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PubMed1986

Evidence for, and nature of, the tonic inhibitory influence of habenulointerpeduncular pathways upon cerebral dopaminergic transmission in the rat.

The potential role of the habenula in the transsynaptic regulation of the activity of ascending dopaminergic systems has been investigated in the rat by studying the effect of an acute interruption of impulse traffic in the diencephalic conduction system (stria medullaris-habenula-fasciculus retroflexus) and of pharmacological manipulation of various neurotransmitter systems in the interpeduncular nucleus on dopamine metabolism in several dopaminergic projection fields. The bilateral infusion of tetrodotoxin into the fasciculus retroflexus (which conveys the habenulointerpeduncular tract) of conscious rats markedly increased homovanillic acid levels and dopamine synthesis and utilization in the medial prefrontal cortex, nucleus accumbens, olfactory tubercle and striatum. Similar changes in dopamine metabolism were observed in these areas after bilateral infusion of tetrodotoxin into the stria medullaris (which conveys most of the afferents to the habenula). Infusion of atropine (0.4-1 micrograms) into the interpeduncular nucleus increased homovanillic acid concentrations and dopamine utilization in the medial prefrontal cortex and nucleus accumbens but not in the olfactory tubercle and striatum. Moreover, intra-interpeduncular injection of oxotremorine (17 micrograms) antagonized the increase in dopamine utilization in the nucleus accumbens (but not in the olfactory tubercle) induced by an intrafasciculus retroflexus infusion of tetrodotoxin. Local infusion of naloxone (20 micrograms) into the interpeduncular nucleus increased homovanillic acid concentrations in the nucleus accumbens and olfactory tubercle but not in the medial prefrontal cortex and striatum. In contrast, intra-interpeduncular nucleus infusion of the substance P antagonist D-Arg1, D-Pro2, D-Trp7,9, Leu11-substance P or of substance P antiserum failed to alter homovanillic acid levels in the 4 dopamine-rich areas investigated. Finally, intraraphé medianus (but not intraraphé dorsalis) infusion of muscimol (25 ng) moderately increased dopamine synthesis in the nucleus accumbens and striatum. The present findings suggest that the habenulointerpeduncular pathways exert a tonic inhibitory influence on mesocortical, mesolimbic and mesostriatal dopaminergic neurons. Cholinergic and/or opioid peptidergic neurons coursing through the fasciculus retroflexus as well as ascending serotonergic neurons originating in the raphé medianus could take part in this inhibitory control of ascending dopaminergic neurons.

Animals↗
PubMedDate not supplied

Characteristics of c-fos gene expression in the brains of rats with different investigative and defensive behaviors.

Differences were found in the expression of the c-fos gene in brain structures of rats with "active" and "passive" types of behavior in the open field, hole exploration, and step-down tests. The most marked and intense expression of the c-fos gene was seen in "passive" rats. After electrocutaneous stimulation in the step-down test, these animals showed maximum expression of the c-fos gene in most areas of the cerebral cortex, the amygdala, in olfactory structures, the hypothalamus, and the brainstem. In "active" rats in the same conditions, expression of the c-fos gene was seen only in the infralimbic cortex and olfactory nuclei. These results, along with existing data on neurological mapping of the c-fos gene, demonstrate a relationship between the level and topography of c-fos expression, and with typological and, perhaps, individual characteristics of rats.

Aggression↗
PubMed1997

The effects of selective cholinergic basal forebrain lesions and aging upon expectancy in the rat.

The effects of selective cholinergic cell loss within the basal forebrain (BF) were determined using a task that requires shifting of attention between two visual stimuli. Discriminability between two stimuli and response bias were determined in young and old F-344 rats given BF injections of IgG-192 saporin (100 ng). The lesion reduced ChAT activity in the frontal and parietal cortices, hippocampus, and olfactory bulbs. The lesion did not significantly alter Na+/K(+)-ATPase activity in cortex, hippocampus, or olfactory bulbs, or endogenous levels of neuropeptide Y and neurokinin B within the BF. The BF lesions impaired both stimulus discriminability and response bias in young and old rats. The BF lesions had a significantly greater effect upon stimulus discriminability and response bias in aged rats, compared to young rats, only when the stimulus duration was very brief, i.e., when the task was most difficult to solve. At longer stimulus durations, aging and lesions showed no interaction. The results suggest that the selective loss of cholinergic cells in the BF, but not normal aging, impairs the ability to discriminate between independent sensory stimuli. The loss of these cells confers a response bias in simple operant tasks involving motor responses to reward-related visual stimuli.

Acetylcholine↗
PubMed1978

[Effect of propyl-2-pentene-2-oic acid on GABA levels in different regions of mouse brain].

An elevation in cerebral GABA level (65%) is observed after administration of an anticonvulsant, sodium propyl 2-pentene-2 oate, a branched chain fatty acid, comformationally restricted GABA analogue, competitive inhibitor of GABA-T in regard to GABA. The concentration of GABA increases in some regions i.e. substantia nigra, frontal and temporal cortex, cerebellum and olfactory bulbs. The GABA level remains unchanged in caudate nucleus, hippocampus and occipital cortex. Results are discussed comparatively to the effect of sodium n-dipropylacetate.

Animals↗
PubMed1980

Intraventricular ACTH and vasopressin cause regionally specific changes in cerebral deoxyglucose uptake.

The cerebral uptake of subcutaneously injected [3H] 2-deoxyglucose (2DG) was used to determine regional changes of cerebral glucose uptake associated with peptide-induced behaviors in mice. Evidence is presented that the use of [3H] 2DG (s.c.) gives results qualitatively similar to those obtained using intravenous [14C] 2DG. Lysine vasopressin, 1 microgram intracerebroventricularly (i.c.v.) induced the characteristic hyperactivity previously described, and significantly decreased [3H] 2DG uptake in frontal cortex. ACTH1-24 (1 microgram i.c.v.) induced excessive grooming and concomitant decreases in [3H] 2DG uptake in the olfactory bulb, pyriform cortex, and amygdala, and an increase in cerebellum. These results are only partly consistent with previous results on the cerebral sites of action of ACTH and vasopressin. These patterns of 2DG uptake are distinct from those observed following footshock, indicating that the peptide hormones mediate the effects of footshock on [3H] 2DG uptake only partially if at all.

Adrenocorticotropic Hormone↗
PubMed1996

Immunocytochemical analyses of astrocyte development in the olfactory bulb.

Several lines of evidence suggest an important role for glia in establishing boundaries during development of mammalian cortex and insect olfactory lobe. In the adult rat olfactory bulb distinct morphological categories of astroglial cells with clear laminar specificity are easily recognized following immunocytochemical staining of glial fibrillary acidic protein (GFAP). To explore the developmental distribution of olfactory bulb astrocytes and their possible role in establishing the segregation of neurons in specific olfactory bulb laminae, we used immunocytochemical localization of GFAP in rats at 0, 6, 9, 12, 15 and 21 days postnatal plus the adult. In the adult we confirmed prior observations and identified five morphological categories of astrocytes: linear, wedge, elongate, semicircular, and circular. Each category had a unique sublaminar distribution across the olfactory bulb, although categories could occur in more than one lamina. Between 0 and 21 days postnatal a 6th category was apparent, radial glial cells. The mature astrocyte morphologies did not emerge uniformly. Astrocytes found in the outermost glomerular layer developed first with the appearance of the linear, wedge and elongate morphologies. Deeper laminate of the olfactory bulb followed in a successive fashion until the adult pattern was evident around 15 days postnatal. As radial glia disappeared, the mature morphologies assumed their final position. The data suggest that the maturation of olfactory bulb astrocytes may be linked to the final migration and maturation of olfactory bulb neurons.

Animals↗
PubMed1988

Selective long-term potentiation in the pyriform cortex.

Electrical stimulation of the olfactory bulb (OB) produces an evoked potential in the pyriform cortex (PC) characterized by an initial surface-negative wave (period 1) representing activation of PC pyramidal cells via the lateral olfactory tract, followed by a surface-positive wave (period 2) which is temporally associated with recurrent and feed-forward inhibition. The experiment reported here examined the changes that occur in the PC evoked potential following a pattern of stimulation that has been found to produce short- and long-term potentiation (LTP) in other areas of the forebrain. Male Long-Evans rats with electrodes in the OB and PC were divided into two groups. LTP animals received high-frequency stimulation of the OB (30 trains of 10 pulses each at a frequency of 100 Hz). Control animals received the same number of pulses at a lower frequency (1 Hz). This procedure was repeated 6 times at 2-day intervals. Neither high- nor low-frequency stimulation altered period 1 of the PC evoked potential, indicating that synaptic input arriving via the lateral olfactory tract was unaffected. However, LTP animals exhibited a marked increase in the amplitude and duration of period 2 which appeared to reflect two separate processes: a short-term change that peaked within 30 min of the trains; and a long-term change that accumulated across the 6 treatments. LTP of period 2 persisted in latent form for at least 32 days after the last treatment. Control animals exhibited only small changes that were attributed to the paired-pulse stimulation used for testing rather than the 1 Hz Control trains. These results suggest that repeated high-frequency stimulation of the OB causes a persistent alteration in the way information is processed within the PC. The form of LTP demonstrated here is markedly different from that found in the hippocampal formation, where potentiation of the monosynaptic excitatory postsynaptic potential is a prominent effect. The functional significance of this change cannot be determined with certainty from the present experiment, but available evidence suggests that it represents an enhancement of inhibitory processes within the PC.

Animals↗
PubMed1990

Disynaptic olfactory input to the hippocampus mediated by stellate cells in the entorhinal cortex.

Electrophysiological and anatomical studies indicate functional relationships between the olfactory bulb and the hippocampus, mediated by the lateral olfactory tract and perforant path. Fibres from the lateral olfactory bulb terminate in the molecular layer of the lateral entorhinal cortex, which contains stellate and pyramidal cells that project to the hippocampus. Therefore this study was performed to analyze whether a trineuronal, disynaptic chain connects the olfactory bulb and the hippocampus. In adult rats, Fast Blue was unilaterally injected into the septal hippocampus to label cells of origin of the entorhinohippocampal pathway. Lesions of the ipsilateral olfactory bulb induced anterograde terminal degeneration in the entorhinal cortex of the same animals. Fast Blue labelled, and thus hippocampally projecting entorhinal neurones in fixed vibratome slices of the operated brains were injected with Lucifer Yellow. Most of these neurones were stellate layer II and pyramidal layer III cells; in addition there were some sparsely spinous multipolar cells in layers II and III and sparsely spinous horizontal cells at the layer I/II border. Injected cells were photoconverted and processed for electron microscopy. Olfactory bulb lesions resulted in electron-dense degeneration of abundant terminal boutons in the outer zone of entorhinal layer I. The relative frequency of degenerating boutons decreased towards deeper zones of the layer. In the outer zone, degenerated terminals predominantly contacted dendritic spines. These contacts could be seen on injected stellate cells but not on pyramidal cells. This study shows that the area dentata of the rat is reached by disynaptic afferent input from the olfactory bulb and thus is likely to process olfactory information. Oligosynaptic pathways might provide the hippocampus also with visual and auditory inputs; such fast transmitted polysensory information could be essential for the proposed participation of the hippocampus in attention-related mechanisms.

Amidines↗
PubMed1999

Assessment of benzydamine N-oxidation mediated by flavin-containing monooxygenase in different regions of rat brain and liver using microdialysis.

N-Oxidation of benzydamine (BZY) mediated by flavin-containing monooxygenase (FMO) was evaluated by microdialysis in vivo in different regions of rat brain and liver. The probe was implanted into local regions of the brain, such as the olfactory bulb, cerebral cortex, corpus striatum, hippocampus and cerebellum, or the hepatic lobe. By perfusing BZY via the probe, BZY N-oxide was identified in the dialysate. The estimated concentrations of BZY N-oxide in extracellular fluid were almost the same as those in the olfactory bulb, hippocampus and cerebral cortex, half the concentration in the hepatic lobe; however, the concentration in the corpus striatum was lower and that in the cerebellum was higher than in the other regions. These results demonstrate that the extracellular concentration of BZY N-oxide formed in vivo was unexpectedly high in every brain region.

Animals↗
PubMed1990

Localization of NGF receptors in normal and Alzheimer's basal forebrain with monoclonal antibodies against the truncated form of the receptor.

Four new monoclonal antibodies to the extracellular domain of the nerve growth factor receptor (NGFR) have been evaluated for their specificity to NGFR and their utility in localizing NGFR in human brain. All four antibodies, as well as Me20.4, show similar cellular localization and patterns of immunoreactivity in basal forebrain neurons. NGFR monoclonal antibody XIF1 stains optimally over the widest range of concentrations, with staining being reduced only slightly at less than 10 pg/ml or more than 100 ng/ml, and produces the lowest background of those tested. Staining with all NGFR monoclonal antibodies is blocked by the addition of as little as 5-fold excess human recombinant truncated NGFR protein. The distribution of NGFR-containing neurons is similar to that previously described in normal human forebrain, as is the reduction in cell size in nucleus basalis (Ch4am) in brains from patients with Alzheimer's disease. In addition, we find evidence in the two Alzheimer's cases examined for a previously unreported loss of cells in the horizontal limb nucleus of the diagonal band (Ch3) in Alzheimer's disease. The loss of these neurons, which in normal brain have characteristic varicose dendritic processes extending to the pial surface adjacent to the cisternal space, may indicate a change in the relationship of NGF-sensitive neurons to the vasculature. Since these neurons project to olfactory bulb and cortex in rodent and primate brains, their loss may also reflect damage to the olfactory system in Alzheimer's disease.

Aged↗
PubMed1995

Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease.

A murine model of Tay-Sachs disease, the prototype of the GM2 gangliosidoses, was produced through the targeted disruption of the Hexa gene encoding the subunit of alpha-hexosaminidase A. The mice were completely devoid of beta-hexosaminidase A activity and accumulated GM2 ganglioside in the CNS in an age-dependent manner. Neurons with membranous cytoplasmic bodies (MCBs), identical to those described in Tay-Sachs disease, were identified in the brain of these mice. The neurons with MCBs were periodic acid-Schiff-positive on frozen sections and immunostained with anti-GM2 ganglioside antibody. However, unlike Tay-Sachs disease in which neurons throughout the brain are affected, the localization of storage neurons in these mice appeared to be limited to certain regions, i.e., cerebral cortex, the hippocampus, amygdala, hypothalamus, mammillary nucleus, etc. Storage neurons were absent in the olfactory bulb, cerebellar cortex and spinal anterior horns. The difference in the distribution of storage neurons suggests a difference of ganglioside metabolism between humans and mice. This model is useful for the study of the pathogenic mechanisms of neuronal storage in Tay-Sachs disease and for the evaluation of therapeutic strategies.

Animals↗
PubMed1999

Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems.

We determined the immunohistochemical distributions of orexin-A and orexin-B, hypothalamic peptides that function in the regulation of feeding behavior and energy homeostasis. Orexin-A and -B neurons were restricted to the lateral and posterior hypothalamus, whereas both orexin-A and -B nerve fibers projected widely into the olfactory bulb, cerebral cortex, thalamus, hypothalamus, and brainstem. Dense populations of orexin-containing fibers were present in the paraventricular thalamic nucleus, central gray, raphe nuclei, and locus coeruleus. Moderate numbers of these fibers were found in the olfactory bulb, insular, infralimbic and prelimbic cortex, amygdala, ventral, and dorsolateral parts of the suprachiasmatic nucleus, paraventricular nucleus except the lateral magnocellular division, arcuate nucleus, supramammillary nucleus, nucleus of the solitary tract, and dorsal motor nucleus of the vagus. Small numbers of orexin fibers were present in the perirhinal, motor and sensory cortex, hippocampus, and supraoptic nucleus, and a very small number in the lateral magnocellular division of the paraventricular nucleus. Intracerebroventricular injections of orexins induced c-fos expression in the paraventricular thalamic nucleus, locus coeruleus, arcuate nucleus, central gray, raphe nuclei, nucleus of the solitary tract, dorsal motor nucleus of the vagus, suprachiasmatic nucleus, supraoptic nucleus, and paraventricular nucleus except the lateral magnocellular division. The unique neuronal distribution of orexins and their functional activation of neural circuits suggest specific complex roles of the peptides in autonomic and neuroendocrine control.

Animals↗
PubMed1992

Comparison of neuronal inositol 1,4,5-trisphosphate 3-kinase and receptor mRNA distributions in the adult rat brain using in situ hybridization histochemistry.

As a result of its interaction with a specific receptor, inositol 1,4,5-trisphosphate mobilizes intracellular calcium. The metabolism of inositol 1,4,5-trisphosphate is rather complex: inositol 1,4,5-trisphosphate 3-kinase produces inositol 1,3,4,5-tetrakisphosphate, a putative second messenger. In order to elucidate inositol 1,3,4,5-tetrakisphosphate function, a comparative in situ hybridization study of the distributions of inositol 1,4,5-trisphosphate 3-kinase and receptor mRNAs was performed in the adult rat brain using oligonucleotides derived from their cDNA sequences. The neuronal distributions of the mRNA for the receptor were larger than for the kinase. Highest levels of both mRNAs were found in the cerebellar Purkinje cells, where they were enriched in their neuronal perikarya and to a lesser extent in their dendrites. In addition to the cerebellum, mRNAs were mainly detected in the hippocampal pyramidal cells of the CA1 sector of the Ammon's horn and in the granule cells of the dentate gyrus, and also in a majority of the neurons in the cortical layers II-III and V, especially in the frontal cortex and cingulate cortex; caudate-putamen, accumbens, olfactory tubercle and Calleja islets; claustrum; anterior olfactory nucleus; taenia tecta; piriform cortex; dorsolateral septum; bed nucleus stria terminalis; amygdala; hippocampal CA2-4 sectors and subiculum. The inositol 1,4,5-trisphosphate receptor mRNA but not kinase mRNA was found in a majority of the neurons in the thalamus, especially in the parafascicular nucleus; hypothalamus, especially the medial hypothalamus; substantia nigra pars compacta and ventral tegmental area; superior colliculus; lateral interpeduncular nucleus and central gray. Taking into account the limitation in sensitivity of the technique, both mRNAs were not detected in glial cells and in the olfactory bulb; basal nucleus of Meynert, diagonal band nuclei; medial septal nucleus; substantia innominata; globus pallidus; entopeduncular nucleus; substantia nigra pars reticulata; ventral pallidum; subthalamic nucleus; spinal cord and dorsal root ganglia. In conclusion, cerebellum and hippocampus appear to contain almost similar levels of kinase mRNA. This is in contrast to receptor mRNA levels which were at much higher levels in the cerebellum when compared with the hippocampus. For this reason, we have chosen hippocampal CA1 pyramidal cells and dentate gyrus granule cells for studying inositol 1,4,5-trisphosphate 3-kinase function.

Animals↗
PubMed1992

Organization of central cholinergic neurons revealed by combined in situ hybridization histochemistry and choline-O-acetyltransferase immunocytochemistry.

Digoxigenin-labeled riboprobes and in situ hybridization of choline-O-acetyltransferase mRNA, both alone and in combination with immunohistochemical procedures for the synthetic enzyme of acetylcholine, were used to map the topography of putative cholinergic neurons in the rat central nervous system. Only the anti-sense riboprobe yielded specific labeling, which was absent in brain sections processed with sense riboprobe. Telencephalic neurons demonstrating the mRNA for choline-O-acetyltransferase and choline-O-acetyltransferase-like immunoreactivity were found in the caudate-putamen nucleus, nucleus accumbens, olfactory tubercule, Islands of Calleja complex, medial septal nucleus, vertical and horizontal limbs of the diagonal band, substantia innominata, nucleus basalis, and nucleus of the ansa lenticularis, as well as occasionally in the amygdala. Neurons in the cerebral cortex, hippocampus, and primary olfactory structures did not demonstrate hybridization signal, even though some cells in those areas were observed to exhibit choline-O-acetyltransferase-like immunopositivity. Thalamic cells were devoid of hybrido- and immunoreactivity, with the exception of several neurons located primarily in the ventral two-thirds of the medial habenula. A few cell bodies labeled with riboprobe and co-localizing choline-O-acetyltransferase-like immunopositivity were found in the lateral hypothalamus, caudal extension of the internal capsule, and zona incerta. Neurons in the pedunculopontine and laterodorsal tegmental nuclei evinced moderate hybridization signal, whereas cells of the parabigeminal nucleus were very weakly reactive. In contrast, motor neurons of the cranial nerve nuclei demonstrated high levels of choline-O-acetyltransferase mRNA and choline-O-acetyltransferase-like immunoreactivity. Putative cholinergic somata in the ventral horns and intermediolateral cell columns of the spinal cord and around the central canal were also labeled with riboprobe. It is concluded that hybridocytochemistry with digoxigenin-labeled riboprobes confirms the existence of cholinergic neurons in most of the neural regions believed to contain them on the basis of acetylcholinesterase pharmacohistochemistry and choline-O-acetyltransferase immunocytochemistry, with the prominent exceptions of the cerebral cortex, hippocampus, olfactory bulb, anterior olfactory nucleus, and caudal raphe nuclei, which apparently do not possess neurons expressing detectable levels of the mRNA for the synthetic enzyme of acetylcholine.

Animals↗
PubMed1995

Elemental imbalances in the olfactory pathway in Alzheimer's disease.

Concentrations of 11 trace elements were determined in 56 control and 98 Alzheimer's disease (AD) olfactory bulb, olfactory tract, olfactory trigone, piriform cortex and amygdala specimens by instrumental neutron activation analysis. Iron and zinc were significantly elevated and bromine was significantly depleted in olfactory regions of AD patients, compared with normal age-matched control subjects. Elevated iron could possibly play a role in neuronal degeneration in AD by enhancing reactive free radical formation.

Aged↗
PubMed2002

Odorant differentiated pattern of cerebral activation: comparison of acetone and vanillin.

Whether different odorous compounds (odorants) are processed by different cerebral circuits is presently unknown. A first step to address this complicated issue is to investigate how the cerebral regions mediating signals from olfactory (i.e., unimodal) odorants, differ from those mediating the olfactory + trigeminal (i.e., bimodal) odorants. [15O]-H2O-PET scans were conducted in 12 healthy females during three separate conditions: birhinal, passive smelling of: 1) the unimodal odorant vanillin; 2) the bimodal odorant acetone; and 3) odorless air. Significant activations were calculated contrasting vanillin to air, acetone to air, and deactivations, running these contrasts in the opposite direction. Smelling of vanillin activated bilaterally the amygdala and piriform cortex. These regions were only engaged slightly by acetone. Instead, strong activations were found in the anterior and central insula and claustrum, the posterior portion of anterior cingulate, the somatosensory cortex (SI for face), cerebellum, ventral medial (VMPo) and dorsal medial (MDvc) thalamus, the lateral hypothalamus, and pons/medulla. In parallel, the somatosensory (SI, below central representation of face), secondary visual and auditory cortices, as well as the supplementary motor area and the parahippocampal gyri were deactivated. No deactivations were observed with vanillin, although the odor components of acetone and vanillin were rated similarly intense (75 +/- 17 mm vs. 61 +/- 22 mm, NS). The differentiated pattern of cerebral activation during odorant perception seems to be dependent on the signal transducing cranial nerves involved. In contrast to vanillin, which solely activates the olfactory cortex, acetone engages predominantly trigeminal projections from the nasal mucosa. Acetone's limited activation of the olfactory cortex may result from a cross-modal interaction, with inhibition of acetone's odor component by its trigeminal component.

Acetone↗
PubMed2006

The risk is in the air: Intranasal administration of MPTP to rats reproducing clinical features of Parkinson's disease.

Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson's disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In the present study, we demonstrated that rats treated with intranasal infusion of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at low concentrations (0.1 mg/nostril) suffered progressive impairments in olfactory, cognitive and motor functions that were assessed with the olfactory discrimination, Morris water maze and open field tests, respectively. Moreover, intranasal administration of MPTP reduced the expression of the enzyme tyrosine hydroxylase in the olfactory bulb and substantia nigra of rats, resulting in a significant reduction of dopamine concentration in the olfactory bulb, prefrontal cortex and striatum, but not in the hippocampus. These results reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. In addition, the time course of the olfactory, cognitive and motor impairments verified in rats treated intranasally with MPTP, which appears to be correlated with different stages of the human PD, suggest that the MPTP intranasal model in rats may provide new insights into the underlying mechanisms of PD pathogenesis.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Brain CYP2E1 is induced by nicotine and ethanol in rat and is higher in smokers and alcoholics.

1. Ethanol and nicotine are commonly coabused drugs. Cytochrome P450 2E1 (CYP2E1) metabolizes ethanol and bioactivates tobacco-derived procarcinogens. Ethanol and nicotine can induce hepatic CYP2E1 and we hypothesized that both centrally active drugs could also induce CYP2E1 within the brain. 2. Male rats were treated with saline, ethanol (3.0 g kg(-1) by gavage) or nicotine (1.0 mg kg(-1) s.c.) for 7 days. Ethanol treatment significantly increased CYP2E1 in olfactory bulbs (1.7-fold), frontal cortex (2.0-fold), hippocampus (1.9-fold) and cerebellum (1.8-fold), while nicotine induced CYP2E1 in olfactory bulbs (2.3-fold), frontal cortex (3.0-fold), olfactory tubercle (3.1-fold), cerebellum (2.5-fold) and brainstem (2.0-fold). Immunocytochemical analysis revealed that the induction was cell-type specific. 3. Consistent with the increased CYP2E1 found in rat brain following drug treatments, brains from alcoholics and alcoholic smokers showed greater staining of granular cells of the dentate gyrus and the pyramidal cells of CA2 and CA3 hippocampal regions as well as of cerebellar Purkinje cells compared to nonalcoholic nonsmokers. Moreover, greater CYP2E1 immunoreactivity was observed in the frontal cortices in the alcoholic smokers in comparison to nonalcoholic nonsmokers and alcoholic nonsmokers. 4 To investigate if nicotine could contribute to the increased CYP2E1 observed in alcoholic smokers, we treated human neuroblastoma IMR-32 cells in culture and found significantly higher CYP2E1 immunostaining in nicotine-treated cells (0.1-10 nM). 5. CYP2E1 induction in the brain, by ethanol or nicotine, may influence the central effects of ethanol and the development of nervous tissue pathologies observed in alcoholics and smokers.

Adult↗