Influence of S‐adenosyl‐ L ‐methionine on chronic mild stress‐induced anhedonia in castrated rats

S‐adenosyl‐ L ‐methionine (SAMe) is the most important methyl donor in the brain and is essential for polyamine synthesis. Methyl group deficiency in the brain has been implicated in depression; on the other hand, polyamines enhance phosphorylation processes, and phosphorylation of functional proteins in neurons is involved in the therapeutic mechanisms of antidepressants. The effect of SAMe in an animal model of ‘depression’, the chronic mild stress‐induced anhedonia, was studied using long‐term castrated male and female Lister hooded rats. Chronic daily exposure to an unpredictable sequence of mild stressors produced, within 3 weeks, a significant reduction of the consumption of a sucrose solution. SAMe (100, 200 or 300 mg kg −1 daily i.m.) while having no influence on sucrose intake in non‐stressed animals, dose‐dependently reinstated sucrose consumption within the first week of treatment, both in male and in female stressed rats. Imipramine (10 mg kg −1 daily i.p.) produced a similar effect after a 3 week treatment. Similarly, a palatable food reward‐induced place preference conditioning was developed in SAMe (200 or 300 mg kg −1 daily i.m.)‐ and in imipramine (10 mg kg −1 daily i.p.)‐treated chronically stressed animals (males and females), whilst it could not be obtained in vehicle‐treated rats. Moreover, the same doses of SAMe (but not of imipramine) restored the exploratory activity and curiosity for the environment (rearing), in the open‐field test. While imipramine caused a blockade of the growth throughout the treatment, SAMe produced only a transient growth arrest during the first week of treatment. These results show that SAMe reverses an experimental condition of ‘depression‐like’ behaviour in rats, the effect being more rapid and complete than that of imipramine, and without apparent side effects.British Journal of Pharmacology (1999) 127 , 645–654; doi: 10.1038/sj.bjp.0702589