Direct agonists for serotonin receptors enhance locomotor function in rats that received neural transplants after neonatal spinal transection.

We analyzed whether acute treatment with serotonergic agonists would improve motor function in rats with transected spinal cords (spinal rats) and in rats that received transplants of fetal spinal cord into the transection site (transplant rats). Neonates received midthoracic spinal transections within 48 hr of birth; transplant rats received fetal (embryonic day 14) spinal cord grafts at the time of transection. At 3 weeks, rats began 1-2 months of training in treadmill locomotion. Rats in the transplant group developed better weight-supported stepping than spinal rats. Systemic administration of two directly acting agonists for serotonergic 5-HT(2) receptor subtypes, quipazine and (+/-)-1-[2, 5]-dimethoxy-4-iodophenyl-2-aminopropane), further increased weight-supported stepping in transplant rats. The improvement was dose-dependent and greatest in rats with poor to moderate baseline weight support. In contrast, indirectly acting serotonergic agonists, which block reuptake of 5-HT (sertraline) or release 5-HT and block its reuptake (D-fenfluramine), failed to enhance motor function. Neither direct nor indirect agonists significantly improved locomotion in spinal rats as a group, despite equivalent upregulation of 5-HT(2) receptors in the lumbar ventral horn of lesioned rats with and without transplants. The distribution of immunoreactive serotonergic fibers within and caudal to the transplant did not appear to correspond to restoration of motor function. Our results confirm our previous demonstration that transplants improve motor performance in spinal rats. Additional stimulation with agonists at subtypes of 5-HT receptors produces a beneficial interaction with transplants that further improves motor competence.

Fetal transplants alter the development of function after spinal cord transection in newborn rats.

Pieces of fetal spinal tissue were transplanted into the site of complete midthoracic spinal transections in neonatal rat pups (transplant rats). The development of locomotion in these animals was compared with that of unoperated control rats and rats that received spinal transections alone (spinal rats). Reflex, treadmill and overground locomotion, staircase descent, and horizontal ladder crossing for a water reward were tested in control, spinal, and transplant rats from 3 weeks to adulthood. All tests were readily performed by control animals. Most spinal rats were unable to make many linked weight-supported steps on these tasks. Transplant rats were variable in their locomotor capabilities, but a subset of rats were able to demonstrate coordinated and adaptable locomotion on these tasks. Some transplant rats performed better on more challenging tasks, suggesting that motor strategies for these tasks used different information, perhaps from descending systems. Transplanted tissue survived, and in most cases there was immunocytochemical staining of serotonergic fibers passing into and caudal to the transplant, supporting the conclusion that descending systems grew through the transplanted tissue. Integration with the host tissue was often poor, suggesting that nonspecific or trophic effects of the transplant might also contribute to the development of locomotor function. Therefore several mechanisms may contribute to the repair of injured spinal cord provided by transplants that permit the development of useful locomotion.

Lesions of area postrema attenuate but do not prevent anorectic action of peripheral serotonin in rats.

These studies assessed the effect of selectively ablating the area postrema (AP) on the action of peripheral serotonin [5-hydroxytryptamine (5-HT)] to reduce food intake in rats. Intraperitoneal 5-HT (0, 2.0, 4.0, and 8.0 mumol/kg) reduced the intakes of sweetened mash during a 30-min test in controls (APC) and in AP-lesioned rats (APX). The anorexia was dose dependent in controls but the dose-response function was flat after AP lesions. In another study, 2.0 mumol/kg 5-HT reduced intakes of both groups by approximately 25%, but AP lesions blunted the effect at 8.0 mumol/kg 5-HT (APX, -30% vs. APC, -85%). Behavioral analysis revealed that, compared with controls, AP lesions eliminated the decrease in frequency of feeding and reduced the incidence of resting and of an aberrant posture observed after 8.0 mumol/kg. Thus peripheral 5-HT decreases food intake in rats with AP lesions. Multiple mechanisms appear to be involved in the ability of peripheral 5-HT to reduce feeding. A high dose of 5-HT promotes responses associated with satiation but also produces behavioral toxicity; these effects involve the AP. Lower doses appear to engage processes that do not rely on the function of this circumventricular organ.

Effect of chronic lithium chloride on membrane adenosine triphosphatases in certain postural muscles of rats.

Lithium has been extensively used as an antidepressant in the treatment of manic depressive disorders requiring chronic administration. Here, we report a study of the effect of long-term lithium treatment on the activities of membrane adenosine triphosphatases (ATPases) in certain postural muscles of rat. Specifically, Ca(2+)-ATPase, Na+,K(+)-ATPase and Mg(2+)-ATPase activities were measured in the soleus, extensor digitorum longus and plantaris muscles following 6 weeks of treatment with LiCl. Increases were observed in the Na+,K(+)-ATPase activity whereas the Mg(2+)-ATPase activity decreased with prolonged LiCl treatment. The most pronounced effect was a highly significant (P < 0.001) increase in the mitochondrial Ca(2+)-ATPase and Na+,K(+)-ATPase activity to almost 50-100% above the control. The increases in the mitochondrial Ca(2+)-ATPase activity of extensor digitorum longus and plantaris were 70% and 100%, respectively. The corresponding increases in the Na+,K(+)-ATPase activity were 127%, 99% and 87% for soleus, extensor digitorum longus and plantaris, respectively. Irrespective of the differences in the fiber pattern and physiological function, all three muscles responded in a similar way to Li+. The changes in the membrane ATPases reflect a deranged ATP turnover, thus affecting the overall energy state of the animal. Based on these results, we hypothesize that Li+ produces its effects by interfering with cation transport processes. Since Li+ affects the neural excitability of the cell it is suggested that the stimulation of the ATPases may be important in the psychotropic properties of the ion.