Striatal dopaminergic D1 and D2 receptors after intracerebroventricular application of alloxan and streptozocin in rat.

Intracerebroventricular application of low, nondiabetogenic doses (500 micrograms kg-1) of alloxan and streptozocin is followed by alterations of the dopaminergic system in rat striatum. In this brain region the dopamine content significantly increased, while the density of dopaminergic D1 receptors significantly decreased seven days after the intracerebroventricular application of betacytotoxics, as compared with the control group. The density of dopaminergic D2 receptors in striatum remained unchanged. Dopaminergic D1 and D2 receptors operate through signalling mechanism of G proteins, but no changes of Gs and Gi proteins content have been found in rat striatum after the intracerebroventricular application of betacytotoxics. As intracerebroventricular, nondiabetogenic administration of betacytotoxics produces changes of the striatal dopamine content and D1 receptor density similar to that produced by peripheral, diabetogenic administration of these drugs, the effect might be related not solely to pancreatic beta cells damage, but to alterations of the brain insulin system, as well.

Brain D1 dopamine receptor in alloxan-induced diabetes.

Specific binding of [3H]SCH 23390 to dopamine D1 receptors in the striatum and olfactory tubercle in 14-day alloxan-induced diabetic rats was investigated. The Scatchard analysis revealed decreased D1 receptor density in the striatum (Bmax values were 548 +/- 23 fmol/mg protein for the control and 466 +/- 33 fmol/mg for the diabetic rats). No change was observed in the olfactory tubercle (Bmax; 299 +/- 27 fmol/mg for the control and 317 +/- 32 fmol/mg for the diabetic rats). Thus, specific binding of [3H]SCH 23390 to striatal and olfactory tubercle membranes showed region-specific changes of brain dopamine D1 receptors in alloxan diabetic rats.

Effect of long-lasting diabetes mellitus on rat and human brain monoamines.

Experimental alloxan- or streptozotocin-produced diabetes in rats was accompanied by an increase in the levels of norepinephrine, dopamine, and serotonin, whereas the contents of metabolites, i.e., 5-hydroxyindoleacetic acid and homovanillic acid, in the whole brain gradually decreased with the duration of diabetes. Among the striatum, thalamus, and hypothalamus of alloxan diabetic rats, monoamine alterations were observed only in the hypothalamus; after 1 week an increase of norepinephrine content and after 13 weeks an increase of norepinephrine and dopamine contents were found. Tissues of 11 brain regions of 10 diabetic and 12 control patients post mortem were investigated for monoamine concentrations. Patients were all male, of similar age and interval between death and autopsy. Diabetic patients had an increase in the content of serotonin in the medial and lateral hypothalamus. The content of dopamine increased in the medial hypothalamus, putamen, and medial and lateral pallidus. In diabetic patients, the content of norepinephrine increased in the lateral pallidus and decreased in the nucleus accumbens and claustrum. Thus, it seems that diabetes mellitus in rats, as well as in humans is associated with regionally specific changes in brain monoamines.

Streptozotocin and alloxan produce alterations in rat brain monoamines independently of pancreatic beta cells destruction.

In recent years the effect of experimental diabetes mellitus on brain neurochemistry has been under an intensive investigation. In most of these studies diabetes was produced by a peripheral administration of streptozotocin or alloxan. In line with previous reports, a week after such an application of alloxan (200 mg/kg s.c.) we found the concentration of serotonin, dopamine and norepinephrine to be increased in the brain of a diabetic rat. Accumulation of these monoamines, produced by inhibition of monoamine oxydase with pargyline (100 mg/kg i.p.) decreased in animals made diabetic by alloxan or streptozotocin (100 mg/kg i.p.) suggesting a decrease in deamination rate. Surprisingly, however, one week after an intracerebroventricular administration of non-diabetogenic doses of streptozotocin (5-20 mg/kg) or alloxan (20 mg/kg), changes in brain monoamines were similar to those observed in diabetic animals. This observation apparently suggests that the CNS effect of streptozotocin or alloxan is not necessarily related to a diabetogenic, beta-cytotoxic action of these substances.