In the present study, the 5-HT(2A) and 5-HT(1A) receptors functional activity and 5-HT(2A) receptor gene expression were examined in the brain of ASC/Icg and congenic AKR.CBAD13Mit76C mouse strains (genetically predisposed to catalepsy) in comparison with the parental catalepsy-resistant AKR/J and catalepsy-prone CBA/Lac mouse strains. The significantly reduced 5-HT(2A) receptor functional activity along with decreased 5-HT(2A) receptor gene expression in the frontal cortex was found in all mice predisposed to catalepsy compared with catalepsy-resistant AKR/J. 5-HT(2A) agonist DOI (0.5 and 1 mg/kg, i.p.) significantly reduced catalepsy in ASC/Icg and CBA/Lac, but not in AKR.CBAD13Mit76C mice. Essential increase in 5-HT(1A) receptor functional activity was shown in catalepsy-prone mouse strains in comparison with catalepsy-resistant AKR/J mice. However, in AKR.CBAD13Mit76C mice it was lower than in ASC/Icg and CBA/Lac mice. The inter-relation between 5-HT(2A) and 5-HT(1A) receptors in the regulation of catalepsy was suggested. This suggestion was confirmed by prevention of DOI anticataleptic effect in ASC/Icg and CBA/Lac mice by pretreatment with 5-HT(1A) receptor antagonist p-MPPI (3 mg/kg, i.p.). At the same time, the activation of 5-HT(2A) receptor led to the essential suppression of 5-HT(1A) receptor functional activity, indicating the opposite effect of 5-HT(2A) receptor on pre- and postsynaptic 5-HT(1A) receptors. Thus, 5-HT(2A)/5-HT(1A) receptor interaction in the mechanism of catalepsy suppression in mice was shown.