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L P Martin

Publications and source records attributed to L P Martin.

13 recordsLinked to original sources
PubMed1998

Expression of a dopamine D2 receptor-activated K+ channel on identified striatopallidal and striatonigral neurons.

One view of the efferent circuitry of the basal ganglia holds that dopamine D1 and D2 receptors are segregated to striatonigral and striatopallidal neurons, respectively. The present studies investigated whether functional D2-like receptors are, in fact, restricted to striatopallidal neurons. Single, freshly dissociated cells from rat striatum were identified as either striatonigral or striatopallidal projection neurons by fluorescence retrograde labeling. By using cell-attached patch-clamp recordings, neurons of each efferent group were evaluated for the presence of a D2-like receptor-activated 85-pS K+ channel as a measure of receptor function. We now report the presence of this D2 receptor-mediated response on both striatal efferent populations, but we observed an approximately 2-fold higher likelihood of encountering the channel on pallidal- versus nigral-projecting neurons. The channel's conductance properties appeared identical in both groups of neurons, but there was a significantly greater open probability for channels detected on striatopallidal neurons. These results indicate that functional D2 receptors are not segregated to striatopallidal neurons, but may be expressed in a higher proportion of, or at a higher density and/or efficiency of coupling on, pallidal- versus nigral-projecting striatal efferents.

Animals↗
PubMed1998

Elongation behavior of calcaneofibular and cervical ligaments during inversion loads applied in an open kinetic chain.

The cervical ligament plays a significant role in lateral stability of the subtalar joint but has received little attention compared with other ankle and subtalar joint ligaments. The purpose of this research was twofold. First, the elongation behavior of the cervical ligament was assessed with the calcaneofibular ligament intact and cut during two different types of inversion loads (manual and mechanical). Second, inversion range of motion was determined concomitantly with inversion loading and the difference in inversion range of motion between the calcaneofibular ligament intact to cut state was compared. The mean elongation of the cervical ligament with the calcaneofibular intact was 0.58 mm (+/- 0.33 mm) and 0.46 mm (+/- 0.23 mm) for manual and mechanical methods, respectively, and 0.88 mm (+/- 0.37 mm) and 0.78 mm (+/- 0.37 mm), respectively, for the same methods in the absence of the calcaneofibular ligament. This difference was statistically significant (P < 0.05 manually and P < 0.02 mechanically). An average increase in the inversion range of motion was noted with both methods [7.5 degrees manually (+/- 2.75 degrees) and 7.7 degrees mechanically (+/- 2.95 degrees)] after lesioning of the calcaneofibular ligament. This difference was statistically significant (P < 0.001) for both manual and mechanical range of motion testing. The results of this study indicate that there is a significant increase in elongation of the cervical ligament in the absence of the calcaneofibular ligament during manual and mechanically applied inversion loads in a open kinetic chain. Clinical and theoretical implications of this data are discussed.

Aged↗
PubMed1998

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Dental Calculus↗
PubMed1997

Functional roles of dopamine D2 and D3 autoreceptors on nigrostriatal neurons analyzed by antisense knockdown in vivo.

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.

Animals↗
PubMed1996

Dopamine D2, receptor-mediated modulation of the GABAergic inhibition of substantia nigra pars reticulata neurons.

Neurons of the substantia nigra pars reticulata can be readily and fully inhibited by endogenously released or iontophoretically applied GABA. We have previously shown that co-application of dopamine or the D2-like agonist quinpirole causes a current-dependent attenuation of the inhibitory response of these neurons to GABA. To determine if the modulation of GABA responsiveness was mediated by activation of D2 receptors, effects of iontophoretic quinpirole were examined after various treatments which block or inactivate D2 receptors, or uncouple D2 receptors from their G-proteins. Results showed that the GABA-attenuating effect of quinpirole could be attributed to stimulation of D2 receptors, and not a non-specific effect of the drug, since (1) co-iontophoresis of the D2 antagonist YM 09151-2 antagonized the GABA-modulatory effect of quinpirole, (2) prior intranigral injection of the receptor inactivator N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 50 nmol/0.5 ml one day before recording) prevented the response to quinpirole, and (3) prior intranigral injection of the Gi-Go-protein inactivator pertussis toxin (1 mg/ml 0.9% NaCl 24 h before recording) completely abolished the ability of quinpirole to lessen the inhibitory response to GABA. The location of the involved D2 receptors was examined using selective lesioning approaches. Kainic acid lesions of the striatonigral pathway did not prevent the ability of quinpirole to attenuate responses of pars reticulata neurons to GABA. Similarly, in previous studies [59], 6-hydroxydopamine lesions of the adjacent pars compacta dopamine neurons were found not to abolish the GABA-attenuating effect of dopamine. Thus, it appears that the receptors mediating the response are not localized to either striatonigral terminals nor to the adjacent dopamine neurons, leaving open the possibility that the response is mediated by D2 receptors located on pars reticulata neurons. Collectively these results suggest that dendritically released dopamine may act via nigral D2 receptors, perhaps located on pars reticulata neurons themselves, to regulate basal ganglia output from the substantia nigra.

Animals↗
PubMed1995

GABAA receptor-mediated inhibition of rat substantia nigra dopaminergic neurons by pars reticulata projection neurons.

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.

Animals↗
PubMed1994

D1 agonist-induced excitation of substantia nigra pars reticulata neurons: mediation by D1 receptors on striatonigral terminals via a pertussis toxin-sensitive coupling pathway.

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.

Animals↗
PubMed1990

Behavioural, biochemical and electrophysiological studies on the motor depressant and stimulant effects of bromocriptine.

Bromocriptine (BRC) produced a biphasic behavioural effect in mice; an early depressant phase which lasted for about 1 h and a later stimulant phase which lasted from about 1 to 5 h. The stimulation was blocked with SCH23390. Both phases of activity were accompanied by marked striatal DA autoreceptor effects as indicated by reductions in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels and by a reduction in the accumulation of DOPA (after inhibition of nigrostriatal DA nerve firing and DOPA decarboxylase). However, while the autoreceptor effects were still evident during the behavioural stimulant phase, there was a gradual rise in DOPAC and HVA from 1 to 4 h after injection, indicating a gradually increasing DA turnover. We were unable, using a variety of behavioural and biochemical paradigms, to demonstrate any change in DA autoreceptor sensitivity after one dose of BRC. In electrophysiological studies, however, it was found that prior exposure of rats to one dose of BRC rendered them subsensitive to the rate-inhibiting effects of a second dose of BRC, as measured in anaesthetized animals using extracellular single cell recordings of identified DA neurons in the substantia nigra pars compacta. It is concluded firstly, that the stimulant phase of BRC in mice occurs despite continued occupation of the DA autoreceptors by BRC because adequate endogenous DA is available to provide the required D1 receptor stimulation and secondly, that the terminal autoreceptors in the striatum (as assessed in mice using biochemical techniques) may be regulated differently to the somatodendritic autoreceptors (as assessed electrophysiologically in rats).

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Efficacy and potency comparisons among aporphine enantiomers: effects on dopamine neurons in substantia nigra of rat.

Extracellular single unit recording studies were carried out on male rats to determine the responses of dopamine neurons of the substantia nigra to intravenous administration of the enantiomers of the aporphine congeners, apomorphine (APO), N-n-propylnorapomorphine (NPA) and 11-hydroxy-N-n-propylnorapomorphine (11-OH-NPa). The R-(-)-configuration was found to be the most critical determinant of the efficacy and potency of the agonists. All R-(-)-aporphines were full agonists, able to inhibit completely firing of dopamine cells. The order of potencies, defined by the ID50s, was: (-)NPA, 2.0 +/- 0.4 nmol/kg greater than (-)11-OH-NPa, 4.7 +/- 0.7 nmol/kg greater than (-)APO, 18.0 +/- 4.0 nmol/kg. Thus, potency was increased about 9-fold by replacing the 6N methyl of APO with an n-propyl (NPA). Conversely, the 10-hydroxy was not essential for agonist activity (11-OH-NPa) but could increase potency. In the S-(+)-series responses varied. (+)N-n-Propylnorapomorphine exhibited agonist properties and could fully inhibit dopamine cells, but its potency was low (ID50 1550 nmol/kg); (+)APO produced only slight but significant decreases in firing at large (8434 nmol/kg) doses and (+)11-OH-NPa was devoid of efficacy in that it caused no significant changes in firing. Despite their loss of efficacy and potency, the (+)-enantiomers apparently did retain affinity for DA receptors, since they could act as antagonists if given before (-)APO or NPA. These findings suggest that stereochemical conformation and key structural elements of the aporphines are interactive in determining agonist efficacy and potency within this physiological test system.

Animals↗