Electrolytic lesions of the medial forebrain bundle induce a fall in histidine decarboxylase activity (the specific synthetic enzyme of brain histamine) in the ipsilateral cerebral cortex and hippocampus of the guinea pig brain; these results suggest the presence of an ascending histaminergic pathway in the guinea pig brain similar to that described in the rat. Possible alterations in the sensitivity of histaminergic receptors present in the target areas were studied following this type of lesion by combining electrophysiological and biochemical approaches. Microiontophoretic applications of histamine or noradrenaline reveal a hypersensitivity (lower ejecting currents for threshold and maximal responses) in cortical neurons ipsilateral but not contralateral to the lesion, whereas responses to iontophoretically applied GABA are not modified. In contrast the responsiveness of histamine-sensitive cyclic AMP generating systems is not modified, neither in the cerebral cortex nor in the hippocampus after this type of lesion. Similar conclusions are reached from the data obtained with specific agonists of the two classes of histaminergic receptors and measurements in the presence of a phosphodiesterase inhibitor. Several hypotheses are discussed in order to reconcile the finding of a denervation hypersensitivity revealed by iontophoresis contrasting with an unaltered responsiveness of the histaminergic receptors linked to the adenylate cyclase.