Ontogeny of the dopamine D2 receptor mRNA expressing cells in the human hippocampal formation and temporal neocortex

The study details the cellular expression of the dopamine D₂ receptor mRNA in the human temporal lobe during prenatal development. At 13 embryonic weeks (E13) D₂ mRNA was widely expressed in the temporal lobe. At this time point in the dentate gyrus D₂ mRNA positive cells first appeared at the outer border of the granular layer and their number increased with development. The CA1 exhibited the highest level of D₂ mRNA expression. By E19–25 the hippocampal formation underwent rapid morphological maturation. D₂ mRNA expression became more uniform and dense in the ammonic subfield. At all ages the subiculum appeared more mature morphologically but less intensely stained for D₂ mRNA than the ammonic fields. In the entorhinal cortex D₂ mRNA expression was most conspicuous in the future layer II at all ages. In the temporal neocortex D₂ mRNA-positive cells were detected in the subplate and cortical plate. Differentiation of the cortical plate was accompanied by concentration of D₂ mRNA-positive cells in layer V. The most conspicuous cells expressing D₂ mRNA were found in the marginal zone of all regions and resembled Cajal–Retzius cells in morphology and location. Density of putative Cajal–Retzius cells expressing D₂ mRNA decreased with development. They all but disappeared from the hippocampal areas by mid gestation, but in the temporal neocortex occasional cells were seen even at term. Early and widespread but region and cell type specific expression of D₂ receptor mRNA suggests an important role of this DA receptor subtype in prenatal development of the human temporal lobe.     

Anatomical and affinity state comparisons between dopamine D1 and D2 receptors in the rat central nervous system

The anatomical distributions and affinity states of dopamine D₁ and D₂ receptors were compared in the rat central nervous system using quantitative autoradiography. [³H]SCH23390 and [³H]spiperone (in the presence of 100 nM mianserin) were used to label the D₁, and D₂ receptors, respectively. The densities of D₁ and D₂ receptors displayed a positive correlation among 21 brain regions (Pearson correlation coefficient, r = 0.80, P < 0.001).

The affinity states for the D₁ and D₂ receptors were found to be quite different from each other, and different from the results obtained by others using homogenate preparations. Both the D₁ and D₂ receptors were best modeled using a two-state model. In the absence of exogenous guanine nucleotides and using the nonselective agonist dopamine as the competitor, the D₁ receptor was primarily in a low affinity agonist state (R_H = 21 ± 6%), whereas the D₂ receptor was primarily in the high affinity agonist state (R_H = 77 ± 3%). In the presence of 10 μM guanylyl-imidodiphosphate orguanosine-5'-O-(2-thiophosphate) both the D₁ and the D₂ receptor were completely in a low affinity agonist state (R_L = 100%). These affinity states were found both in the nucleus accumbens and olfactory tubercle using dopamine as the competitor and in the striatum using selective D₁ or D₂ agonists as competitors.

Receptor occupancy of the D₂ receptor with either an agonist or antagonist did not alter the affinity states of the D₁ receptor, and conversely, receptor occupancy of the D₁ receptor did not alter the affinity states of the D₂ receptor.

The correlation between densities of D₁ and D₂ receptors provides an anatomical framework for evaluating behavioral and electrophysiological evidence of an interaction between the two dopamine receptor subtypes. This interaction does not appear to be due to a sharing or coupling of G-proteins in such a way that binding to one dopamine receptor subtype alters the affinity state of the other receptor subtype. The differences between dopamine receptor distributions described by labeled agonists and antagonists may be due in part to differences in their affinity states. The low proportion of high affinity state D₁ receptors may explain some of the difficulties in assigning specific behavioral roles to the D₁ receptor.     

The D1 dopamine agonist SKF 38393, but not the D2 agonist LY 171555, decreases the affinity of type II corticosteroid receptors in rat hippocampus and ventral striatum

Type I and type II brain corticosteroid receptors are regulated by adrenal hormones as well as being under neural control. Recent studies have indicated that neurotransmitters such as serotonin and noradrenaline are also involved in the regulation of corticosteroid receptors. In a previous study, we showed that dopamine also modulates activity of the corticosteroid receptor system. In the present study, we examined the roles of the dopamine D₁ and D₂ receptor subtypes in the regulation of corticosteroid receptors. Adrenalectomized rats whose corticosterone levels were maintained within normal limits by corticosterone replacement implants, were injected intraperitoneally with the D₁ agonist SKF 38393 or the D₂ agonist LY 171555. Corticosteroid receptors were assayed in the ventral striatum and hippocampus. We have shown that the D₁ agonist SKF 38393 decreased type II receptor affinity in both regions, whereas the D₂ agonist LY 171555 had no effects.

The results show that the influence of the dopaminergic system on corticosteroid receptors appears to be mediated by D₁ receptors.     

Effects of dopamine D3 receptor agonists on pilocarpine-induced limbic seizures in the rat

The discrete localization of D₃ receptors in the nucleus accumbens and subjacent islands of Calleja bears a close resemblance to the dopamine-sensitive anticonvulsant site in the anteroventral striatum. To determine if these D₃ receptors were capable of attenuating limbic motor seizures induced by pilocarpine, dopamine agonists with preferential or non-selective D₃ affinity were injected stereotaxically into these limbic brain regions of the rat via indwelling cannulae prior to pilocarpine challenge. Reliable clonic seizures were obtained by administering the proconvulsive dopamine D₁ agonist SKF 38393 (10mg/kg i.p.) followed by a subconvulsant dose of pilocarpine (280–300 mg/kg i.p.). Bilateral intra-accumbens pretreatment with the D₃ > D₂ agonist RU 24213 (0.2 pmol-7 nmol) significantly delayed the onset of seizures, with a minimum effective dose of 2 pmol, without altering their frequency or severity. The more selective D₃ agonist LY 171555 (0.2 pmol-7.8 nmol) was less potent, and only attenuated pilocarpine-induced seizures at a dose (500 pmol) that would have stimulated accumbens D2 receptors as well. Intra-accumbens injections of the highly potent and selective D₃ agonist 7-OH-DPAT (20 pmol to 7 nmol) afforded no protection against pilocarpine-induced seizures. Apomorphine, a mixed D₁D₂D₃ agonist, delayed seizure onset at 100–500 pmol, but not at higher doses. RU 24213, LY 171555 and 7-OH-DPAT were all modestly anticonvulsant when microinjected into the islands of Calleja at D₂D₃ unselective doses.

These data support the notion that dopamine systems limit seizure propagation through the limbic forebrain, but suggest this protective effect is mediated by D₂ rather than D₃ receptors.     

Inhibition of inositol phospholipid breakdown by D2 dopamine receptors in dissociated bovine anterior pituitary cells

Inositol phospholipids have been labelled with [³H]inositol in a lactotroph-enriched preparation of dissociated bovine anterior pituitary cells. Stimulation of cells with thyrotropin-releasing hormone receptor agonists leads to accumulation of [³H]inositol phosphates, and this effect may be inhibited by dopamine (DA) agonists. The DA agonist effect may be prevented by D₂ DA receptor selective antagonists. Thus the D₂ receptors on these cells are linked to inhibition of inositol phospholipid metabolism, and this provides a functional assay for the receptor.     

Characterization of a neuronal interleukin-1 receptor and the corresponding mRNA in the mouse anterior pituitary cell line AtT-20.

The serotonin (5-HT)_1A agonist, LY 165,163 (1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine), also known as PAPP, has been suggested to exert effects via an interaction with dopamine receptors. Thus, in this study, we examined its ability to induce rotation in rats sustaining unilateral 6-hydroxy-dopamine lesions of the substantia nigra, an in vivo model of dopaminergic activity. In analogy to the direct dopamine (mixed D₁/D₂) agonist, apomorphine, (0.01–0.63 mg/kg), LY 165,163 (0.16–10.0 mg/kg) dose-dependently elicited robust and substained contralateral rotation. Its maximal effect was comparable to that of apomorphine and its duration of action more extended. Rotation elicited by LY 165,163 (10.0 mg/kg) was resistant to the 5-HT_1A antagonist, (−)-alprenolol. It was also unaffected by the selective D₁ antagonist, SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,tetraphydro-1H-3- benzazepine) (2.5 mg/kg) or the selective D₂ antagonist, raclopride (10.0 mg/kg) when each was administered alone. However, upon joint administration they clearly diminished the effect of LY 165,163. The dopamine antagonist, haloperidol (D₂ > D₁) also reduced the action of LY 165,163. This profile of partial antagonism by mixed D₁ and D₂ receptor blockade has been reported previously for apomorphine and contrasts to that seen with selective D₁ or D₂ agonists, the actions of which are completely blocked by D₁ or D₂ antagonists, respectively. In conclusion, the present data demonstrate that LY 165,163 exerts pronounced rotation in nigral-lesioned rats: this reflects a mixed D₁/D₂ action rather than an activation of 5-HT_1A sites. Thus, in addition to an agonist action at 5-HT_1A receptors, dopaminergic effects contribute to the pharmacological profile of LY 165,163.     

Stimulation of adenosine A2 receptors induces catalepsy.

The central administration of the adenosine A₂ agonist CGS 21680 induced catalepsy in the rat. This effect was counteracted by the previous systemic administration of the adenosine antagonist theophylline or the D₂ agonist BHT-920. These results are in agreement with the view that adenosine A₂ receptors regulate central dopamine D₂ transmission and underline the potential antipsychotic activity of A₂ agonists.     

Decline in striatal dopamine D1 and D2 receptor activation in aged F344 rats

Aging differentially affects receptor function. In the present electrophysiological study we compared neuronal responsiveness to locally applied dopamine D₁ and D₂ receptor agonist in the striatum of female Fischer 344 rats aged 3 and 26–27 months. In a subgroup of the old rats, the nigrostriatal dopamine bundle was destroyed unilaterally with 6-hydroxydopamine (6-OHDA) to assess receptor plasticity in response to denervation. Spontaneous firing rate of striatal neurons was higher in aged compared to young rats. Higher doses of the D₁ agonist SKF 38393 or the D₂ agonist quinpirole were required to elicit a 50% change in firing rate in aged compared to young rats. No difference with SKF 38393 or quinpirole was detected between 6-OHDA denervated and control (nonlesioned) striatum in aged rats. Supersensitivity to D₂ agonists has been reported following 6-OHDA lesions in young rats. These observations suggest that D₂ receptors in aged rat striatum might not be as plastic as in younger rats.     

Quantitative autoradiography of dopamine D2 sites in rat caudate-putamen: Localization to intrinsic neurons and not to neocortical afferents

Dopamine D₂ receptors, labeled with [³H]spiroperidol or [³H]sulpiride, show a lateral-to-medial gradient in the caudate-putamen, with a more than two-fold greater density laterally than medially. It has been thought that D₂ receptors are located on at least two neuronal elements of the caudate-putamen, neurons intrinsic to this structure and axons whose cell bodies reside in the cortex. As a first step in establishing what neuronal elements underlie this heterogeneous organization of D₂ receptors, we took advantage of quantitative autoradiography to examine the association of these receptors with those elements. The present findings show that the D₂ sites are almost exclusively located on neurons whose somata reside in the caudate-putamen and are not located on terminals of corticostriatal axons. A detailed comparison of the distribution of histochemically identified acetylcholinesterase neurons with that of D₂ receptors in serially adjoining sections suggests a common organizational pattern.

The density of [³H]spiroperidol sites in rat caudate-putamen was determined after unilateral injection of the neurotoxin quinolinic acid into this structure or after ablation of neocortical regions. Quantification of the tissue damage was achieved by acetylcholinesterase histochemistry (following diisopropylfluoro-phosphate treatment), as well as by thionin and luxol fast staining of sections adjacent to those used for [³H]spiroperidol autoradiography. In identically treated animals, biochemical determination of the extent of tissue damage was made utilizing assays for high-affinity [³H]choline and [³H]glutamate uptake in the caudate-putamen. In quinolinic acid-injected rats, the density of D₂ sites was decreased by 90–95% at the site of complete loss of large acetylcholinesterase-positive neurons. Other animals, given ablations of specific neocortical fields (medial prefrontal, motor, somatosensory) or of the entire parietal-frontal cortex of one hemisphere, showed no loss of caudate-putamen D₂ sites unless the cortical ablation caused accompanying damage of the caudate-putamen. In the caudate-putamen of all animals there was a close correspondence between the D₂ sites and the striatal neurons (and processes) that show strong acetylcholinesterase reactivity.

We suggest that the caudate-putamen topography of D₂ sites is based largely on the internal organization of this structure and may preferentially involve acetylcholine-containing intrinsic neurons.     

Distribution and postnatal ontogeny of adenosine A2A receptors in rat brain: comparison with dopamine receptors

In adult rat brain, adenosine A_2A receptors and dopamine D₂ receptors are known to be located on the same cells where they interact in an antagonistic manner. In the present study we wanted to examine when this situation develops and compared the postnatal ontogeny of the binding of the adenosine A_2A receptor agonist [³H]CGS 21680, the binding of the dopamine D₁ receptor antagonist [³H]SCH 23390 and the dopamine D₂ receptor antagonist [³H]raclopride.

All three radioligands bound to the striatum at birth and this binding increased several-fold during the postnatal period. [³H]SCH 23390 binding developed first (mostly during the first week), followed by [³H]raclopride binding (first to third week) and [³H]CGS 21680 binding (only during second and third week). For all three radioligands the binding tended to decrease between 21 days and adulthood. This occurred earlier and was more pronounced in the globus pallidus than in the other examined structures. The increase in [³H]CGS 21680 binding from newborn to adult was mainly due to four-fold increase in the number of binding sites. The pharmacology of [³H]CGS 21680 binding to caudate–putamen was similar in newborn, one-week-old and adult animals, and was indicative of A_2A receptors. The binding was inhibited by guanylyl imidodiphosphate at all ages, indicating that A_2A receptors are G-protein-coupled already at birth. In contrast to the large increase in [³H]CGS 21680 binding, there was a decrease in the levels of A_2A messenger RNA during the postnatal period in the caudate–putamen. In cerebral cortex [³H]CGS 21680 bound to a different site than the A_2A receptor. From birth to adulthood cortical binding of [³H]CGS 21680 increased four-fold and that of the adenosine A₁ agonist [³H]cyclohexyladenosine 19-fold. During early postnatal development [³H]SCH 23390 binding was higher in deep than in superficial cortical layers, but this difference disappeared in adult animals. There was binding of both [³H]CGS 21680 and [³H]cyclohexyladenosine to the olfactory bulb, suggesting a role of the two adenosine receptors in processing of olfactory information. [³H]CGS 21680 binding was present in the external plexiform layer and glomerular layer, and increased during development, but the density of binding sites was about one tenth of that seen in caudate–putamen. [³H]cyclohexyladenosine showed a very different labelling pattern, resembling that observed with [³H]SCH 23390.

Postnatal changes in adenosine receptors may explain age-dependent differences in stimulatory caffeine effects and endogenous protection against seizures. Since A_2A receptors show a co-distribution with D₂ receptors throughout development, caffeine may partly exert such actions by regulating the activity of D₂ receptor-containing striatopallidal neurons     

Distribution of dopaminergic receptors in the primate cerebral cortex: Quantitative autoradiographic analysis using [H]raclopride, [H]spiperone and [H]SCH23390

A widespread distribution of dopamine D₁ receptors in the neocortex is well recognized. However, the presence of dopamine D₂ receptors in this structure has only recently been established [Martres et al. (1985) Eur. J. Pharmac.118, 211–219; Lidow et al. (1989) Proc. natn. Acad. Sci. U.S.A.86, 6412–6416]. In the present paper, a highly specific antagonist, [³H]raclopride, was used for autoradiographic determination of the distribution of D₂ receptors in 12 cytoarchitectonic areas of the frontal, parietal, and occipital lobes of the rhesus monkey. A low density of D₂-specific [³H]raclopride binding (1.5–4.0 fmol/mg tissue) was detected in all layers of all cortical areas studied. Throughout the entire cortex, the highest density of binding was consistently found in layer V. This is a unique distribution not observed so far for any other neurotransmitter receptor subtype in monkey cerebral cortex, including D₁ receptor. In addition, a comparison was made of the distribution of [³H]raclopride and [³H]spiperone, which has been commonly used in previous attempts to label cortical D₂ receptors. We found marked differences in the distribution of these two radioligands. In the prefrontal cortex, the pattern of [³H]spiperone binding in the presence of ketanserin resembled the combined distribution of 5-HT_ic serotoninergic and ₂-adrenergic sites as well as D₂ receptors. Thus, [³H]raclopride provides a better estimation of the D₂ receptor distribution than does [³H]spiperone. The distribution of D₂-specific binding of [³H]raclopride was also compared with the D₁-specific binding of [³H]SCH23390 in the presence of mianserin to block labeling to 5-HT₂ and 5-HT_IC sites. The density of D₁-specific [³H]SCH23390 binding was 10–20 times higher than that of D₂-speciflc [³H]raclopride binding throughout the cortex. The densities of both [³H]raclopride and [³H]SCH23390 binding sites display a rostral-caudal gradient with the highest concentrations in prefrontal and the lowest concentrations in the occipital cortex. However, the binding sites of these two ligands had different laminar distributions in all areas examined. In contrast to preferential [³H]raclopride binding in layer V, a bilaminar pattern of [³H]SCH23390 labeling was observed in most cytoarchitectonic areas, with the highest concentrations in supragranular layers I, II and IIIa and infragranular layers V and VI. Whereas [³H]raclopride binding was similar in all cytoarchitectonic areas, [³H]SCH23390 exhibited some region-specific variations in the primary visual and motor cortex.

The different regional and laminar distributions of D₁ and D₂ dopaminergic receptors indicates that they may subserve different aspects of dopamine function in the cerebral cortex.     

Localization of NADPH-diaphorase activity in the salt gland of the saltwater-acclimated Pekin duck

The pharmacological properties and the anatomical localisation of dopamine D₃ receptor were assessed in the rat cerebellar cortex using radioligand binding techniques associated with light microscope autoradiography and 7-[³H]hydroxy-N,N-di-n-propyl-2-aminotetralin (7-[³H]OH-DPAT) as a ligand. 7-[³H]OH-DPAT was specifically bound to sections of rat cerebellar cortex with a dissociation constant (K_d) of 0.5 nM and a maximum density of binding sites (B_max) of 97 ± 4 fmol/mg tissue. The rank order of potency of competitors of 7-[³H]OH-DPAT binding and the observation that guanosine triphosphate did not affect radioligand binding suggest the labelling of a dopamine D₃ receptor. 7-[³H]OH-DPAT binding sites are located mainly in the molecular layer and in lesser amounts in the Purkinje neuron layer, primarily within the cell body of Purkinje neurons. No specific accumulation of silver grains was observed in the granule neuron layer or in the white matter of the cerebellar cortex. The localisation of a putative dopamine D₃ receptor within Purkinje neurons suggests that this site may have functional relevance in the cerebellar cortex.     

Modulation of cell-cell and cell-antigen interactions by 1,25-dihydroxyvitamin D3 and vitamin D3 sulfate in vitro: a study on pregnancy lymphocytes and hybridoma cells

The effect of 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃ was investigated in single cell cytotoxicity assays, using K-562 target cells. The action of vitamin D₃ sulfate (VD₃S) in natural cytotoxicity assays as well as its effect on the antigen-specific adherence of hybridoma cells has also been studied. In the single cell cytotoxicity assay 1,25(OH₂)D₃ dose-dependently and significantly increased the binding of PBMC to target, the number of lysed target cells and NK activity, RU486, a compound known as a potent blocker of progesterone and glucocorticoid receptors, suppressed the effect of 1,25(OH₂)D₃ in all systems. VD₃S dose-dependently decreased the natural cytotoxicity of PBMC and the binding of hybridoma cells to antigen immobilized on plastic surfaces. The results suggest that both 1,25(OH₂)D₃ and VD₃S are potent     

Irreversible blockade of D2 dopamine receptors by fluphenazine-N-mustard increases glutamic acid decarboxylase mRNA in rat striatum

The influence of dopaminergic activity on the function of GABAergic neurons in striatum was examined by administrating rats the irreversible D₂ dopamine receptor antagonist, fluphenazine-N-mustard (FNM), and determining the level of glutamic acid decarboxylase (GAD) mRNA in striatum. Rats were given either an acute single injection or chronic daily injections of FNM (20 gmmol/kg, i.p.) for 6 days. The level of GAD mRNA in striatum was determined by in situ hybridization histochemistry. The results showed that acute treatment with FNM failed to significantly change striatal GAD mRNA. However, chronic FNM treatment significantly increased in the level of striatal GAD mRNA. These results demonstrate that irreversible blockade of D₂ dopamine receptors increases the expression of GAD mRNA in rat striatum.     

大麻素受体二聚化及其激活机理

Cannabinoid receptor 1 (CB₁) and cannabinoid receptor 2 (CB₂) are important members of G protein-coupled receptors (GPCRs). Numerous studies have shown that CB₁ receptor can form heterodimers with dopamine receptors (D₂), μ-opioid receptor (μOR), orexin-1 receptor, adenosine receptor (A_2A) or β2 adrenergic receptors, and then forming an essential functional entity. This review summarizes the research progress on heterodimers of cannabinoid CB₁ or CB₂, the function of heterodimers as well as the downstream signalings. The different pharmacological properties of the receptor heterodimer lead to bringing a change in receptor pharmacology, which will have a profound impact on drug development.     

Electron Microscopic Definition of Intestinal Endocrine Cells: Immunogrold Localization and Review

Intestinal mucosal biopsy specimens processed during the past 25 years were used to example the ultrastructural characteristics of intestinal endocrine cells. The cells were defined on the basis of morphologic criteria and, when feasible, with specific antisera and immunogold staining. The hypothesis was that each endocrine cell, once well defined, should be identifiable on the basis of standard morphologic criteria not requiring specific immunostaining. This was not the case. D, G, EC₁, EC₂, ECn, D₁, and intestinal gastrin cells have characteristic secretory granules and, when sufficient granules are present, can be identified consistently on the basis of morphologic criteria. Absolute identification of D, G, IG, and TG cells requires staining with specific antisera, a condition easily obtainable only for D, G, and IG cells. D₁, EC₁, EC₂, and ECn cells must be identified morphologically until secretory products specific for each of these cells are identified. I, L, N, and K cells are remarkably similar in appearance and must be distinguished by specific staining. Mo, S, and P cells were not identified by either morphologic appearance or immunostaining. It is suggested that a cell similar to the D₁ cell but with exceptionally small granules may be the P cell. Absolute identification of intestinal enteroendocrine cells by electron microscopy requires specific staining. The characteristic appearance of the secretory granules of many of these cells (D, G, EC₁, EC₂, ECn, D₁, and IG) permits morphologic identification when numerous secretory granules are present.     

Effects of cholinergic depletion on experience-dependent plasticity in the cortex of the rat

Clinical and functional studies have strongly suggested that acetylcholine input from the nucleus basalis of Meynert is important for the cortex's adaptive response to experience. The purpose of this study was to investigate the effects of depletion of acetylcholine inputs from nucleus basalis of Meynert on experience-dependent plasticity in the cortex of young adult male rats. The posteromedial barrel subfield in the primary somatosensory cortex was studied. Experience-dependent plasticity was elicited using a whisker-pairing paradigm in which all whiskers except D₂ and D₃ were trimmed daily. Plasticity within barrel D₂ of the posteromedial barrel subfield was measured using the electrophysiological extracellular recording technique. An index of plasticity was determined in two ways: as an increase in the magnitude of evoked activity to stimulation of whisker D₂ and as a bias in the ratio of evoked activity for stimulation of paired whisker D₃ and cut whisker D₁ (D₃/D₁). Whiskers D₂, D₃ and D₁ were stimulated (deflected) by a Chubbuck electromechanical stimulator. Cholinergic neurons in the nucleus basalis of Meynert were selectively lesioned with an immunotoxin, 192 IgG-saporin, injected into the left lateral ventricle. Lesions of cholinergic neurons in the nucleus basalis of Meynert were verified using choline acetyltransferase immunocytochemistry and radioenzymatic assay. Experience-dependent plasticity was significantly reduced in cholinergic-depleted animals. The magnitude of evoked activity to stimulation of whisker D₂ increased by 16–100% in control animals compared with 0–20% in cholinergic-depleted animals. Similarly, compared to a 60–100% increase in the D₃/D₁ ratio of evoked activity for phosphate-buffered saline-injected control animals, cholinergic-depleted rats showed no significant increase in the D₃/D₁ ratio (0–15%) after undergoing the whisker-pairing paradigm. After whisker trimming, the D₃/D₁ response ratio in immunotoxin-treated animals was essentially the same as in control animals that had not been subjected to the whisker-pairing paradigm.

This study showed that no significant plasticity response was observed in the absence of cholinergic input from the nucleus basalis of Meynert. The mechanisms of the action of acetylcholine in cortical plasticity are still not known, but we hypothesize that this type of plasticity is activity dependent and is significantly enhanced in the presence of acetylcholine.     

Differential Effect of Mixed D1/D2 and Selective D2 Dopaminergic Antagonists on Mouse T and B Lymphocyte Proliferation and Interleukin Production In Vitro

The effects of some dopaminergic antagonists were investigated on mouse lymphocyte proliferative responses in vitro. The mixed D₁/D₂ dopaminergic antagonists chlorpromazine, haloperidol and fIupentixol inhibited ³H-Thymidine incorporation into adult BALB/c mouse spleen cells stimulated by concanavalin A, lipopolysaccharide from Escherichia coli, and allogenic cells in a mixed lymphocyte reaction. The inhibition was achieved at concentrations greater than 10^-6M. It was not accounted for by decreased cell viability and it was no longer demonstrable when the compound was added 24h or 48h after the mitogenic stimulus. Conversely selective D₂ dopaminergic antagonists sulpiride, metoclopramide and domperidone had no inhibitory effect at concentrations ranging from 10^-9 to 10^-5 or 10^-4M. The three mixed D_l/D₂ antagonists inhibited the mitogenic effect of interleukin-1 on concanavalin A-stimulated thymocytes, but not the activity of interleukin-2 on the proliferaiton of the CTLL-2 cell line. The mixed D_l/D₂ antagonists interfered with the production of interleukin-2 but not with that of interleukin-1. These results indicate that dopaminergic antagonists may differerentially affect lymphocyte proliferative responses to T or B cell mitogens or alloantigens. The mechanisms involved in terms of receptor specific or non specific phenomenons are discussed.