Heterologous regulation of receptors on target cells of dopamine neurons in the prefrontal cortex, nucleus accumbens, and striatum.
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Animals↗
Biomedical subjects
J Glowinski
Publications and source records attributed to J Glowinski.
Mu and delta opiate receptors coupled negatively to adenylate cyclase on embryonic neurons from the mouse striatum in primary cultures.
Primary cultures of pure populations of neuronal or glial cells from the striatum, the cerebral cortex, and the mesencephalon of the mouse embryo were used to look for the presence of opiate receptors coupled to adenylate cyclase. Leu-enkephalin inhibited cAMP production in membranes of embryonic striatal neurons but not in those of other cell types examined. Mu and delta opiate receptors seemed to be coupled negatively to adenylate cyclase in embryonic striatal neurons. It was found that DTLET (a selective delta agonist), as well as DAGO (a selective mu agonist), inhibited cAMP production on these cells. DTLET but not, however, DAGO produced a similar effect on homogenates from the adult rat striatum and on membranes from the neuroblastoma x glioma hybrid cell line NG 108-15, two preparations known to possess only delta receptors negatively coupled to adenylate cyclase. The selective kappa agonist U 50.488 was ineffective on all types of membrane preparations used. The inhibitory effects of both DTLET and DAGO on basal adenylate cyclase activity in striatal neurons were reversed by naloxone with a similar efficacy. Two other selective mu agonists, trimu 5 and morphiceptin, inhibited cAMP production in membranes of striatal neurons as well. The nonadditivity of the inhibitory effects of DTLET and DAGO on basal or forskolin-induced activation of adenylate cyclase suggested that mu and delta receptors were colocalized on a similar subpopulation of striatal cells in primary culture. These cells possess dopaminergic receptors of the D1 subtype as well since the amplitude of the inhibitory effects of DTLET and DAGO on cAMP production was increased in the presence of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenylyl Cyclase Inhibitors↗
[Primary hyperparathyroidism and secondary polycythemia].
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Humans↗
[Chronic refractory pain in cancer patients. Value of the spinal injection of lysine acetylsalicylate. 60 cases].
Several animal studies have demonstrated that pain is modulated by spinal mechanisms involving prostaglandins and that acetylsalicylic acid (ASA) administered intrathecally has an analgesic effect. We report our experience of this treatment in 60 patients with proven and advanced cancer. An isobaric solution of lysine acetylsalicylate was administered by lumbar puncture in doses ranging from 120 to 720 mg of ASA. The results were evaluated using the habitual criteria: scoring system, behaviour, consumption of analgesic drugs. In this trial the method proved astonishingly effective (78% of the cases). Analgesia was strong, almost immediate and without influence on motricity. No thermic or neurovegetative changes were noted. The effect of one injection lasted from 3 weeks to 1 month on average; it was reproduced and often more prolonged after a repeat injection. Pain associated with bone metastases seems to constitute the best indication, notably in breast and lung cancer and in myeloma. Visceral (pancreas) or neural pain requires higher doses to respond. Failures (22%) were due to such factors as insufficient dosage at the very beginning of our experience or severe depressive syndrome. The perineal and sphincteral pain of rectal cancer often resists treatment. This simple, inexpensive and very effective method with no other complication than a frequent tendency to fatigue should rank among other analgesic measures in cancer. The lack of respiratory depression is a major advantage over catheter spinal opiate analgesia. We consider that its main indications are pain associated with osteolytic metastases of adenocarcinomas, and myelomas. Owing to the absence of formal toxicological data, its use must be limited to cancer pain and to patients with a life expectancy of less than 2 years.
Adult↗
Interhemispheric and subcortical collaterals of medial prefrontal cortical neurons in the rat.
Efferent neurons of rat medial prefrontal cortex, projecting to subcortical structures and contralateral homotypical areas, were analyzed using anatomical and electrophysiological methods. Anterograde labelling with radioactive amino acids demonstrated the pathways of these efferents in the rostral part of the brain; terminal fields in contralateral cortical areas and localization of fibers projecting subcortically were particularly examined. The laminar location of cells projecting to the contralateral prefrontal cortex or through the striatum was investigated by means of the retrograde transport of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) injected in these two structures. Cells innervating the contralateral prefrontal cortex were distributed in layers II-III and V, whereas injection of WGA-HRP in the striatum labelled cells in layer V. The antidromic activation technique was used to identify the cortical neurons which innervate the ipsilateral and contralateral subcortical structures as well as contralateral homotypical cortical areas. Among 743 recorded neurons, 282 neurons were antidromically driven from at least one of the stimulated sites (e.g. right striatum (RS), left striatum (LS), and contralateral prefrontal cortex (L-Cx]. The mean conduction velocities were 0.6 m/s and 0.8 m/s for subcortical and cortical efferents, respectively. The reciprocal collision test provided evidence for the existence of branched axons for 35% of the antidromically activated cells. All the possible branching patterns were found. The results of this study thus demonstrate the existence of single neocortical neurons that send axon collaterals to contralateral cortex and subcortical structures.
Action Potentials↗
Different effects of electrical stimulation of the mesencephalic and pontine reticular formation on the release of dopamine and acetylcholine in the cat caudate nucleus.
The effects of unilateral electrical stimulation of the pontine (PRF) and mesencephalic (MRF) reticular formation on the release of acetylcholine (ACh) and of [3H]dopamine continuously synthesised from [3H]tyrosine were examined in both caudate nuclei of halothane-anaesthetised cats implanted with push-pull cannulae. Stimulation of PRF led to a prolonged bilateral increase in the release of [3H]dopamine, whereas a significant reduction in [3H]amine release was observed in the ipsilateral caudate nucleus following stimulation of the MRF. Changes in ACh release were also seen, but they seemed to be independent from those in dopamine release: the release of ACh was enhanced markedly in both caudate nuclei following stimulation of the MRF, whereas a more moderate increase in the release of ACh occurred ipsilaterally following stimulation of the PRF. These data indicate that both the MRF and the PRF are involved in the control of dopaminergic and cholinergic transmission in the basal ganglia.
Acetylcholine↗
Somatostatin receptors on cortical neurones and adenohypophysis: comparison between specific binding and adenylate cyclase inhibition.
Primary cultures of mouse embryonic neurones from the cerebral cortex and rat pituitary membranes were used to identify and characterize further the somatostatin receptors coupled to an adenylate cyclase and to compare these receptors with specific binding sites for a non-reducible somatostatin analog. 125I-CGP 23996 on both tissues. 125I-CGP 23996 bound specifically to a single population of sites on cortical neurones and pituitary membranes, with a high affinity (Kd = 2.76 and 1.95 nM respectively). The rank order of potency of somatostatin-(1-14) and some analogs (somatostatin-28, [D-Trp8,D-Cys14]somatostatin-(1-14), native CGP) to displace 125I-CGP 23996 from its binding sites was similar on both tissues. Furthermore this rank order was also found identical for the inhibition of adenylate cyclase activity on cortical neuronal and pituitary membranes. Finally a good correlation was found between the order of potencies of somatostatin analogs evaluated from binding experiments and adenylate cyclase assays, suggesting the presence of the same receptor observed under two different affinity states. According to the classification of somatostatin receptors by Tran and his colleagues (1985) these results support the hypothesis that SSA is the somatostatin receptor coupled with an adenylate cyclase.
Adenylyl Cyclase Inhibitors↗
Anatomical and electrophysiological evidence for a direct projection from Ammon's horn to the medial prefrontal cortex in the rat.
Following microinjection of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) into the medial prefrontal cortex (defined as the neocortical area innervated by the thalamic mediodorsal nucleus) labelled cells were observed in the pyramidal layer of the CA1 field of Ammon's horn. Observations made using antidromic stimulation confirmed these results, and revealed that slow conduction velocity of the fibers of the hippocampal cells innervating the prefrontal cortex. Taken together, these data provide evidence for a direct projection of CA1 cells to the medial prefrontal cortex.
Animals↗
The role of dopamine released from distal and proximal dendrites of nigrostriatal dopaminergic neurons in the control of GABA transmission in the thalamic nucleus ventralis medialis in the cat.
Halothane-anaesthetized cats implanted with push-pull cannulae were used in this study. Amphetamine was applied in the pars reticulata or pars compacta of the substantia nigra in order to determine the role of dopamine released from distal or proximal dendrites of dopaminergic cells in the control of GABAergic transmission in the nucleus ventralis medialis of the thalamus. When applied for 30 min in either the pars reticulata or the pars compacta, amphetamine (10(-6) M) enhanced to a similar extent the local release of [3H]dopamine synthesized from [3H]tyrosine, these effects being seen mainly during the drug application. The amphetamine-evoked release of dopamine in the pars reticulata produced a long lasting reduction in the release of [3H]GABA synthesized from [3H]glutamine in the nucleus ventralis medialis as well as in the paralamellar zone of the nucleus ventralis lateralis. Opposite effects were observed when amphetamine (10(-6) M) was applied in the pars compacta. In complementary experiments, single unit recordings were made in the intermediate part of the pars reticulata, some of the cells being identified by antidromic activation from the nucleus ventralis medialis. Whether applied in the pars reticulata or pars compacta, amphetamine (10(-6) M, 10 min) evoked a reversible decrease in the firing rate of most recorded cells whether or not they were identified as projecting to the nucleus ventralis medialis. Therefore, the decreased release of [3H]GABA in the nucleus ventralis medialis seen following application of amphetamine in the pars reticulata of the substantia nigra could result from an inhibition of nigrothalamic GABAergic neurons. Since the nucleus ventralis medialis is also innervated by GABAergic neurons originating in the entopeduncular nucleus, single unit recordings were made from cells in this nucleus during the application of amphetamine (10(-6) M, 10 min) into the pars compacta of the substantia nigra, some of which were identified antidromically as projecting to the nucleus ventralis medialis. Most cells identified or not were found to be activated during this treatment. These results suggested that the increased release of [3H]GABA seen in the nucleus ventralis medialis following application of amphetamine in the pars compacta of the substantia nigra might be linked to the enhanced firing rate of entopeduncular-thalamic GABAergic neurons.
Action Potentials↗
Tachykinin receptors in the CNS.
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Animals↗
[3H]neurokinin B and 125I-Bolton Hunter eledoisin label identical tachykinin binding sites in the rat brain.
[3H]Neurokinin B ([3H]NKB) of high specific activity (75 Ci/mmol) was synthesized for study of its binding to crude synaptosomes from the rat cerebral cortex. The specific binding of [3H]NKB (75% of total binding) was temperature dependent, saturable, and reversible. Scatchard analyses and Hill plots showed the existence of a single population of noninteracting binding sites (KD = 4.3 nM; Bmax = 123 fmol/mg of protein). Competition studies indicated the following rank order of potencies among tachykinins: NKB greater than eledoisin (E) greater than kassinin greater than physalaemin greater than neurokinin A (NKA) greater than substance P (SP), a result suggesting that NKB might be the endogenous ligand for [3H]NKB binding sites. It is of interest that 127I-Bolton Hunter (BH) NKA (127I-BHNKA) was much more potent than NKA in inhibiting the specific binding of [3H]NKB, which raises certain questions concerning the use of 125I-BHNKA as a ligand for NKA binding sites in the brain. These results, as well as those obtained with different SP analogues, show a close similarity to those obtained previously with 125I-BHE binding to cortical synaptosomes. This suggested that the two ligands labeled identical binding sites. In addition, using either [3H]NKB or 125I-BHE as ligands, similar displacement curves were obtained with increasing concentrations of NKB and 127I-BHE. The similarity of the [3H]NKB and 125I-BHE binding sites was further confirmed by comparison of their localization on rat brain sections by autoradiography. The distribution of binding sites for [3H]NKB and 125I-BHE was identical throughout the brain, and the highest density of binding sites for the two ligands was found in layers IV and V of the cerebral cortex, the paraventricular nucleus of the hypothalamus (magnocellular part), and the ventral tegmental area.
Animals↗
Adaptive responsiveness of some central receptors to the denervation of heterologous afferent fibers: functional significance and possible behavioral consequences.
As shown in the rat brain, the development of the classical "denervation supersensitivity" of receptors does not always occur despite the complete destruction of the corresponding afferent fibers. This is due to the concomitant destruction of heterologous fibers which directly or indirectly contribute to the regulation of the denervated receptors. In this review, on the basis of data obtained in rats with lesions of ascending DA neurons, three examples of hetero-regulation of receptors will be provided. In the prefrontal cortex, the concomitant destruction of afferent noradrenergic fibers (NA) prevents the development of the denervation supersensitivity of DA receptors of the D1 type. In the nucleus accumbens, the development of the denervation supersensitivity of D1 receptors seems to be dependent on the state of activity of the cortico-nucleus accumbens glutamatergic projection. Finally, in cortico-limbic structures, the prolonged interruption of DA transmission leads to an increased density of 125I-neurotensin binding sites. These hetero-regulations reflect the existence of possible functional relationships between the two types of neuronal populations under investigation. As an example, it will be shown that some dysfunctions seen following the degeneration of the mesocortico-prefrontal and mesolimbic DA neurons disappear following the combined destruction of ascending NA neurons.
Adrenergic Fibers↗
MAP2 expression and neuritic outgrowth and branching are coregulated through region-specific neuro-astroglial interactions.
Embryonic neurons from the rat striatum and mesencephalon were plated on mesencephalic or striatal astrocytes in 4 possible combinations. It was found that specific traits are expressed by the neurons when they are grown on homotopic astrocytes (neurons and astrocytes from the same region). These traits are the following: 1. The number of cells stained with an antibody raised against the microtubule-associated protein 2 (MAP2) is higher in homotopic than in heterotopic cocultures. This is true for both mesencephalic and striatal neurons. 2. In homotopic conditions, there is an increase in the number of cells having more primary neurites and branching points. This effect is observed for both neuronal populations but is more pronounced in mesencephalic neurons. 3. The intensity of MAP2 staining was correlated with the branching ability of the neurons. First, on comparing MAP2-positive and MAP2-negative cells, it was found that, in any combination (homotopic and heterotopic cocultures), the number of primary neurites and branching points was much higher in MAP2-positive cells. In fact, almost no branching activity was found in MAP2-negative neurons. Second, within the MAP2-positive neuronal population, the higher number of branching points observed under homotopic neuro-astroglial conditions was mostly due to the neuritic compartment, which was strongly and homogeneously stained with the anti-MAP2 antibody. These observations strongly suggest that the astrocytic environment regulates the synthesis and/or intracellular distribution of MAP2, as well as the morphology of the neurons, and that this regulation is region specific.
Animals↗
3H-neurokinin A labels a specific tachykinin-binding site in the rat duodenal smooth muscle.
3H-Neurokinin A (3H-NKA) with high specific activity (75 Ci/mmol) was synthesized to study NKA (NK-2)-binding sites on membrane preparations of various tissues in the rat, including brain, spinal cord, duodenum, vas deferens, and ileum. The binding capacity of 3H-NKA (0.9 nM) was very low in membrane preparations of different central nervous system regions and the ileum smooth muscle (0.2-2 fmol/mg of protein). In contrast, relatively high specific binding was found in membrane suspensions of the rat duodenal smooth muscle (18 fmol/mg of protein) and the vas deferens (8 fmol/mg of protein). 3H-NKA-binding sites were further characterized on the rat duodenal smooth muscle. The specific binding of 3H-NKA was shown to be temperature dependent, saturable, reversible, and increased in parallel with the protein concentration. Scatchard analyses and Hill plots of equilibrium binding studies in the concentration range of 0.40-30 nM revealed that 3H-NKA bound to a single class of noninteracting binding sites (Bmax = 270 fmol/mg of protein, KD = 13.3 nM). Displacement of 3H-NKA with different tachykinin-related peptides gave the following rank order of potencies: NKA greater than NKA (4-10) greater than kassinin greater than eledoisin greater than NKB much greater than substance P greater than physalaemin, which suggests that the binding site labeled by 3H-NKA is different from substance P (NK-1)-and NKB (NK-3)-binding sites. The biological activities of tachykinins and related peptides were tested by measuring their contractile effects on the rat duodenum and rabbit pulmonary artery, two tissues known to be sensitive for NKA. Ki values were correlated with the EC50 obtained in biological assays. The results revealed a significant correlation (r = 0.86, p less than 0.01) between Ki and EC50 values obtained in the isolated rabbit pulmonary artery, whereas there was no significant correlation between binding affinities and biological responses on the rat duodenum (r = 0.62, p greater than 0.05).
Animals↗
[Relation between GABAergic and dopaminergic neurons in the basal ganglia].
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Animals↗
Partial protection by desmethylimipramine of the mesocortical dopamine neurones from the neurotoxic effect of 6-hydroxydopamine injected in ventral mesencephalic tegmentum. The role of noradrenergic innervation.
As shown in the rat by estimation of dopamine (DA) and noradrenaline (NA) levels, bilateral 6-hydroxydopamine (6-OHDA, 4 micrograms/microliter) lesions made in the ventral mesencephalic tegmentum (VMT) destroy both ascending DA and NA neurones. Pretreatment of rats with desmethylimipramine (DMI, 30 mg/kg, i.p.), 30 min before microinjection of 6-OHDA into the VMT partially prevented the destruction of the DA neurones innervating the prefrontal and cingulate cortices but not those innervating subcortical structures (nucleus accumbens, olfactory tubercles, septum). Results obtained from the prefrontal cortex of rats with extensive lesions of the ascending NA neurones performed 15 days prior to the 6-OHDA lesions of the VMT in the presence of DMI, imply that NA innervation of the VMT seems to be required for DMI to protect the cortical DA neurons from the neurotoxic effect of 6-OHDA.
Animals↗
A cyclic analogue selective for the NKB specific binding site on rat brain synaptosomes.
The cyclic analogue of NKB, [Cys2,Cys5]NKB is as active as SP and NKB in the guinea-pig ileum bioassay. Furthermore, [Cys2,Cys5]NKB is a selective substrate for the [3H]NKB specific binding site on rat cortical synaptosomes. Its binding potencies for [3H]NKB and 125I-BHSP binding sites, IC50 = 5.2 nM and 3.4 microM respectively were close to those observed for NKB.
Animals↗
Further evidence for a role of delta-opiate receptors in the presynaptic regulation of newly synthesized dopamine release.
The effects of the specific delta-agonist of opiate receptors, DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr), the specific mu-agonist DAGO (Tyr-D-Ala-Gly-(Me)Phe-Gly-ol) and of kelatorphan (N-((2R)-3-(hydroxyaminocarbonyl-2-benzyl-1-oxopropyl)-L-alanine), a potent inhibitor of the enkephalin-degrading enzymes, on the spontaneous release of [3H]dopamine ([3H]DA) synthesized from [3H]tyrosine were examined in rat striatal slices. DTLET (10(-7) M, 10(-6) M) and kelatorphan (5 X 10(-6) M) enhanced markedly the release of newly synthesized [3H]DA, while DAGO (10(-6) M) was inactive. The stimulatory effects of DTLET (10(-7) M) and kelatorphan (5 X 10(-6) M) were prevented in the presence of naloxone (3 X 10(-6) M; 10(-4) M respectively) or ICI 154,129 (10(-5) M), a selective antagonist of delta-opiate receptors. While DTLET (10(-7) M) stimulated the 30 mM potassium-evoked release of newly synthesized [3H]DA, it did not affect the potassium-evoked release of [3H]DA previously synthesized in tissues. A higher concentration of DTLET (10(-6) M) was required in the latter case. In contrast to the release observed with striatal slices, DTLET (10(-7) M), 10(-6) M) or DAGO (10(-6) M) did not affect the spontaneous release of newly synthesized [3H]DA from nucleus accumbens slices. In addition, DTLET (10(-6) M) was without effect on the potassium-evoked release of newly synthesized [3H]DA in this structure. The present results confirmed that delta-opiate receptors are involved in the presynaptic regulation of [3H]DA release.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗