The effects of histamine on excitatory synaptic transmission between the external capsule and basolateral amygdala (BLA) were examined using intracellular and field potential recordings in rat amygdala slices. Bath application of histamine (20 μM) suppressed intracellular excitatory postsynaptic potentials (EPSPs; 70.3±5.1% of control amplitude) in 43 of 64 BLA neurons, and potentiated EPSPs (341±81% of control amplitude) in 21 neurons, without changing resting membrane potential or input resistance. The histamine-induced suppression of EPSPs was accompanied by an increase in paired-pulse facilitation of the slopes of EPSPs, suggesting a presynaptic locus of the action. The suppressive effect could be blocked by the selective H 3 antagonist thioperamide, and mimicked by the selective H 3 agonist R-α-methylhistamine, indicating that the suppressive effect is mediated by the presynaptic H 3 receptor. The potentiating effect of histamine on EPSPs was not accompanied by the change of paired-pulse facilitation and was not affected by the presence of H 1, H 2 or H 3 receptor antagonists. In addition, the effective concentration of agonist to produce 50% of maximal response (EC 50) of the potentiating action of histamine is 49 nM, much lower than the EC 50 (470 nM) of the H 3 receptor-mediated suppressive effect characterized here. These observations suggest a novel, high affinity and postsynaptically mediated effect of histamine. In extracellular recordings, histamine, at low concentration (200 nM), consistently potentiated field potentials. At high concentration (20 μM), histamine suppressed field potentials, but potentiated field potentials when H 3 receptors were blocked. Taken together, these results revealed that histamine, via the presynaptic H 3 receptor and a currently unknown mechanism, decreases or increases excitatory synaptic transmission in the BLA respectively. This specific histaminergic modulation of neuronal activity in the amygdala may play an important role in amygdala-mediated physiological and pathophysiological processes, such as fear, emotional learning and memory, temporal lobe epilepsy, and affective disorders.