Clomipramine and clonazepam increase cholecystokinin levels in rat ventral tegmental area and limbic regions

Abstract

Recent reports suggest that a cholecystokinin (CCK)-related dysfunction may be a target by which drugs can modulate anxiety and panic disorders. In the present study, effects of subchronic (14 days) treatment with the monoamine uptake inhibitors nortriptyline (30 μmol/kg per day), amitriptyline (29 μmol/kg per day), clomipramine (32 μmol/kg per day) and alaproclate (39 μmol/kg per day), as well as with the benzodiazepine clonazepam (0.25 μmol/kg per day), on rat brain levels of CCK- and substance P-like immunoreactivity, were compared. The drugs were administered by continuous s.c. infusion using implanted osmotic pumps. The plasma concentrations of the monoamine uptake inhibitors were similar after 1 and 2 weeks of treatment, indicating that steady-state plasma levels had been reached during the first week. Treatment with clomipramine or clonazepam increased the CCK-like immunoreactivity level in the ventral tegmental area ( by 64.4 ± 28.8% and 105.1 ± 28.8% , respectively) and in the cingulate cortex ( by 30.3 ± 10.1% and 36.0 ± 11.8% , respectively) ( P < 0.05 or P < 0.01 ). Clomipramine also significantly increased the CCK-like immunoreactivity level in the periaqueductal grey by 85.1 ± 29.7%. Neither nortriptyline nor amitriptyline or alaproclate produced any significant alterations in the CCK- or substance P-like immunoreactivity levels in the areas examined. The present results may suggest that an altered utilization of CCK in limbic circuits could be of importance for the well documented clinical effect of clomipramine and clonazepam in panic disorders.