
- This suggests a potential risk for adenosine receptor-related behavioral dysfunction in treated preterm infants.
Rationale:
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.
Objectives:
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.
Conclusion:
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.
