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ABSTRACT: Aim: H1 Antihistamines are classified into first generation and second generation agents. The main differences between the first and second generations of drugs are their propensity to cause central nervous system (CNS) side effects. Therefore, present study was aimed to analyze the effects of different H1 antihistamines (first and second generation) on CNS using different animal experimental models. Materials & methods: H1 antihistamines such as pheniramine maleate (3 mg/kg, 6 mg/kg), cetirizine (0.6 mg/kg, 1.2 mg/kg), levocetirizine (0.6mg/kg, 1.2 mg/kg), loratadine (1 mg/kg, 2 mg/kg) and desloratidine (0.6 mg/kg, 1.2 mg/kg) are evaluated and compared for their effects on CNS using experimental animal model (Pentobarbitone sleeping time, spontaneous motor activity, motor co-ordination) in Swiss albino mice. Results & Discussion: Desloratadine (0.6mg/kg, 1.2 mg/kg) and loratadine (1 mg/kg, 2 mg/kg) did not produce significant (P < 0.05) effect on sleeping time when compared to control. At 120 minutes time interval after treatment with cetirizine (1.2 mg/kg) and levocetirizine (1.2 mg/kg) was shown reduction in locomotor activity and remainin