Histamine regulates neurotransmitter release in the central and peripheral nervous systems through H(3) presynaptic receptors. cDNAs coding for human, guinea pig and rat histamine H(3) receptors have recently been cloned. Cloning of rat and guinea pig H(3) receptors demonstrated the existence of multiple isoforms displaying deletions in the third cytoplasmic loop coding region. We investigated whether a similar splicing pattern might also occur in the human H(3) gene. Using both RT-PCR and RNase protection assays, we detected H(3) receptor mRNA expression in human brain, testes and a cell line expressing recombinant human H(3) receptor (SK-N-MC/H(3)). In all samples tested by both detection methods, only the long mRNA form was detected. We could not find any evidence that humans express other forms equivalent to that seen in the rat or guinea pig. If the alternative splicing seen in rats and guinea pigs presents itself through pharmacological variation, our current findings then have implication for the use of rats or guinea pigs as model system for the development of therapeutic targeting the human H(3) receptor.