Behavioral, neuroendocrine and neurochemical effects of the imidazoline I2 receptor selective ligand BU224 in naive rats and rats exposed to the stress of the forced swim test

Rationale: There is evidence for alterations in imidazoline(2) (I-2) receptor density in depressed patients. Selective I-2 receptor ligands modulate central monoamine levels and activate the hypothalamo-pituitary-adrenal (HPA) axis and may have potential as antidepressants. Objectives: To study the behavioral effects of the selective I-2 receptor ligand BU224 in the rat forced swim test (FST) and its effects on the HPA axis and central monoaminergic responses. Methods: Rats received saline or BU224 (10 mg/kg IP) 24, 18 and I h prior to 15 min exposure to the FST. Saline- and BU224-treated non-stressed groups were included. Time spent immobile, struggling and swimming calmly was measured. Plasma adrenocorticotrophic hormone (ACTH) and corticosterone levels 90 min post-BU224 were measured in addition to tissue levels of monoamines and metabolites in the frontal cortex, hippocampus and hypothalamus. Results: Administration of BU224 significantly reduced immobility and increased mild swimming without affecting struggling. Exposure to the FST significantly increased plasma ACTH and corticosterone levels. BU224 administration also increased ACTH and potentiated the ACTH response to FST with no effect on corticosterone. BU224 administration significantly increased frontal cortex 5-hydroxytryptamine (5-HT) levels and decreased 5-HT turnover in the frontal cortex and hypothalamus of rats exposed to FST. In non-stressed rats, BU224 decreased 5-HT turnover in the hippocampus and hypothalamus and decreased norepinephrine turnover in the frontal cortex. Conclusions: The selective 12 receptor ligand BU224 reduces immobility of rats in the FST, indicative of antidepressant-like activity. This effect is accompanied by alterations in HPA axis and central monoaminergic activity.