Streptozotocin-Induced Decreases in Serotonin Turnover Are Prevented by Thyroidectomy

Abstract

Although characterized as hypothyroid, streptozotocin-diabetic rats have reduced serotonin turnover (5-hydroxyindoleacetic acid/serotonin, 5-HIAA/ 5-HT) in brain stem, while hypothyroid rats have increased 5-HIAA/5-HT. In the present study the two treatments were combined to determine if they affected 5-HIAA/5-HTthrough the same mechanism. In addition, an alternative method was used to assess 5-HT activity in thyroidectomized (TX) rats, i.e. measurement of 5-HT disappearance after inhibition of tryptophan hydroxylase with/7-chlorophenylalanine (PCPA). Adult male rats were first TX (experiment 1) or given methimazole (METH; experiment 3). Two weeks later, diabetes (DB) was induced with streptozotocin in hypothyroid rats and euthyroid controls. Two weeks later, functional measurements were taken. Rats were then killed, and spinal cord and brain stem serotonin turnover (5-HIAA/5-HT), as well as plasma T₃, T₄ and corticosterone (CORT) concentrations were measured. TX attenuated diabetic hyperphagia and weight loss. DB alone led to moderate reductions in T₃ and T₄, but the hormones were barely detectable in plasma of TX and METH rats. CORT was elevated in DB but was not affected by TX. Open field activity was not affected by DB or TX. TX and METH significantly increased 5-HIAA/5-HT in both spinal cord and brain stem. TX also led to enhanced disappearance of 5-HT after PCPA. DB significantly reduced 5-HIAA/5-HT, suggesting independent effects of the treatments. However, DB-TX rats still had significantly higher 5-HIAA/5-HT than control-sham surgery rats, while DB-METH rats had 5-HIAA/5-HT indistinguishable from controls. In both cases, prior induction of primary hypothyroidism interfered with the expected diabetes-induced reduction in 5-HTturnover.

Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain

“…One early study measured brainstem 5-HT concentrations and did not find significant differences compared to euthyroid animals. 40 Later, using more sensitive assay techniques, five studies measured 5-HT and 5-HIAA concentration or the 5-HIAA/5-HT ratio as an indicator of the serotonin turnover and reported increased 5-HT metabolites in the brainstem [41][42][43][44][45] (notice: one study calculated the inverse ratio, 5-HT/5-HIAA 41 ). Reduced 5-HT concentrations in the cortex, 46,47 and reduced concentrations of the serotonin precursor 5-HTP were reported in the whole brain 48 of hypothyroid adult rats.…”

Thyroid hormones and the treatment of depression: An examination of basic hormonal actions in the mature mammalian brain

“…The suggestion that impaired transport of 5HIAA out of the hypothyroid brain is the basis for neurochemical findings (Savard et al, 1983) is unlikely given that inhibition of serotonin synthesis with i.c.v. p-chlorophenylalanine caused larger drops in 5HT and 5HIAA in hypothyroid rats (Henley and Bellush, 1992).…”

“…In spite of the uniform findings in discrete locations of the hypothyroid brain (Savard et al, 1983), an obligatory relationship between hypothyroidism and changes in serotonin metabolism is unlikely since streptozotocin-diabetic rats that are mildly hypothyroid exhibit decreases in 5HIAA (Henley and Bellush, 1992). Although prior induction of hypothyroidism blunts the expected streptozotocin-induced decrease in 5HIAA (Henley and Bellush, 1991), prior administration of streptozotocin blunts an expected hypothyroid-induced increase (unpublished findings).…”

“…Increased concentration of 5-hydroxyindoleacetic acid (5HIAA), the principal metabolite of serotonin, is a robust, widespread finding throughout the brain and spinal cord of the adult hypothyroid rat that is reversible with hormonal replacement (Henley et al, 1991;Henley and Bellush, 1992;Savard et al, 1983). Further, T 3 implants caused suppression of 5HIAA within 7 days in a dose-dependent manner in thyroid intact rats (Henley et al, 1996).…”

The Relationships between Thyroid Hormones and the Brain Serotonin (5-HT) System and Mood: Of Synergy and Significance in the Adult Brain- A Review

“…One early study measured brainstem 5-HT concentrations and did not fine significant differences compared to euthyroid animals 34 . Later, using more sensitive assay techniques, five studies measured 5-HT and 5-HIAA concentration or the 5-HIAA/5-HT ratio as an indicator of the serotonin turnover and reported increased 5-HT metabolites in the brainstem [35][36][37][38][39] (notice: one study calculated the inverse ratio, 5-HT/5-HIAA 41 ). Reduced 5-HT concentrations in the cortex 40,41 and reduced concentrations of the serotonin precursor 5-HTP were reported in the whole brain 42 of hypothyroid adult rats.…”