摘要:

AbstractThe expression of the c‐fos proto‐oncogene, as estimated by immunohistochemistry of the FOS nuclear protein, was studied in both focal and generalized seizures induced in rats by systemic administration of pilocarpine. Focal seizures, as indicated by the occurrence of stereotyped oral movements, chewing and sniffing, were evoked by either a subconvulsant dose of pilocarpine (200 mg/kg) or the association of a convulsant dose of pilocarpine (400 mg/kg) with SCH 23390, a selective D‐1 dopamine receptor antagonist. This seizure pattern resulted in FOS accumulation in certain limbic areas, namely, the piriform cortex, amygdala, and olfactory tubercle. On the other hand, in rats developing generalized seizures, accumulation of FOS was also found in hippocampus, cingulate cortex, frontal cortex, striatum, accumbens, as well as in certain thalamic nuclei. Generalized seizures, including motor limbic seizures and status epilepticus, were induced by either a convulsant dose of pilocarpine (400 mg/kg) or a low dose of pilocarpine (15–200 mg/kg) combined with either lithium or the D‐1 selective agonist SKF 38393. These findings indicate a close correlation between the sequence of behavioural alterations induced by pilocarpine and the proto‐oncogene activation. The results provide the basis for mapping the areas of origin and the pathways of generalization of seizure activity. As shown by the effects of dopamine receptor agonists and antagonists, the process of generalization appears to be controlled by the dopamine system. © Wil

ISSN:0887-4476    

DOI:10.1002/syn.890140102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractDaily cocaine administration has been shown to alter G proteins in mesolimbic nuclei, and these changes have been implicated in the initiation and expression of behavioral sensitization. To evaluate the robustness of changes in G proteins induced by daily cocaine treatments capable of producing behavioral sensitization, the levels of Gi1α, Gi2α, Goα, Gsα, and Gβprotein were measured by immunoblotting at 1 hr after an acute injection of cocaine or saline given 1 or 14 days following the last injection of daily cocaine or saline. A significant decline in Gi1αwas seen in the nucleus accumbens at 14 days following daily cocaine administration regardless of whether they received an acute challenge with cocaine or saline 1 hr prior to decapitation. No alterations were observed in the ventral tegmental area, substantia nigra, dorsolateral striatum, or prefrontal cortex in the levels of Gi1α, Gi2α, or Goα. No change in G protein immunoreactivity was measured in the nucleus accumbens or ventral tegmental area of rats decapitated 1 hr after discontinuing daily cocaine. The possibility that a long‐term change in Gi1αin the nucleus accumbens may be related to cocaine‐induced behavioral sensitization is discussed. © W

ISSN:0887-4476    

DOI:10.1002/syn.890140103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe reproducibility of endogenous GABA release evoked by multiple periods of electrical field stimulation was examined in rat striatal slices. In these experiments, NO‐328 was used to block GABA uptake, and evoked GABA release (overflow) was completely Ca2+dependent. A seemingly invariant observation in these experiments was that spontaneous GABA release (outflow) progressively decreased as a function of superfusion time and that GABA overflow decreased 25–30% in response to the second of two periods of stimulation (S2/S1 ratios = 0.70 to 0.75). The attenuation of GABA release was not explained by the amount of GABA lost to the superfusion buffer (fractional release), direct depletion of releasable pools of GABA, or slice viability. Furthermore, the decreases in GABA release were not dependent on stimulation frequency (5–15 Hz) or the absolute amount of GABA evoked by electrical stimulation. However, the GABABreceptor antagonist 2‐hydroxy‐saclofen (2‐OH‐saclofen; 316 μM) not only enhanced GABA overflow, when superfused throughout both periods of stimulation, but also resulted in S2/S1 ratios of unity. When 2‐OH‐saclofen was superfused throughout the second stimulation period only, GABA overflow was almost two‐fold greater than that evoked by the initial period of stimulation (2‐OH‐saclofen‐free). In addition, these S2 responses were ∼30% greater than S1 responses that were observed when 2‐OH‐saclofen was present throughout the entire superfusion period. These results indicate that activation of GABABreceptors was involved in the progressive attenuation of GABA release and further emphasize that GABABreceptors play an important role in modulating endogenous GABA release from st

ISSN:0887-4476    

DOI:10.1002/syn.890140104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractSuperoxide dismutase (SOD) plays an important role in the protection of cells against the deleterious effects of free radicals by dismutating the toxic superoxide anion radical. Although oxygen‐based radicals have been implicated in the process of aging and in neurodegenerative disorders such as Parkinson's disease, the contribution of these free radicals to the pathology of these entities has yet to be clarified. It is also not certain that increased levels of free radical scavenging enzymes would attenuate the molecular and cellular processes that lead to these pathological states. In order to asses the contribution of increased SOD gene dosage to the pathogenesis of Down's syndrome, transgenic mice have been constructed that overexpress the human CuZnSOD. We are also using this model to evaluate the role of free radicals in age‐associated changes in brain neurotransmitters and their receptors. In the present study, transgenic mice and their nontransgenic littermates, aged 6 weeks and 21 months, were used in an autoradiographic receptor study of the distribution of brain neurotensin receptors. At 6 weeks of age, there were no significant differences between the two groups of mice in most brain regions. In addition, [3H]NT binding sites showed parallel age‐related decreases in the majority of the areas examined in both groups. However, significant age‐related decreases in the septum, the diagonal band of Broca, and in some subdivisions of the caudate‐putamen were observed only in SOD‐Tg mice. In contrast, significant age‐related decreases in the core area of the nucleus accumbens and the dorsal aspect of the dentate gyrus of the hippocampus were seen only in non‐Tg mice. Interestingly, there were increases in NT binding sites in the CA2 area of the hippocampus in both groups of mice. These results suggest that oxygen‐based radicals might play a role in the biochemical changes that occur in NT receptors during the process of aging since these receptors were differentially affected in some regions of the brains of SOD‐Tg mice and of their littermates, which contrast in their ability to scavenge the superoxide radical. Published 1

ISSN:0887-4476    

DOI:10.1002/syn.890140105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe di‐substituted piperazines, GBR12909 (1‐[2‐[bis(4‐fluorophenyl)‐methoxy]ethyl]‐4‐[3‐phenylpropyl]piperazine) and GBR12935 (1‐[2‐(diphenyl‐methoxy)‐ethyl]‐4‐(3‐phenylpropyl)piperazine), are potent and selective (20‐to 100‐fold) inhibitors of [3H]dopamine reuptake, relative to [3H]5‐HT and [3H]norepinephrine uptake. The GBR12935 analog, 1‐(2‐(diphenylmethoxy)ethyl)‐4‐(3‐phenylpropyl)homopiperazine (LR1111), was synthesized as part of a systematic structure‐activity study of analogs of GBR12935 and GBR12909. LR1111 differs from GBR12935 by the addition of a methylene group into the piperazine ring to yield a compound with a seven‐member homopiperazine ring. The IC50 values for LR1111 at the dopamine, norepinephrine, and serotonin transporters were 7.2 nM, 34, 072 nM, and greater than 20,000 nM, respectively, whereas the IC50 values of GBR12935 were 3.7 nM, 289 nM, and 1261 nM for these same transporters. This demonstrates that the addition of a single methylene group in the piperazine ring results in a compound with similar affinity but significantly higher selectivity for the dopamine transporter. LR1111 increased motoric activity in rats after intravenous administration. These indicate that LR1111 is a potent and highly selective inhibitor of the dop

ISSN:0887-4476    

DOI:10.1002/syn.890140106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe purpose of the present study was to examine the effects of chronic cocaine on dopamine (DA) and serotonin (5‐HT) synthesis in several rat brain regions implicated in drug reinforcement. Male rats were treated twice daily with cocaine (15 mg/kg, ip) or saline for 1 week. After 42 hr of abstinence, rats were challenged with either cocaine (15 mg/kg, ip) or saline, followed by the aromaticL‐amino acid decarboxylase inhibitor 3‐hydroxybenzylhydrazine (NSD‐1015; 100 mg/kg, ip). Animals were decapitated 30 min after NSD‐1015 and discrete brain regions were microdissected from 300 μm frozen sections. Postmortem tissue levels of 3, 4‐dihydroxyphenylalanine (DOPA) and 5‐hyroxytryptophan (5‐HTP) were quantified by HPLC with electrochemical detection and used to estimate biosynthesis of DA and 5‐HT, respectively. In chronic saline‐treated rats, cocaine dramatically suppressed DA and 5‐HT synthesis in all forebrain regions examined, including: medial prefrontal cortex, nucleus accumbens, caudate nucleus, olfactory tubercle, and basolateral amygdala. The degree of inhibition ranged from 35‐65% and was more pronounced in 5‐HT neurons compared to DA neurons in the same tissue sample. In general, chronic cocaine did not significantly alter basal levels of DOPA or 5‐HTP; a notable exception was lateral hypothalamus, where chronic cocaine reduced basal DA synthesis to 75% of control. After repeated cocaine injections, the synthesisiinhibiting effect of a challenge injection of cocaine was attenuated in many brain areas. These data suggest that whereas acute cocaine decreases DA and 5‐HT synthesis in forebrain, chronic cocaine is not neurotoxic to DA and 5‐HT neurons. In addition, the mechanism(s) mediating cocaine‐induced suppression of monoamine synthesis may become desensitized by chronic exposure to the dr

ISSN:0887-4476    

DOI:10.1002/syn.890140107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractPhysiological studies and inferences from invertebrate models implicate Ca2+/calmodulin‐sensitive adenylyl cyclase with memory processes. However, Ca2+/calmodulin‐insensitive adenylyl cyclase also occurs in brain, and its neuronal functions are less clear. Two oligonucleotide probes, based on rat cDNAs for Types I and II adenylyl cyclase, which appear to correspond to these functional forms, were used to conduct in situ hybridization analysis of the relative abundance and localization of these two species in the rat brain as a first step in evaluating their neuronal role. Quite discrete patterns of expression were encountered; in some areas, both species were co‐expressed, but in others, little overlap was observed. The differential expression of the two mRNAs suggests that discrete roles may be fulfilled by the two adenylyl cyclases in neural tissues. © Wiley‐L

ISSN:0887-4476    

DOI:10.1002/syn.890140108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractHigh‐speed chronoamperometry was used to monitor dopamine‐related electrochemical signals in the nucleus accumbens of rats allowed to self‐administer heroin intravenously and rats that received similar injections passively. Rats self‐administered 100 μg/kg of heroin at ∼20‐min intervals. Dopamine‐related electrochemical signals increased monotonically after the first injection of each day; the effect was weaker on the first than on the second and subsequent days. The second and subsequent injections in each session caused biphasic effects: the initial effect was a decrease in signal‐a minor one when compared to the increase caused by the first injection‐and this was followed by an increase that brought the signal back to or somewhat higher than the level at the time of the injection. Over the course of each 4‐h session, the electrochemical signal reached and fluctuated around an elevated plateau; doubling the injection dose did not elevate this plateau but did cause larger phasic decreases and subsequent increases. Qualitatively similar electrochemical changes were seen in the animals passively receiving the drug, but there were two notable quantitative differences. First, in the passive animals the initial depressions in signal were of shorter duration. Second, in the passive animals (which were injected at intervals determined by the self‐administering animals) the electrochemical signal reached a maximum and began to fall prior to the time of the next injection; in the animals that self‐administered the drug, the signal was still rising at the time of the next injection. The changes in electrochemical signal are unlikely to represent fluctuations of ascorbate or dopamine metabolites; thus it appears that whereas self‐administered heroin injections cause a slow and long‐lasting elevation of extracellular dopamine concentration, short‐term increases in dopamine concentration are associated with the behavioral activation that precedes the injections and it is short‐term decreases that appear to be associated with the period usually thought to be most significant for positive reinf

ISSN:0887-4476    

DOI:10.1002/syn.890140109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractThe quantitative [14C]‐2‐deoxyglucose autoradiographic method was utilized to assess regional cerebral metabolic rate for glucose (rCMRglc) in rat brain during withdrawal from cocaine self‐administration. RCMRglcwas determined in 62 regions from brains of naïve rats which were placed into an empty operant chamber for 12 hr continuously, and rats trained to self‐administer cocaine during 3 hr training sessions and subsequently placed into the operant chamber for 12 hr continuously with or without access to cocaine. Animals placed into the chamber without access to cocaine were examined 6 hr later, while animals allowed access to the 12 hr cocaine binge were examined either 6 or 72 hr post‐cocaine. Metabolic activity was reduced during withdrawal in the nucleus accumbens, olfactory tubercle, islands of Calleja region, basolateral and central amygdaloid nuclei, medial septum, piriform and cingulate cortices, rostral caudatoputamen, entopeduncular nucleus and the adjacent lateral hypothalamus, somatosensory, auditory, and motor cortices compared to the naïve state. These effects were usually more severe at 72 than at 6 hr after binge exposure, with intermediate values observed in cocaine trained animals without binge exposure. The response was negatively correlated with the amount of cocaine consumed during binge exposure in the striatum, olfactory tubercle, piriform, cingulate, somatosensory, and motor cortices. Thus, the amount of cocaine consumed can affect the extent of metabolic depression after sustained drug exposure. The pattern of regional effects suggests that mesolimbic and rostral extrapyramidal dopamine terminal regions and certain of their efferent pathways are preferentially affected during cocaine withdrawal. The reduction of basal metabolic rate observed in these brain regions during cocaine withdrawal may become more severe with time despite the apparent recovery of certain behavioral‐motivational responses. © W

ISSN:0887-4476    

DOI:10.1002/syn.890140110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY

摘要:

AbstractWe have characterized the kinetic and pharmacological properties of stimulation‐induced increases of synaptic efficacy in the embryonic chick ciliary ganglion. We found what appear to be four components of increased ganglionic efficacy with average time constants of decay of about 60 msec, 400 msec, 30 sec, and 200 sec. These time constants are similar to the those describing the decay of the four components of stimulation‐induced increases in neurotransmitter release characterized at other synapses. These components have been termed first and second components of facilitation, augmentation, and potentiation. We found that the addition of small amounts of Ba2+to the low Ca2+bathing solution led to an increase in the magnitude of the augmentation‐like component, whereas Sr2+enhanced the magnitude and time course of the component resembling the second component of facilitation. These effects of Ba2+and Sr2+are similar to the effects of these same divalent cations on augmentation and the second component of facilitation, respectively, at the frog neuromuscular junction and rabbit superior cervical ganglion. Based on these similar kinetic and pharmacological properties, we conclude that the four components of stimulation‐induced increases in release that have been described in other synaptic preparations also appear to be present in the chick ciliary ganglion. Published 1993 Wiley‐

ISSN:0887-4476    

DOI:10.1002/syn.890140111

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1993

数据来源: WILEY