Evidence from electrophysiological studies has suggested an inhibitory interaction between GABAergic neurons in substantia nigra pars reticulata and dopaminergic neurons in pars compacta. However, that this inhibitory interaction is due to a projection from pars reticulata to pars compacta has never been demonstrated directly, nor has the GABAergic neuron that mediates the interaction been identified either electrophysiologically or anatomically. To more closely examine interactions between substantia nigra pars reticulata GABA neurons and dopaminergic neurons, single unit extracellular recordings were obtained from antidromically identified nigrostriatal neurons and their response to antidromic activation of nigral GABAergic projection neurons observed. Stimulation of superior colliculus or thalamus produced a short latency inhibition of dopaminergic neurons. This inhibition was blocked by local application of bicuculline but not 2-hydroxysaclofen. Bicuculline caused most dopaminergic neurons to fire in a bursty mode, whereas saclofen caused most dopaminergic neurons to fire in a pacemaker-like mode. The thalamic-evoked inhibition was not affected by kainate lesions of the globus pallidus, but these lesions produced effects on firing pattern identical to those produced by saclofen. These data demonstrate a short latency inhibition of nigral dopaminergic neurons mediated by GABAA receptors that arises from the axon collaterals of pars reticulata projection neurons. We propose a model in which the firing pattern of nigral dopaminergic neurons in vivo is modulated differentially by disinhibition of GABAA inputs arising from pars reticulata projection neuron axon collaterals and disinhibition of pallidonigral GABAergic inputs mediated by GABAB receptors.

Two different 19-mer antisense oligodeoxynucleotides complementary to the initial coding regions of dopamine D2 or D3 receptor mRNA were infused unilaterally into the substantia nigra of rats for 3-6 d to suppress synthesis of D2 and/or D3 receptors on substantia nigra dopaminergic neurons, thereby producing specific reductions of D2 and/or D3 receptors. Autoradiographic receptor binding revealed that D2 and D3 antisense oligodeoxynucleotides specifically and significantly reduced D2 or D3 binding in the ipsilateral substantia nigra, respectively, without affecting dopamine receptor binding in the neostriatum. Either D2 or D3 antisense oligodeoxynucleotides greatly attenuated the ability of apomorphine to inhibit dopaminergic neurons in vivo, an effect that was potentiated by simultaneous administration of D2 and D3 antisenses. Despite these effects, neither the rate nor the pattern of spontaneous activity of antisense-treated nigrostriatal neurons differed from those in the control groups. The proportion of antidromic responses consisting of full spikes from antisense-treated rats was significantly greater, and the mean antidromic threshold was significantly lower than in controls, indicating that autoreceptor knockdown increased both somatodendritic and terminal excitability. These data demonstrate that selective reduction of specific dopamine receptor subtypes by antisense infusion can be effected in vivo, and that nigrostriatal neurons express both D2 and D3 autoreceptors at their somatodendritic and axon terminal regions. Although the somatodendritic and terminal autoreceptors modulate dendritic and terminal excitability, respectively, the interaction of endogenously released dopamine with somatodendritic autoreceptors does not appear to exert a significant effect on spontaneous activity in anesthetized rats.

Background/Aims: Abnormal bone and mineral metabolism is common in patients with kidney failure and often persists after successful kidney transplant. Methods: To better understand the natural history of this disease in transplant patients, we reviewed the literature by searching MEDLINE for English language articles published between January 1990 and October 2006 that contained Medical Subject Headings and key words related to secondary or persistent hyperparathyroidism and kidney transplant. Results: Parathyroid hormone levels decreased significantly during the first 3 months after transplant but typically stabilized at elevated values after 1 year. Calcium tended to increase after transplant and then stabilize at the higher end of the normal range within 2 months. Phosphorus decreased rapidly to within or below normal levels after surgery and hypophosphatemia, if present, resolved within 2 months. Low levels of 1,25(OH)₂ vitamin D typically did not reach normal values until almost 18 months after transplant. Conclusion: This review provides evidence demonstrating that abnormal bone and mineral metabolism exists in patients after kidney transplant and suggests the need for treatment of this condition. However, better observational and interventional research is needed before advocating such a treatment guideline.

Bilateral infusions of d-amphetamine into the rat ventral-lateral striatum (VLS) were previously shown to cause a robust behavioral activation that was correlated temporally with a net increase in firing of substantia nigra pars reticulata (SNpr) neurons, a response opposite predictions of the basal ganglia model. The current studies assessed the individual and cooperative contributions of striatal D 1 and D 2 dopamine receptors to these responses. Bilateral infusions into VLS of the D 1 /D 2 agonist apomorphine (10 g/l/side) caused intense oral movements and sniffing, and an overall increase in SNpr cell firing to 133% of basal rates, similar to effects of d-amphetamine. However, when striatal D 2 receptors were stimulated selectively by infusions of quinpirole (30 g/l/side) ϩ the D 1 antagonist R-(ϩ) -7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390; 10 g/l/ side), no behavioral response and only modest and variable changes in SNpr cell firing were observed. Selective stimulation of striatal D 1 receptors by (Ϯ) 6-chloro-APB hydrobromide (SKF 82958; 10 g/l/side) ϩ the D 2 antagonist cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-5-chloro-2-methoxy-4-methyl-aminobenzamide (YM 09151-2; 2 g/l/side) caused a weak but sustained increase in oral movements and modestly increased SNpr cell firing, but neither response was of the magnitude observed with apomorphine. When the two agonists were infused concurrently, however, robust oral movements and sniffing again occurred over the same time period that a majority of SNpr cells exhibited marked, sometimes extreme and fluctuating, changes in firing (net increase, 117% of basal rates). These data confirm that concurrent striatal D 1 /D 2 receptor stimulation elicits a strong motor activation that is correlated temporally with a net excitation rather than inhibition of SNpr firing, and reveal that D 1 and D 2 receptors interact synergistically within the striatum to stimulate both forms of output.The basal ganglia functional model predicts that dopamine, by stimulating the striatonigral pathway via D 1 receptors and inhibiting the striatopallidal pathway via D 2 receptors, should inhibit output from the substantia nigra pars reticulata and internal pallidal segment (SNpr/GPi). Inhibition of output from the SNr/GPi should in turn disinhibit the thalamus to facilitate movement (for review, see Alexander and Crutcher, 1990). Many of the predictions of the model have been supported by electrophysiological studies in humans with Parkinson's disease and animal models of this disorder (Filion and Tremblay, 1991;Bergman et al., 1994;Papa et al., 1999;Levy et al., 2001). However, the question of whether these predictions are valid and supported in normal animals without dopaminergic lesions has been less rigorously addressed.A definitive test of this hypothesis has been made difficult by the complexity of the circuitry, in particular by the fact that D 1 and D 2 receptors are expressed not only within the striatum but also in other nuclei of th...

Iontophoresis of dopamine or the D1 agonist SKF 38393 has been shown to elicit current-dependent increases in the firing of rat substantia nigra pars reticulata neurons, suggesting a discrete physiological role for the D1 dopamine receptor population in the substantia nigra. The effects of SKF 38393 differed from those of dopamine, however, in that the D1 agonist also augmented inhibitory responses to applied GABA, whereas dopamine and D2-like agonists were previously found to attenuate responses to GABA. The present studies involved various manipulations of the nigral D1 receptors in order to examine the pharmacological specificity, receptor localization, and second messenger coupling underlying the D1 agonist response. The excitatory and GABA-potentiating effects of SKF 38393 were found to be attributable to D1 receptor stimulation, rather than a nonspecific action, since (1) the effect was mimicked by iontophoresis of A-68930, a D1 agonist of a different structural class than SKF 38393, and (2) the response to SKF 38393 was prevented by intranigral injection of the receptor inactivator N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 50 nmol/0.5 microliter) 1 d before, or the D1 antagonist SCH 23390 (1 microgram/microliter) 1 hr before electrophysiological testing. Additional studies revealed that the involved D1 receptors were located presynaptically on striatonigral terminals. For instance, in rats given ipsilateral striatal kainic acid lesions 1 week earlier, application of SKF 38393 failed to elicit the usual increases in cell firing, but loss of the response was observed only among the group of pars reticulata neurons that were shown to be unresponsive to striatal stimulation (i.e., those whose striatonigral inputs had been terminated by the lesion). Finally, to examine the second messenger coupling characteristics of the involved D1 receptors, several membrane- permeable analogs of cAMP were tested iontophoretically in place of SKF 38393. Surprisingly, none of these compounds gave a pattern of response typical of the D1 agonist, raising questions about the involvement of cAMP. Even more suggestive of an unconventional D1 coupling pathway, the excitatory and GABA-potentiating effects of applied SKF 38393 were completely abolished by prior intranigral injection of the G(i)/G(o) protein inactivator, pertussis toxin. Collectively, these results suggest that stimulation of D1 receptors on striatonigral terminals causes an excitation of substantia nigra pars reticulata neurons with an exaggerated responsiveness to GABA, and the effects appear to be mediated by a pertussis toxin-sensitive (i.e., a non-G-like) G-protein and possibly a second messenger other than cAMP.