Effects of long-term treatment of rats with antidepressants on adrenergic-receptor sensitivity in cerebral cortex: Structure activity study

The effects of 20 tricyclic and 12 chemically unrelated ‘atypical’ antidepressant drugs on the noradrenaline (NA) receptor coupled adenylate cyclase system were investigated in slices of the rat cerebral cortex. While no changes occurred after a single dose, 14 tricyclic compounds down-regulated the receptor system when administered for 9 days. Six tricyclic antidepressants (trimipramine, butriptyline, noxiptyline, doxepine, dosulepine, propizepine) failed to desensitize the NA sensitive adenylate cyclase although some were potent inhibitors of the neuronal uptake of NA. Using the two optically active enantiomers of oxaprotiline inhibition of NA uptake was observed with the (+)-enantiomer while the (?)-enantiomer had only weak inhibitory potency. However, in contrast to published data, both enantiomers and the racemate administered at 30 mg/kg for 9 days did down-regulate the NA receptor coupled adenylate cyclase. Therefore, the experiments were repeated with Sprague-Dawley rats from a different supplier. Now, data published earlier were reproducible, only the racemate and the (+)-enantiomer of oxaprotiline being significantly active on the desensitization of the NA sensitive adenylate cyclase. Using F-344, Long Evans and Wistar rats significant differences were found in the response of the adrenoceptor coupled adenylate cyclase to a 9 day treatment with 30 mg/kg imipramine. Although some of the atypical antidepressants are potent inhibitors of the biogenic amine uptake systems none of these compounds lead to statistically significant changes of the NA stimulated cAMP formation after a 9-day treatment period. Only with the NA uptake inhibitor tandamine and with the serotonin uptake inhibitors zimelidine and fluoxetine a trend toward adrenergic down-regulation was recognized. Using enantiomers of mianserin only the (?)-isomer which is a poor NA uptake inhibitor, was slightly active. It thus appears that the therapeutic action of antidepressant drugs cannot generally be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system. Variabilities in pharmacokinetics and in NA sensitivity of the cAMP generating system in various rat strains and possibly in different animal species may be important factors determining whether β-receptor down-regulation will occur during chronic treatment with antidepressant drugs.     

Effect of vitamin E (alpha-tocopherol) on the spontaneous activity of the cerebral cortex

In experiments on 55 Meriones tamariscinus and 49 white rats the influence of D, L, alpha-tocopherolacetate on background activity of the sensorimotor and visual zones of the cerebral cortex of intact and castrated rodents was studied. Species and sex differences were revealed in animals reaction to vitamin E in doses commensurable with therapeutic ones. It is shown that tocopherol elicits a reduction of frequency and increase of amplitude of ECoGs in Meriones males and female white rats. After animal castration tocopherol action basically changes. It is suggested that the inhibitory effect of vitamin E on bioelectric processes in the cerebral cortex results from a change in the level of free-radical oxidation of lipid components of cellular membranes of cortical neurones due to an intensification of activity of their antioxidant system.     

Effects of the infusion with ACTH or CRH on the secretory activity of rat adrenal cortex

Six-hour infusion with ACTH or CRH induced a dose-dependent rise in the plasma concentrations of ACTH, corticosterone (B) and aldosterone (A). Positive linear correlations between the plasma levels of ACTH and B or A were found in both ACTH-or CRH-infused animals. Regression curves for B were similar in both groups of animals, while the regression line for A was significantly (P less than 0.05) steeper in CRH-than in ACTH-treated rats. These findings suggest that, in the rat, the mechanism underlying the CRH-induced stimulation of A secretion does not exclusively involve the enhancement of ACTH release.     

Bilaterally propagating waves of spontaneous activity arising from discrete pacemakers in the neonatal mouse cerebral cortex

Spontaneous electrical activity that moves in synchronized waves across large populations of neurons plays widespread and important roles in nervous system development. The propagation patterns of such waves can encode the spatial location of neurons to their downstream targets and strengthen synaptic connections in coherent spatial patterns. Such waves can arise as an emergent property of mutually excitatory neural networks, or can be driven by a discrete pacemaker. In the mouse cerebral cortex, spontaneous synchronized activity occurs for approximately 72 h of development centered on the day of birth. It is not known whether this activity is driven by a discrete pacemaker or occurs as an emergent network property. Here we show that this activity propagates as a wave that is initiated at either of two homologous pacemakers in the temporal region, and then propagates rapidly across both sides of the brain. When these regions of origin are surgically isolated, waves do not occur. Therefore, this cortical spontaneous activity is a bilateral wave that originates from a discrete subset of pacemaker neurons. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009     

Effects of oxiracetam and piracetam on the electrical activity of neurons of the cerebral cortex

The effect of oxiracetam and piracetam on the spontaneous impulse neuronal activity of the somatosensory cortex of the cat and rabbit was studied. Oxiracetam and piracetam when applied microiontophoretically changed neuronal activity by depressing in the majority of the cases studied or sometimes facilitating the spontaneous firing rate. A small percentage of neurons (about 30%) remains unaffected by the application of the nootropics. In some cases oxiracetam and piracetam diminished the depress effect of morphine and DADLE on the spontaneous impulse neuronal activity.     

Effects of lower alcohols on potassium transport and microsomal adenosine-triphosphatase activity of rat cerebral cortex

1. Slices of rat cerebral cortex, incubated anaerobically at 37 degrees , lost K(+) from an initial concentration of 102m-equiv./kg. to a concentration of 57m-equiv./kg. after 10min. On subsequent aerobic incubation they regained K(+) rapidly at a rate that varied with the K(+) concentration of the medium. 2. Lower aliphatic alcohols, present at equal thermodynamic activity, produced approximately equal degrees of inhibition of K(+) uptake during the aerobic incubation. This inhibition was reduced by an increase in K(+) content of the medium. Ethanol did not affect the rate of K(+) loss during anaerobic incubation. 3. Li(+), in concentrations of 1-10mm, also inhibited K(+) uptake by brain-cortex slices, the degree of inhibition varying with the Li(+) concentration. Ouabain also inhibited K(+) uptake. 4. The same series of alcohols, at equal thermodynamic activity, produced comparable degrees of inhibition of Na(+),K(+),Mg(2+)-stimulated adenosine-triphosphatase activity in brain microsomes. 5. It is suggested that inhibition of cation transport is an important, but not a primary, mechanism in the production of central nervous depression by alcohols and other substances.