A behavioral tolerance to the ambulation-increasing effect of scopolamine (SCP: 2 mg/kg s.c.), a muscarinic anti-cholinergic drug, was induced following the repeated administration to mice at 3-day intervals. The combined administration of SCP + bethanechol (BET: 0.01, 0.03, 0.1 and 0.3 mg/kg s.c.), a peripheral muscarinic cholinergic drug, resulted in sensitization, although the single treatment with 0.03-0.1 mg/kg of BET did not modify the ambulation-increasing effect of SCP at the first administration. In addition, the treatment with BET (0.1 mg/kg) at post-SCP period of 5-20 min also induced the sensitization to SCP after the repeated administration. The post-SCP treatment with BET at 30 min and later produced the tolerance to SCP. The repeated administrations of BET alone did not change the sensitivity to the ambulation-increasing effect of SCP. Furthermore, the mice showing sensitization to SCP + BET, but not tolerance to SCP, demonstrated a cross-sensitization to methamphetamine (2 mg/kg s.c.). These results suggest that the tolerance to SCP is produced by the interaction of the stimulation of central dopaminergic system (reward effect) through the blockade of peripheral muscarinic cholinergic receptors (harmful effect), and that the latter effect overwhelms the former effect of SCP. It is also suggested that the selective inhibition of the peripheral anti-cholinergic effect of SCP increases the dependence liability of SCP, and psychotoxicity of anti-cholinergic drugs including SCP and psychomotor stimulant drugs such as methamphetamine
