Cyclo(leu-gly) reverses the permanent dopamine receptor up-regulation induced by ovariectomy

Abstract

Several neuropsychiatric diseases, including tardive dyskinesia and schizophrenia, are thought to involve increased neurotransmission at dopaminergic synapses. Although many animal models of this dopaminergic hyperactivity have been studied, the ovariectomized (OVX) rat model, which we recently developed, appears to be unique. The brain D2 DA receptor up-regulation (increases in receptor number) and the behavioral hypersensitivity to dopamine (DA) agonists that develop in this model after a few months appear to be permanent. Using this model, it is now possible to screen for agents that can reverse a permanent dopaminergic supersensitivity. In this report, we document such a reversal by cyclo(leu-gly) (CLG), a dopaminergic neuromodulator, in the OVX model. Female Fisher rats were ovariectomized and allowed to recover for 3 months. Following a challenge dose of apomorphine (0.45 mg/kg, i.p.) OVX rats showed significantly more stereotypic sniffing (+ 175%) than sham controls. Following lower doses of APO (125 and 150 μ/kg, i.p.), OVX rats showed significantly more locomotor activity (+ 105 and + 365%). CLG (4 daily doses, 8 mg/kg, s.c.) reversed these hypersensitive responses. In parallel, OVX rats showed a significant increase (+ 35%) in [3H]-spiroperidol binding (Bmax) in corpus striatum relative to sham rats; this dopamine receptor up-regulation was also reversed by CLG. We conclude (1) that the long-term OVX rat is useful for modelling the permanent or irreversible aspect of supersensitivity to DA; and (2) CLG may be useful in the treatment of dopaminergic diseases.