Abstract Spontaneously occurring and drug-induced high voltage spike-and-wave electroencephalogram patterns were examined in inbred rats of the Fischer 344 and Buffalo strains and of the random-bred Sprague-Dawley strain at different ages. In addition, tyrosine hydroxylase activity and dopamine D 2; receptor density were determined in the substantia nigra, corpus striatum, olfactory tubercle and ponsmedulla areas of Fischer 344 and Buffalo animals. High voltage spike-and-wave episodes were present in 87.5% of the 3-month-old and in 100% of the older Fischer 344 rats. High voltage spike-and-wave episodes were completely absent in 3-month-old Buffalo and Sprague-Dawley animals but could be induced by systemic injection of pentylenetetrazol and at an older age they appeared in 58.3% (12-month) and 71.4% (> 26-month) of the subjects of these strains. The incidence and duration of high voltage spike-and-wave episodes were significantly higher/longer in Fischer 344 rats than in the age-matched Buffalo and Sprague-Dawley animals. The dopamine Mocker acepromazine induced a several-fold increase of the incidence and duration of high voltage spike-and-wave episodes in 3-month-old Fischer 344 rats, but failed to induce high voltage spike-and-wave episodes in Buffalo animals at this age. However, acepromazine also triggered high voltage spike-and-wave episodes in Buffalo rats when they were pretreated with subthreshold doses of pentylenetetrazol. Tyrosine hydroxylase activity was significantly higher in the substantia nigra, corpus striatum and olfactory tubercle of the Fischer 344 strain than in Buffalo rats. The higher tyrosine hydroxylase activity was paralleled with significantly higher D; binding values in the corpus striatum and olfactory tubercle of Fischer 344 rats. These findings suggest that the neocortical high voltage spike-and-wave phenotype is genetically mediated and that the inbred Fischer 344 and Buffalo rats with defined bilineal origin will facilitate future works aimed at the identification of genetic elements involved in the generation of neocortical high voltage spike-and-wave episodes. The significant genotype × age interaction supports the suggestion, however, that high voltage spike-and-wave episodes are likely to be influenced by more than one gene; some of them are probably related to the regulation of brain aminergic systems.