Could early-life caffeine exposure program preterm infants for later-life caffeine dependence? A mechanistic hypothesis
Medical Hypotheses, cilt.209, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 209
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.mehy.2026.111921
- Dergi Adı: Medical Hypotheses
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CINAHL, EMBASE
- Anahtar Kelimeler: Neonatal caffeine exposure, Adenosine receptor blockade, Dopamine signaling, Caffeine dependence, Neurodevelopment
- Sağlık Bilimleri Üniversitesi Adresli: Evet
Özet
Caffeine remains a primary therapeutic agent for apnea of prematurity and continues to improve respiratory stability and neurodevelopmental outcomes. Treatment occurs during a developmental window in which synaptic connectivity is rapidly expanding, receptor expression is shifting, and neuromodulatory systems are establishing long-term regulatory patterns. During this period, the maturation of A1 and A2A receptors influences neuronal excitability, sleep–wake organization, and endogenous protective mechanisms. Experimental studies demonstrate that neonatal caffeine exposure modifies A1 receptor ontogeny, alters ligand sensitivity, and induces lasting changes in ventilatory control. Considering the functional interaction between A2A and dopamine D2 receptors in striatal pathways, early adenosine antagonism may also influence the developmental calibration of reward circuitry. Animal data consistently show that neonatal caffeine exposure produces behavioral and neuromodulatory alterations that persist into later life, affecting motor activity, sleep organization, memory performance, and responsiveness to stimulant agents. Human studies, however, have not assessed reward sensitivity, stimulant responsivity, or caffeine-use patterns in individuals born preterm, leaving an important developmental gap. These observations support a biologically grounded hypothesis: early-life caffeine therapy may shift the maturation of arousal and reward systems in ways that shape later susceptibility to altered caffeine sensitivity or reinforcement patterns. If this connection is confirmed, clinical approaches may need to reconsider dosing strategies and broaden long-term follow-up to include behavioral and neurophysiological assessments in former preterm infants treated with caffeine.