Effects of ceruletide on perioral movements and the dopamine receptor-adenylate cyclase system in rats chronically treated with fluphenazine

Abstract

The effects of repeated administration of ceruletide (100 micrograms/kg/perday, i.p. for 3 days) on perioral movements and the striatal dopamine receptor adenylate cyclase system were examined in rats chronically treated with fluphenazine enanthate (FPZ) (25 mg/kg i.m. every 3 weeks for 30 weeks) and sesame oil-treated (control) rats. After the tenth injection of fluphenazine, the rats started to display five types of perioral movements (teeth chattering, chewing, tongue protrusion, mouth opening and perioral tremors). Moreover, increases in SCH23390 binding and spiperone binding to striatal membranes, were found in the FPZ-treated rats. Furthermore, dopamine receptor-coupled adenylate cyclase activity was potentiated in striatal membranes. High amplitude EMG discharges (8-10 Hz), recorded from the masseter in the FPZ-treated rats occurred concurrently with perioral tremors. Repeated ceruletide (CLT) injections abolished perioral movements, and reversed both the elevated SCH23390 binding and the dopamine stimulated adenylate cyclase (AC) activity to the control level. The effect of CLT on perioral movements, D1 receptors and dopamine-stimulated AC activity continued for 6 days after the final CLT injection. These findings suggest that systemically administered CLT affects the D1 receptor adenylate cyclase system and that an increase of the D1 receptor mechanism may play an important role in the pathogenesis of tardive dyskinesia.

Ceruletide, an Analog of Cholecystokinin Octapeptide: New Perspectives on Its Efficacy

“…Another study showed that ceruletide, administered 24 h prior to the dopamine D 1 -receptor agonist SKF 38393, attenuated SKF 38393-induced grooming behavior in rats (54). Studies in animal models of dyskinesia also reported similar long-lasting effects of ceruletide (3,74,75), as described later in this review.…”

“…Chronic treatment with the antipsychotic drug fluphenazine produced perioral movements in rats, together with increases in dopamine D 1 receptor binding and dopamine-receptor-coupled adenylate cyclase activity in the striatum (3). Repeated administration of ceruletide for 3 d abolished the perioral movements and reversed the increases in both D 1 -receptor binding and dopamine-stimulated adenylate cyclase activity to the control level.…”

“…It should be noted that most of these studies reported on the long-lasting effects of ceruletide on dyskinesia in model animals (3,74,75). These findings are consistent with clinical findings that ceruletide-induced amelioration of dyskinesia was maintained for over 1 w following a single injection.…”

The Effect of a Cholecystokinin Agonist on Masseter Muscle Activity in the Cat

“…There are several studies that support the findings of these experiments (Boyce et al, 1990a). In particular, the effects of repeated administrations of a CCK agonist, ceruletide, on perioral movements and the striatal dopamine receptor adenylase cyclase (Ac) system (Ashizawa et al, 1996) support these findings. Although body movement is a less sensitive measure of motor activity than EMG, in rats chroniically treated with fluphenazine to produce repetitive oral tremor, ceruletide, a CCK agonist, produced a cessation of repetitive oral movements with an increase in dopamine receptor sensitivity and dopamine-sensitive Ac activity in the striatum.…”

“…An understanding of the mode of action of CCK is of importance, since: (1) it may further our understanding of hypothalamic control of muscle activity; and (2) as a reported dopamine modulator, it is a candidate in the management of musculoskeletal disorders such as tardive dyskinesia (Van Kampen et al, 1996), Parkinson's disease (Boyce et al, 1990a), and 1823 myofascial disorders (Ashizawa et al, 1996).…”