Dopamine enhancement of NMDA currents in dissociated medium-sized striatal neurons: role of D1 receptors and DARPP-32

Dopamine (DA), via activation of D1 receptors, enhances N-methyl-D-aspartate (NMDA)-evoked responses in striatal neurons. The present investigation examined further the properties of this enhancement and the potential mechanisms by which this enhancement might be effected. Dissociated medium-sized striatal neurons were obtained from intact rats and mice or mutant mice lacking the DA and cyclic adenosine 3',5' monophosphate (cAMP)-regulated phosphoprotein of M(R) 32,000 (DARPP-32). NMDA (10-1,000 microM) induced inward currents in all neurons. In acutely dissociated neurons from intact rats or mice, activation of D1 receptors with the selective agonist, SKF 81297, produced a dose-dependent enhancement of NMDA currents. This enhancement was reduced by the selective D1 receptor antagonist SKF 83566. Quinpirole, a D2 receptor agonist alone, produced small reductions of NMDA currents. However, it consistently and significantly reduced the enhancement of NMDA currents by D1 agonists. In dissociated striatal neurons, in conditions that minimized the contributions of voltage-gated Ca(2+) conductances, the D1-induced potentiation was not altered by blockade of L-type voltage-gated Ca(2+) conductances in contrast to results in slices. The DARPP-32 signaling pathway has an important role in D1 modulation of NMDA currents. In mice lacking DARPP-32, the enhancement was significantly reduced. Furthermore, okadaic acid, a protein phosphatase 1 (PP-1) inhibitor, increased D1-induced potentiation, suggesting that constitutively active PP-1 attenuates D1-induced potentiation. Finally, activation of D1 receptors produced differential effects on NMDA and gamma aminobutyric acid (GABA)-induced currents in the same cells, enhancing NMDA currents and inhibiting GABA currents. Thus simultaneous activation of D1, NMDA, and GABA receptors could predispose medium-sized spiny neurons toward excitation. Taken together, the present findings indicate that the unique potentiation of NMDA receptor function by activation of the D1 receptor signaling cascade can be controlled by multiple mechanisms and has major influences on neuronal function.     

Effects of repeated maternal separations on the adrenocortical response to stress of preweanling rats.

Previous data indicate that the infant rat shows a marked increase in adrenocortical responsiveness to stress immediately following prolonged maternal separation. In Experiment 1 we studied the immediate effects of repeated maternal deprivation. Our results indicate that the increase in basal as well as stress-induced corticosterone levels is a direct function of the length of the deprivation period immediately preceding testing, and is not cumulative. In Experiment 2 we examined the long-term consequences of maternal deprivation on adrenal responsivity. Four days following a single 24-h period of maternal deprivation, pups remained hyperresponsive to stress, although their basal levels of corticosterone had returned to control values. Shorter periods of deprivation (which did result in increased responsivity immediately following deprivation) did not have persistent effects. Our data suggest: 1) short periods of deprivation do not have a cumulative effect, and 2) there is a critical length of deprivation beyond which persistent changes in adrenocortical responsivity ensue.     

Noxious stimulus-induced increase in spinal prostaglandin E2 is noradrenergic terminal-dependent

Prostaglandins (PGs) were measured in perfusate from the lumbar intrathecal (IT) space of pentobarbital anaesthetized rats. The level of PGE2, but not of PGF2 alpha or 6-keto PGF1 alpha, was increased by immersion of a hindpaw in water at a noxious temperature (50 degrees C). No increase in PGE2 was produced by non-noxious thermal stimulation (35 degrees C water). The noxious stimulus-evoked increase in PGE2, and increases in PGE2 during norepinephrine infusion (10 micrograms/ml), were significantly decreased in rats pretreated with intrathecal 6-hydroxydopamine. These data suggest that noxious stimuli induce an increase in the production of spinal PGE2 and that this production derives from, or requires the presence of noradrenergic terminals in the spinal cord.     

The social worker's interview in chronic urticaria.

Ten patients with chronic urticaria were interviewed by a psychiatric social worker as part of the clinical examination. The information obtained was evaluated in comparison with the allergist-internist's history by the allergist-internist, psychiatrist and social workers. The social worker's interview offered relatively little help to the managing physician or patient in this setting.     

Development of circadian periodicity in base and stress levels of corticosterone.

Base and stress levels of corticosterone were assessed at 4-h intervals over a 24-h period in male and female rats at age 18, 22, and 26 days. A significant periodicity in base levels of corticosterone is present at 22 days of age; however, a rhythm in stress values does not appear until age 26 days. At age 26 days the pattern of the circadian periodicity in both base and stress concentrations of corticosterone resembles that of the mature rhythm.     

Postnatal development of neurogenic inflammation in the rat.

We have studied the development in the rat of neurogenic inflammatory mechanisms that mediate cutaneous plasma extravasation. At birth and at postnatal day 10, intradermal injection of substance P, histamine, and bradykinin produced no significant plasma extravasation. At day 13 through adulthood (days 42-49), all test agents produced significant plasma extravasation which increased with increasing age. In the adult rat, pretreatment with 6-hydroxydopamine, to eliminate sympathetic postganglionic nerve terminals, attenuated the plasma extravasation elicited by substance P, histamine and bradykinin. The possible role of the sympathetic postganglionic neuron in the age-dependent changes in neurogenic inflammation is discussed.     

Physiological and behavioral effects of prior aversive stimulation (preshock) in the rat

Physiological and behavioral measures were assessed in rats that had been previously exposed to unsignaled inescapable intense shock (preshock). Animals subjected to such prior aversive stimulation exhibited greater adrenocortical steroid response compared to nonpreshocked controls when subsequently tested in the open field. An increment in defecation was also observed, with ambulation and rearing behavior being markedly inhibited in the preshocked rat during these sessions.     

Orexin A mediation of time spent moving in rats: Neural mechanisms

The brain regulates energy balance and spontaneous physical activity, including both small- and large-motor activities. Neural mediators of spontaneous physical activity are currently undefined, although the amount of time spent in sedentary positions versus standing and ambulating may be important in the energetics of human obesity. Orexin A, a neuropeptide produced in caudal hypothalamic areas and projecting throughout the neuraxis, enhances arousal and spontaneous physical activity. To test the hypothesis that orexin A affects the amount of time spent moving, we injected orexin A (0–1000 pmol) into three orexin projection sites in male Sprague–Dawley rats: hypothalamic paraventricular nucleus, rostral lateral hypothalamic area and substantia nigra pars compacta, and measured spontaneous physical activity. Orexin A affects local GABA release and we co-injected orexin A with a GABA agonist, muscimol, in each brain site. Dopamine signaling is important to substantia nigra function and so we also co-injected a dopamine 1 receptor antagonist (SCH 23390) in the substantia nigra pars compacta. In all brain sites orexin A significantly increased time spent vertical and ambulating. Muscimol significantly and dose-dependently inhibited orexin A effects on time spent moving only when administered to the rostral lateral hypothalamic area. In the substantia nigra pars compacta, SCH 23390 completely blocked orexin A–induced ambulation. These data indicate that orexin A influences time spent moving, in three brain sites utilizing separate signaling mechanisms. That orexin A modulation of spontaneous physical activity occurs in brain areas with multiple roles indicates generalization across brain site, and may reflect a fundamental mechanism for enhancing activity levels. This potential for conferring physical activity stimulation may be useful for inducing shifts in time spent moving, which has important implications for obesity.