AbstractSleep pressure builds during wakefulness, but the mechanisms underlying this homeostatic process are poorly understood. One zebrafish model suggests that sleep pressure increases as a function of global neuronal activity, such as during sleep deprivation or acute exposure to drugs that induce widespread brain activation. Given that the arousal-promoting noradrenergic system is important for maintaining heightened neuronal activity during wakefulness, we hypothesised that genetic and pharmacological reduction of noradrenergic tone during drug-induced neuronal activation would dampen subsequent rebound sleep in zebrafish larvae. Unexpectedly, dampening noradrenergic tone with the α2-adrenoceptor agonist clonidine during acute caffeine or pentylenetetrazol treatment enhanced subsequent rebound sleep, while stimulating noradrenergic signalling during caffeine exposure with a cocktail of α1- and β-adrenoceptor agonists did not enhance sleep. Similarly, CRISPR/Cas9-mediated elimination of thedopamine β-hydroxylase(dbh) gene, which encodes an enzyme required for noradrenalin synthesis, enhanced baseline sleep in larvae but did not prevent additional rebound sleep following acute induction of neuronal activity. Across all drug conditions,c-fosexpression immediately after drug exposure varied inversely with noradrenergic tone and correlated strongly with the amount of induced rebound sleep. These results are consistent with a model in which increases in neuronal activity, as reflected by brain-wide levels ofc-fosinduction, drive a sleep pressure signal that promotes rebound sleep independently of noradrenergic tone.