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PubMed1989

Novel localizations of central- and peripheral-type cholecystokinin binding sites in Syrian hamster brain as determined by autoradiography.

Neuronal cholecystokinin (CCK) binding sites were studied in the Syrian hamster, a species with unique CNS localizations of CCK immunoreactivity. Preliminary studies of hamster forebrain sections using 125I-Bolton-Hunter-(BH)-CCK-8 indicated that radioligand binding kinetics and receptor selectivity for various unlabelled CCK peptides were similar to those reported for other species. Autoradiographic visualization of CCK binding sites revealed that the highest binding densities were distributed in the cerebral cortex, olfactory bulb, dorsal vagal complex, raphe obscurus and cochlear nuclei. Moderate binding densities were present in the amygdala, hippocampus, hypothalamus, thalamus, central grey and medial vestibular nucleus. Comparison of autoradiograms generated from adjacent sections incubated in 125I-BH-CCK-8 with unlabelled sulfated or desulfated CCK-8 confirmed the presence of peripheral-type CCK binding sites (i.e. at which desulfated CCK-8 has weak displacing activity) in the hamster dorsal vagal complex. Peripheral-type CCK binding sites were also distributed in regions of the hypothalamus (e.g. the magnocellular cell groups) where similar receptor selectivity had not been previously demonstrated. These observations provide further evidence of species differences in CCK receptor distribution and specificity, which may account for species differences in responsiveness to intracranial administration of CCK peptides.

Animals↗
PubMed1998

Synthesis and biological evaluation of [11C]MK-912 as an alpha2-adrenergic receptor radioligand for PET studies.

In vitro studies showed that MK-912 ((2S, 12bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12b-octahydro -2H-benzo[b]furo[2,3-a]quinolizine)-2,4'-pyrimidin-2'-one) is a potent alpha2-adrenergic receptor antagonist with high affinity (Ki = 0.42, 0.26 and 0.03 nM to alpha2A, alpha2B and alpha2C, respectively) and high selectivity (alpha2A/alpha1A = 240; alpha2A/D-1 = 3600; alpha2A/D-2 = 3500; alpha2A/5-HT1 = 700; alpha2A/5-HT2 = 4100). The compound was labeled with 11C and evaluated in rodents and monkey as a specific radioligand for studying alpha2-adrenergic receptors using PET. [11C]MK-912 was synthesized by methylation of its desmethyl precursor, L-668,929, with [11C]CH3I in (Bu3O)P=O at 85 degrees C for 8 min followed by purification with HPLC in 18% yield in a synthesis time of 45 min from end of bombardment (EOB). The specific activity was 0.83-0.93 Ci/micromol and the radiochemical purity was 97%. The initial uptake of [11C]MK-912 in mouse brain, heart, lung, liver and kidney was high (5%, 4%, 5%, 17% and 8% per gram of organ, respectively, at 5 min postinjection) and the activities were then slowly cleared from these organs. The uptake of [11C]MK-912 in rat olfactory tubercle, a brain region with high density of alpha2-adrenergic receptors, was reduced by 30%, and the ratio of radioactivity in olfactory tubercle/cerebellum was reduced from 2:1 to 1:1 by coinjection of [11C]MK-912 with a potent alpha2-adrenergic receptor antagonist, atipamezole (3 mg/kg), indicating that compound 2 binds to alpha2-adrenergic receptors. However, a PET study in a rhesus monkey revealed that the initial influx of [11C]MK-912 into various brain regions (cerebellum, cortex, olfactory tubercle and striatum) was high (0.02%/cc), and the radioactivity was then washed out slowly and without significantly differential retention in these brain regions. This, coupled with the fact that none of the high-density alpha2-adrenergic receptor brain regions exceeds a few millimeters in diameter, suggests that [11C]MK-912 is probably not an ideal radioligand for studying alpha2-adrenergic receptors in humans using commercially available PET.

Adrenergic alpha-Antagonists↗
PubMed1994

Neuronal expression of glypican, a cell-surface glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan, in the adult rat nervous system.

Cell-surface proteoglycans have been implicated in cell responses to growth factors, extracellular matrix, and cell adhesion molecules. M12, one of the most abundant membrane-associated proteoglycans in the adult rat brain, is a approximately 65 kDa glycosylphosphatidylinositol-linked protein that bears heparan sulfate chains (Herndon and Lander, 1990). To assess its identity, M12 was purified and internal peptide sequences obtained. Comparison of the results with protein sequence predicted by a cDNA cloned from PC12 cells indicated that M12 is rat glypican, a proteoglycan first cloned from human fibroblasts. In addition, antibodies raised against a rat glypican fusion protein specifically detected the 65 kDa brain proteoglycan core protein, both by immunoprecipitation and by Western blotting. Northern blot analysis using a rat glypican probe also detected glypican message in the adult, as well as the developing rat brain. In situ hybridization with glypican RNA probes showed that glypican is expressed in a subset of structures in the adult rat nervous system. These include the hippocampus, dorsal thalamus, amygdala, cerebral cortex, piriform cortex, olfactory tubercle, several cranial nerve nuclei, the ventral horn of the spinal cord, and the dorsal root ganglia. Several other brain regions exhibited little or no hybridization over background. In most cases where glypican hybridization was observed, the signal could be localized specifically to the cell bodies of identifiable neurons, for example, spinal motoneurons, hippocampal pyramidal cells. In the cerebral cortex, glypican hybridization was found in layers 2/3, 5, and 6, but was missing from 1 and 4. The data suggest that glypican is expressed primarily by subpopulations of projection neurons in the adult rat nervous system.

Amino Acid Sequence↗
PubMed1996

Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction.

Melanocortin peptides are reported to antagonize opiate dependence and tolerance, but the neural substrates underlying these actions are unknown. In this study, we characterize the rat melanocortin-4 receptor (MC4-R) and demonstrate that this receptor is regulated by opiate administration. The rat MC4-R is 95% identical to the human MC4-R, and the potency of melanocortin peptides to stimulate cAMP production is similar in these two species homologs (alpha-melanocyte-stimulating hormone = adrenocorticotropic hormone > gamma-melanocyte-stimulating hormone). Expression of MC4-R mRNA was found to be enriched in the striatum, nucleus accumbens, and periaque-ductal gray, all of which are regions implicated in the behavioral effects of opiates. In contrast, MC1-, MC3-, and MC5-R are expressed at very low or undetectable levels in these brain regions. Chronic administration of morphine (5 days) resulted in a time-dependent down-regulation of MC4-R mRNA expression in the striatum and periaqueductal gray. Expression of MC4-R mRNA was also decreased in the nucleus accumbens/ olfactory tubercle, but this effect was observed after 1 or 3 days of morphine treatment. In the striatum, the reduction of MC4-R mRNA was accompanied by a concomitant decrease in melanocortin receptor levels, shown by quantitative radioligand binding and autoradiography. In contrast, morphine administration did not influence levels of MC4-R mRNA in several other brain regions, including frontal cortex, olfactory bulb, hypothalamus, and ventral tegmentum/substantia nigra. In light of previous findings that melanocortins antagonize opiate self-administration, analgesic tolerance, and physical dependence, we hypothesize that decreased melanocortin function, via down-regulation of MC4-R expression, may contribute to the development of these opiate-induced behaviors.

Animals↗
PubMed2001

Expression of estrogen receptor (ER) -alpha and -beta transcripts in the neonatal and adult rat cerebral cortex, cerebellum, and olfactory bulb.

In the present study expression of estrogen receptor subtype -alpha (ERalpha) and -beta (ERbeta) in the cerebral cortex, cerebellum, and olfactory bulb was investigated and compared between neonatal (1 to approximately 3-days-old) and adult (250 to approximately 350 g) rats, using reverse transcription-polymerase chain reaction (RT-PCR). No ERalpha transcripts were detectable in the adult cerebellum and olfactory bulb, whereas very weak expression of ERalpha was present in the adult cerebral cortex. No significant difference in ERbeta transcripts was detectable between the neonatal and adult rats. While transcripts for both ER subtypes were co-expressed in these brain areas of neonatal rats, although ERalpha expression was significantly weaker than ERbeta. Even in the cerebral cortex known to contain both ER subtypes in adult rats, ERalpha transcripts in neonatal rats were much higher than in adult. These observations provide evidence for the existence of different expression patterns of ERalpha/ERbeta transcripts in these three brain areas between the neonatal and adult rats, suggesting that each ER subtype may play a distinct role in the regulation of differentiation, development, and functions of the brain by estrogen.

Animals↗
PubMed1994

Localization of a novel pathway for the liberation of GABA in the human CNS.

Serum carnosinase is a dipeptidase, which is synthesized in human brain, where it hydrolyzes homocarnosine to release free GABA. Immunohistochemical procedures were used to demonstrate the presence of this enzyme in several layers of the retina and in certain neuronal tracts of the cerebral cortex, cerebellar cortex, olfactory bulb, hippocampus, and in disseminated tracts presumably from the internal capsule, interspersed among the basal ganglia. The enzyme was also present in the epithelial cells of the choroid plexus and in corpora amylacea, which were seen in many regions of the CNS. Homocarnosine was localized either in the same tracts or in nearby neurons. For example, the Purkinje cells of the cerebellar cortex contained homocarnosine, whereas serum carnosinase was localized in adjacent neuronal projections apparently originating from outside the cerebellar cortex and having probable synaptic contact with the Purkinje cells. These findings suggest that in addition to glutamate decarboxylation, a second metabolic reaction for the formation of free GABA exists in specific neuronal tracts of the human CNS where GABA is released from homocarnosine by the action of serum carnosinase.

Animals↗
PubMed1990

Characterisation and autoradiographic localisation of 5-HT3 receptor recognition sites identified with [3H]-(S)-zacopride in the forebrain of the rat.

The pharmacological characterisation and topographical distribution of [3H]-(S)-zacopride recognition sites in the forebrain of the rat was studied using homogenate and autoradiographic radioligand binding techniques. [3H]-(S)-Zacopride labelled a single, saturable, specific binding site (defined by 10.0 microM granisetron) in homogenates prepared from the entorhinal cortex of the rat (pKD = 9.51 +/- 0.08; Bmax = 104 +/- 7 fmol mg-1 protein; mean +/- SEM, n = 8). Pharmacological characterisation of the recognition site, within the entorhinal cortex, suggested that [3H]-(S)-zacopride selectively labelled the recognition site of the 5-HT3 receptor. Specific binding of [3H]-(S)-zacopride (defined by 1.0 microM granisetron) was differentially distributed throughout the forebrain of the rat; highest densities were located within sub-nuclei of the amygdala (cortical amygdaloid nucleus, amygdalohippocampal area, posterior medial cortical amygdaloid nucleus, posterior lateral amygdaloid nucleus), cortical areas (primary olfactory cortex, entorhinal cortex) and hippocampus. Non-specific binding was distributed homogeneously, although lower in myelinated structures. It is concluded that [3H]-(S)-zacopride selectively labels 5-HT3 receptor recognition sites within the forebrain of the rat; the topographical distribution of these sites, within the limbic nuclei, is consistent with the behavioural actions in animal models of the selective 5-HT3 receptor antagonists.

Animals↗
PubMed1998

Distribution and developmental regulation of metabotropic glutamate receptor 7a in rat brain.

To determine the regional and cellular distribution of the metabotropic glutamate receptor mGluR7a, we used rabbit anti-peptide polyclonal-targeted antibodies against the C-terminal domain of mGluR7a. Here we report that immunocytochemistry at the light-microscopic level revealed that mGluR7a is widely distributed throughout the adult rat brain, with a high level of expression in sensory areas, such as piriform cortex, superior colliculus, and dorsal cochlear nucleus. In most brain structures, mGluR7a immunoreactivity is characterized by staining of puncta and fibers. However, in some regions, including the locus ceruleus, cerebellum, and thalamic nuclei, both cell bodies and fibers are immunopositive. The changes in levels of mGluR7a during development were investigated with immunoblotting and immunocytochemical analysis. Immunoblot analysis revealed that the levels of mGluR7a are differentially regulated across brain regions during postnatal development. In cortical regions (hippocampus, neocortex, and olfactory cortex), mGluR7a levels were highest at postnatal day 7 (P7) and P14, then declined in older rats. In contrast, mGluR7a levels were highest at P7 in pons/medulla and cerebellum and decreased markedly between P7 and P14. In these regions, mGluR7a immunoreactivity was at similar low levels at P14 and P21 and in adults. Immunocytochemical analysis revealed that staining for mGluR7a was exceptionally high in fiber tracts in P7 animals relative to adults. Furthermore, the pattern of mGluR7a immunoreactivity in certain brain structures, including cerebellum, piriform cortex, and hippocampus, was significantly different in P7 and adult animals. In summary, these data suggest that mGluR7a is widely distributed throughout the rat brain and that this receptor undergoes a dynamic, regionally specific regulation during postnatal development.

Age Factors↗
PubMed1993

Learning and memory of odor-reward association: selective impairment following horizontal diagonal band lesions.

Rats with horizontal diagonal band of Broca (HDBB) lesions were trained in a successive-cue olfactory discrimination using different intertrial intervals (ITIs). They learned the paradigm of the task, but substantial impairment in performance of odor-reward associations was observed when the ITIs were longer than 15 s. They performed as well as control animals with short ITIs when they were trained previously with long ITIs, but forgetting appeared very soon thereafter (24 hr later). The finding is that the HDBB is an essential relay between the hippocampal system and the olfactory cortex: The HDBB allows associative memory storage when a limited-duration short-memory system located elsewhere is overloaded.

Animals↗
PubMed1989

Modulations of EEG activity in the entorhinal cortex and forebrain olfactory areas during odour sampling.

With the aim of determining a possible role of the entorhinal cortex (EC) in the processing of olfactory information, its electrical activity was recorded during different types of odour sampling behaviour. The EC spontaneous field potentials (EEGs) were related to those recorded simultaneously from the more rostrally lying olfactory bulb (OB) and prepiriform cortex (PPC), using coherence functions. The coherence values are measures of coupling between two neuronal populations. Auto- and coherence spectra were characterized by a peak in the beta-band (35-36 Hz) and another in the 16-20 Hz band. For the beta-peak of the PPC-EC coherence it was shown that both the maximal values and the median frequency decrease during the first 0.5-1.0 s of a trial in a two-choice odour discrimination task. These transients differed significantly for CS+ and CS- trials. However, no such difference was observed during exploratory sniffing at the same pair of odorants. It was concluded that during sniffing the degree of coupling of the EC with the PPC depends on the behavioural context but not on the quality of the odorants. As regards the 16-20 Hz components it was shown, using bispectral analysis, that these components represent the 1/2 subharmonic of the beta-components. The subharmonic components were enhanced during the initiation of sniffing. This means that the neural networks of OB, PPC and EC have non-linear dynamic properties. These networks show different modes of oscillatory behaviour, characteristic of the restful state and of the active sniffing state. Theoretical implications of these experimental results are discussed. In conclusion, it was demonstrated that modulations with sniffing behaviour are present in the beta-EEG components and their subharmonics in the olfactory brain areas including the EC. This indicates that the latter is involved in processes of the evaluation of olfactory cues in relation to the animal's behaviour.

Animals↗
PubMed1994

Seizures increase basic fibroblast growth factor mRNA in adult rat forebrain neurons and glia.

The distribution of basic fibroblast growth factor (bFGF) mRNA in normal rat forebrain, and the influence of recurrent seizure activity on the expression of this mRNA, was evaluated using in situ hybridization and S1 nuclease protection techniques. In the untreated adult rat, hybridization of 35S-labeled bFGF cRNA densely labeled neurons in a few discrete areas including the tenia tecta, indusium gresium, and hippocampal stratum pyramidale of regions CA2 and rostromedial CA1. Neurons in the prosubiculum and rostromedial dentate gyrus stratum granulosum were lightly labeled. In addition, a diffuse distribution of autoradiographic labeling in areas such as the hippocampal molecular layers, olfactory cortical layer I, and the olfactory nerve layer was suggestive of localization in glial cells. Platinum wire hilar lesions, which did not induce seizures, increased cRNA hybridization in glial cells in primary and secondary areas of degeneration in the ipsilateral hemisphere only; hybridization was not noticeably increased in neurons in these lesion-control rats. Focal stainless-steel wire hilar lesions, which caused recurrent seizures 2-10 h postlesion, induced bilaterally distributed increases in cRNA hybridization in hippocampus, neocortex, olfactory cortex, amygdala, and septum. These seizure-dependent increases in hybridization were evident 6 h postlesion, were maximal from 12 to 24 h postlesion, and declined to near control levels by 4 days. In most regions the elevated hybridization appeared to be associated primarily with astroglia but in experimental seizure rats sacrificed 12 and 24 h postlesion hybridization was also markedly increased in the dentate gyrus granule cells and olfactory cortical neurons. These results demonstrate that recurrent seizures increase bFGF mRNA expression by both forebrain neurons and glia and implicate bFGF in the coordination of other changes in the biosynthetic activities of forebrain neurons that occur after seizures.

Animals↗
PubMed1999

Gonadotropin-releasing hormone immunoreactivity in the adult and fetal human olfactory system.

Studies in fetal brain tissue of rodents, nonhuman primates and birds have demonstrated that cells containing gonadotropin-releasing hormone (GnRH) migrate from the olfactory placode across the nasal septum into the forebrain. The purpose of this study was to examine GnRH neurons in components of the adult and fetal human olfactory system. In the adult human brain (n=4), immunoreactive GnRH was evident within diffusely scattered cell bodies and processes in the olfactory bulb, olfactory nerve, olfactory cortex, and nervus terminalis located on the anterior surface of the gyrus rectus. GnRH-immunoreactive structures showed a similar distribution in 20-week human fetal brains (n=2), indicating that the migration of GnRH neurons is complete at this time. In 10-11-week fetal brains (n=2), more cells were noted in the nasal cavity than in the brain. Our data are consistent with observations made in other species, confirming olfactory derivation and migration of GnRH neurons into the brain from the olfactory placode.

Adult↗
PubMed1997

A hierarchy of Hu RNA binding proteins in developing and adult neurons.

The Hu proteins are a group of antigens targeted in an immune-mediated neurodegenerative disorder associated with cancer. We have cloned and characterized four members of the Hu gene family from mouse. We find that the Hu genes encode a large number of alternatively spliced transcripts to produce a series of related neuron-specific RNA binding proteins. Despite this complexity, we have discerned several ordered features of Hu expression. In the embryo, specific Hu genes are expressed in a hierarchy during early neurogenesis. In the E16 developing cortex, mHuB is induced in very early postmitotic neurons exiting the ventricular zone, mHuD is expressed in migrating neurons of the intermediate zone, and mHuC is expressed in mature cortical plate neurons. Such a hierarchy suggests distinct functional roles for each gene in developing neurons. In the adult, all neurons express some set of Hu mRNA and protein. However, specific patterns are evident such that individual neuronal types in the hippocampus, cerebellum, olfactory cortex, neocortex, and elsewhere express from one to several Hu genes. The complexity of potential protein variants within a gene family and of different Hu family members within a neuron suggests a diverse array of function. Given the strong homologies among the Hu proteins, the Drosophila neurogenic gene elav, and the Drosophila splicing factor sxl, we predict that different combinations of Hu proteins determine different neuron-specific aspects of post-transcriptional RNA regulation. Our findings of specific developmental patterns of expression and the correlation between immune targeting of the Hu proteins and adult neurodegenerative disease suggest that the Hu proteins are critical in both the proper development and function of mature neurons.

Animals↗
PubMed1999

Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat.

Light and electron microscope immunocytochemistry with a monoclonal antibody against the N-terminal domain of the human protein was used to determine the cellular and subcellular localization of serotonin 5-HT2A receptors in the central nervous system of adult rat. Following immunoperoxidase or silver-intensified immunogold labeling, neuronal, somatodendritic, and/or axonal immunoreactivity was detected in numerous brain regions, including all those in which ligand binding sites and 5-HT2A mRNA had previously been reported. The distribution of 5-HT2A-immunolabeled soma/dendrites was characterized in cerebral cortex, olfactory system, septum, hippocampal formation, basal ganglia, amygdala, diencephalon, cerebellum, brainstem, and spinal cord. Labeled axons were visible in every myelinated tract known to arise from immunoreactive cell body groups. In immunopositive soma/dendrites as well as axons, the 5-HT2A receptor appeared mainly cytoplasmic rather than membrane bound. Even though the dendritic labeling was generally stronger than the somatic, it did not extend to dendritic spines in such regions as the cerebral and piriform cortex, the neostriatum, or the molecular layer of the cerebellum. Similarly, there were no labeled axon terminals in numerous regions known to be strongly innervated by the immunoreactive somata and their axons (e.g., molecular layer of piriform cortex). It was concluded that the 5-HT2A receptor is mostly intracellular and transported in dendrites and axons, but does not reach into dendritic spines or axon terminals. Because it has previously been shown that this serotonin receptor is transported retrogradely as well as anterogradely, activates intracellular transduction pathways and intervenes in the regulation of the expression of many genes, it is suggested that one of its main functions is to participate in retrograde signaling systems activated by serotonin.

3T3 Cells↗
PubMed2006

Long-term effects of a single adult methamphetamine challenge: minor impact on dopamine fibre density in limbic brain areas of gerbils.

BACKGROUND: The aim of the study was to test long-term effects of (+)-methamphetamine (MA) on the dopamine (DA) innervation in limbo-cortical regions of adult gerbils, in order to understand better the repair and neuroplasticity in disturbed limbic networks. METHODS: Male gerbils received a single high dose of either MA (25 mg/kg i.p.) or saline on postnatal day 180. On postnatal day 340 the density of immunoreactive DA fibres and calbindin and parvalbumin cells was quantified in the right hemisphere. RESULTS: No effects were found in the prefrontal cortex, olfactory tubercle and amygdala, whereas the pharmacological impact induced a slight but significant DA hyperinnervation in the nucleus accumbens. The cell densities of calbindin (CB) and parvalbumin (PV) positive neurons were additionally tested in the nucleus accumbens, but no significant effects were found. The present results contrast with the previously published long-term effects of early postnatal MA treatment that lead to a restraint of the maturation of DA fibres in the nucleus accumbens and prefrontal cortex and a concomitant overshoot innervation in the amygdala. CONCLUSION: We conclude that the morphogenetic properties of MA change during maturation and aging of gerbils, which may be due to physiological alterations of maturing vs. mature DA neurons innervating subcortical and cortical limbic areas. Our findings, together with results from other long-term studies, suggest that immature limbic structures are more vulnerable to persistent effects of a single MA intoxication; this might be relevant for the assessment of drug experience in adults vs. adolescents, and drug prevention programs.

Journal Article↗
PubMedDate not supplied

Brain gangliosides during the life span (embryogenesis to senescence) of the rat.

The concentration of gangliosides, sialoglycoproteins and proteins was studied in the whole brains and single brain structures (cortex, olfactory bulb, corpora quadrigemina region equals midbrain, cerebellum, thalamic region and oblongated medulla) of female rats from 14 developmental stages ranging from day 8 of gestation to more than 3 years of age. The content of protein- and ganglioside-bound neuraminic acid showed a peak at 3 weeks of age and then decreased with aging, whereas that of proteins increased until senescence. All over the life span the developmental profiles of 12 individual gangliosides in the different brain structures (cortex, corpora quadrigemina region approximately midbrain, cerebellum, thalamic region, medulla) and in whole brain samples were followed. There are distinct differences between the brain structures. Additionally each brain region is characterized by specific developmental ganglioside profiles. However, some ganglioside changes are common to all regions: GD3 in general is a marker for cell division and migration, whereas the polar ganglioside fractions GQ1b and GP1 are characteristic for nerve cell sprouting and arborization. Especially in the cortex GD1a seems to be the marker for synaptogenesis and GM1 and GM4 for myelination. The results were discussed in view of the main morphological patterns of differentiation.

Age Factors↗
PubMed2002

Kallmann syndrome: adhesion, afferents, and anosmia.

Three new studies into the function of human anosmin-1 and related proteins in C. elegans and rodents show that these influence axon branching and axon targeting. The rodent anosmin appears to work at two stages of development, initially promoting axon outgrowth from the olfactory bulb and then stimulating branching from axons into the olfactory cortex. CeKal-1 further influences morphogenesis, and, as the human and nematode anosmins are functionally conserved, these studies provide insights into the pathogenesis of Kallmann syndrome (KS).

Animals↗
PubMed1992

Ganglionic nicotinic receptor agonists exhibit anti-muscarinic effects in guinea-pig olfactory cortical brain slices.

The action of some nicotinic acetylcholine receptor agonists was re-examined on the surface field potentials (N-waves) evoked by electrical stimulation of the lateral olfactory tract in guinea-pig olfactory cortical brain slices. Bath superfusion of nicotine or the nicotinic stimulants dimethylphenylpiperazinium (DMPP), lobeline, cytisine, tetramethylammonium or suberyldicholine (up to 100 microM) had little or no effect on the extracellular N-wave amplitude, or the membrane potential, input resistance or excitability of olfactory neurones recorded intracellularly. In contrast, the muscarinic agonists, carbachol or oxotremorine-M consistently depressed the field in a reversible dose-dependent manner. Interestingly, in the presence of the ganglionic stimulants DMPP (n = 6 slices) or lobeline (n = 5 slices) (10-50 microM), the effects of carbachol or oxotremorine-M were antagonized in a weak competitive-type manner (pA2 values = 5.58 and 5.63 respectively, estimated from Schild plots, constrained to unity slope). This anti-muscarinic action was unaffected by d-tubocurarine or hexamethonium. Nicotine, cytisine, tetramethylammonium and suberyldicholine showed much weaker and inconsistent carbachol-blocking effects. Combination of DMPP with atropine produced dose ratio shifts close to those predicted for a common-site interaction of two competitive antagonists. In conclusion, consistent pre- or postsynaptic nicotinic agonist actions could not be detected in olfactory cortex slices; however, some ganglionic nicotinic agonists were shown to exhibit significant anti-muscarinic effects on this preparation. We suggest this action might be due to a direct atropine-like mechanism.

Alkaloids↗