Neurochemical Nature of Cognitive and Emotional Disorders under Conditions of Experimental Diabetes Mellitus

Experimental diabetes mellitus (EDM) was induced in rats by injections of alloxan (125 mg/kg); this disease was manifested in a rise in the mean level of glucose in the blood from 5.0 to 18.7 mM. On the 4th week of the development of EDM, rats demonstrated increased levels of depression and anxiety and worsening of the processes of formation and reproduction of trained skills. Behavioral modifications were developed against the background of decreases in the amplitudes of NMDA components of field EPSPs (fEPSPs) of pyramidal neurons of the hippocampus and prefrontal neocortex, weakening of the expression of long-term potentiation, and, concurrently, intensified development of long-term depression of synaptic transmission. Injections of insulin (durable action, 2 U per animal) during 2 days resulted in a decrease in the level of glucose in the blood but did not change behavioral and neurochemical disorders typical of EDM. The action of glucose in a high concentration (30 mM) on cerebral slices obtained from intact rats did not influence the relay and plastic properties of glutamatergic synapses of neurons of the hippocampus and neocortex; the action of 0.1 U/ml insulin under these conditions led to an increase in the amplitude of NMDA EPSPcomponents and facilitated the development of plastic phenomena. A blocker of calcium L-type channels, verapamil (20 mg/kg), exerted no significant effect on the relay and plastic properties of synapses between hippocampal and neocortical neurons but partially weakened disorders of behavior and synaptic plasticity under EDM conditions. Such disorders were eliminated by chronic (2 weeks) injections of antidepressants, imipramine and fluoxetine (doses 20 mg/kg), against the background of clearly pronounced hyperglycemia and weakening of functional activity of neuronal NMDA receptors. We hypothesize that a deficiency of activation of insulin receptors of cerebral neurons and hyperglycemia cause a rise in the level of corticosteroids in the blood and brain, and this disturbs synaptic plasticity and behavior. This supposition is based on the ability of calcium channel blockers and (especially) antidepressants to reduce behavioral and neurochemical abnormalities in EDM.