Hypothalamic neuropeptide Y (NPY) and the attenuation of hyperphagia in streptozotocin diabetic rats treated with dopamine D1/D2 agonists

Abstract

1. Dopamine is an appetite suppressant, while neuropeptide Y (NPY), an appetite stimulant in the brain, is reported to be involved in anorectic action induced by a combined administration of D1/D2 agonists in normal rats. In diabetic rats, however, these factors have not been studied. 2. Rats (including normal, diabetic and insulin-treated diabetic rats) were given daily injections of saline or D1/D2 agonists for 6 days. Changes in food intake and hypothalamic NPY content of these rats were assessed and compared. 3. The D1/D2 agonist-induced anorectic responses were altered in diabetic rats compared to normal rats treated similarly. Both the anorectic response on the first day of dosing and the tolerant response on the subsequent days were attenuated. 4. This alteration was independent of the neuroendocrine disturbance on feeding behavior since the basic pattern of food intake during the time course of a 24-h day/night cycle was similar in normal and diabetic rats; the decrease of food intake following drug treatment was only shown at the initial interval of 0-6 h in both groups of rats. 5. However, this alteration coincided with changes in NPY content following D1/D2 coadministration. The replacement of insulin in diabetic rats could normalize both NPY content and D1/D2 agonist-induced anorexia. 6. It is demonstrated that the response of D1/D2 agonist-induced appetite suppression is attenuated in diabetic rats compared to normal rats and that elevated hypothalamic NPY content may contribute to this alteration.

Figure 1

The comparison of daily food intake between diabetic and normal rats during a 6-day repeated coadministration of D1/D2 agonists. SKF/QNP at a dose ratio of 1/0.1 or 2/0.2 mg kg⁻¹ was injected at 18:00 of each treatment day. Comparisons were made using two-way ANOVA followed by Dunnett's test. ^*Indicated P<0.05 compared to the control group of each treatment day.

Figure 2

The effect of insulin replacement on D1/D2 agonists-induced daily food intake in diabetic rats over a 6-day period. To normalize the daily food intake before SKF/QNP coadministrations, insulin (1 U kg⁻¹; i.p.) was administered to diabetic rats twice a day for 7 days and was continuously administered to these rats for 6 days during SKF/QNP coadministrations. SKF/QNP at a dose ratio of 1/0.1 or 2/0.2 mg kg⁻¹ was injected at 18:00 of each treatment day. Comparisons were made using two-way ANOVA followed by Dunnett's test. ^*Indicated P<0.05 compared to the insulin-treated control group of each treatment day.

Figure 3

Effects of repeated coadministrations of D1/D2 agonists on changes of hypothalamic NPY content in normal, diabetic and insulin-treated diabetic rats. Levels of NPY were measured by a radioimmunoassay technique. SKF/QNP (2/0.2 mg kg⁻¹; i.p.) was injected at 18:00 of each treatment day. Values are represented as mean±standard error (s.e.m.), n=6–8 per group. ^*P<0.05 vs the control group of each treatment day in normal or diabetic rats.

Figure 4

Upper part: the effect of D1/D2 agonists (2/02 mg kg⁻¹; i.p.) on hypothalamic NPY mRNA level in diabetic and normal rats. NPY mRNA levels were measured using RT–PCR. Lower part: relative values between D1/D2 agonist- and saline-treated groups. Contents of NPY mRNA in D1/D2 agonist-treated group were indicated as the percentage of control. Bars are mean±s.e.m. N=6–8 each group. ^*Indicates P<0.05 compared to control group.

Figure 5

Comparisons for the time course of a 24-h feeding behavior between normal (left panel) and diabetic rats (right panel) after a single dosing of SKF/QNP coadministration. A 24-h food intake was divided into four intervals (0–6, 6–12, 12–18 and 18–24 h). Rats were given with SKF/QNP (2/0.2 mg kg⁻¹; i.p.) or saline at 18:00 (i.e. at the beginning of dark-on period) on each testing day. Comparisons were made using t-test. ^*Indicated P<0.05 compared to the control group of each time intervals.