Amphetamine (AMPH) is known as an anorectic agent. The anorectic action of AMPH has been attributed to its inhibitory action on hypothalamic neuropeptide Y (NPY), an appetite stimulant in the brain. The molecular mechanisms behind this anorectic action of AMPH are still unclear. This study investigated the possible role of protein kinase C (PKC) isotypes in this anorectic action. Results revealed that most PKC isotypes (alpha, betaII, gamma, delta, eta, lambda and zeta), except betaI and epsilon isotypes, were stimulated during a repeated treatment of AMPH. Among these stimulated isotypes, three isotypes (alpha, delta, lambda) were activated and expressed in a similar manner, while the other isotypes were expressed differently and specifically. To determine if PKCalpha was involved in the anorectic response of AMPH, the infusions of antisense oligonucleotide into the brain were performed 1 h before daily AMPH treatment in freely moving rats, and the results showed that PKCalpha knock down could block the anorectic response and restore NPY mRNA levels in AMPH-treated rats. These results suggest that PKC isotypes- (at least the alpha isotype), related modification of NPY gene expression in hypothalamus might play an essential role in the central regulation of AMPH-mediated feeding suppression.