Biomedical subjects

J F Marshall

Publications and source records attributed to J F Marshall.

At least 19 recordsLinked to original sources

PubMed2006

Running wheel exercise enhances recovery from nigrostriatal dopamine injury without inducing neuroprotection.

Forced use of the forelimb contralateral to a unilateral injection of the dopaminergic neurotoxin 6-hydroxydopamine can promote recovery of motor function in that limb and can significantly decrease damage to dopamine terminals. The present study was conducted to determine (1) whether a form of voluntary exercise, wheel running, would improve motor performance in rats with such lesions, and (2) whether any beneficial effects of wheel running are attributable to ameliorating the dopaminergic damage. In experiment 1, rats were allowed to run in exercise wheels or kept in home cages for 2 1/2 weeks, then given stereotaxic infusions of 6-hydroxydopamine into the left striatum. The rats were replaced into their original environments (wheels or home cages) for four additional weeks, and asymmetries in forelimb use were quantified at 3, 10, 17, and 24 days postoperatively. After killing, dopaminergic damage was assessed by both quantifying 3 beta-(4-iodophenyl)tropan-2 beta-carboxylic acid methyl ester ([(125)I]RTI-55) binding to striatal dopamine transporters and counting tyrosine hydroxylase-positive cells in the substantia nigra. Exercised 6-hydroxydopamine-infused rats showed improved motor outcomes relative to sedentary lesioned controls, effects that were most apparent at postoperative days 17 and 24. Despite this behavioral improvement, 6-hydroxydopamine-induced loss of striatal dopamine transporters and tyrosine hydroxylase-positive nigral cells in exercised and sedentary groups did not differ. Since prior studies suggested that forced limb use improves motor performance by sparing nigrostriatal dopaminergic neurons from 6-hydroxydopamine damage, experiment 2 used a combined regimen of forced plus voluntary wheel running. Again, we found that the motor performance of exercised rats improved more rapidly than that of sedentary controls, but that there were no differences between these groups in the damage produced by 6-hydroxydopamine. It appears that voluntary exercise can facilitate recovery from partial nigrostriatal injury, but it does so without evident sparing of dopamine nerve terminals.

Animals↗

PubMed2006

Alphavbeta6 integrin in wound healing and cancer of the oral cavity.

Integrins are a family of heterodimeric cell surface receptors, which are expressed on most cells where they mediate cell-cell and cell-extracellular matrix (ECM) interactions. The alphavbeta6 integrin is epithelial-specific and binds to the ECM proteins fibronectin, vitronectin and tenascin, and also to the latency associated peptide of TGF-beta. Unlike most epithelial integrins, alphavbeta6 is not expressed constitutively by healthy oral epithelia, but is up-regulated during tissue remodelling, including that accompanying wound healing and carcinogenesis. Although, the data at present have been generated principally from in vitro studies, there is increasing evidence to suggest that alphavbeta6 may promote carcinoma progression: alphavbeta6 has been shown to modulate invasion, inhibit apoptosis, regulate protease expression and activate TGF-beta1. This review examines the current literature, and discusses the possible role of alphavbeta6 in wound healing, and in the development and progression of oral squamous cell carcinoma.

Antigens, Neoplasm↗

PubMed2005

Alpha v beta 6 integrin down-regulates the MMP-13 expression in oral squamous cell carcinoma cells.

The integrin alphavbeta6, a receptor for fibronectin, vitronectin, tenascin and TGF-beta latency-associated peptide (LAP), is not detectable on normal oral epithelium but is neo-expressed in oral squamous cell carcinomas (OSCC) and epithelial dysplasia. Previously it has been shown that alphavbeta6 integrin can up-regulate MMP-3 and -9 expression in OSCC cells. Using beta6-transfected and control OSCC cells we demonstrate that alphavbeta6 integrin down-regulates MMP-13 expression at both mRNA and protein level. Although expressing less MMP-13, beta6-transfected cells were found to have similar collagenolytic activity as control cells and invade at similar levels through type I collagen. Growth of the tumour cells in organotypic culture and confocal microscopy confirmed low levels of MMP-13 in cells with high alphavbeta6 expression. Furthermore, human squamous cell carcinomas of the tongue with high expression of alphavbeta6 showed lower MMP-13 levels than carcinomas with low levels of alphavbeta6. Our results suggest that alphavbeta6 down-regulates MMP-13 expression in OSCC cells and that MMP-13 is not essential for the degradation of type I collagen by OSCC cells.

Antigens, Neoplasm↗

PubMed2005

Development of a quantitative method to analyse tumour cell invasion in organotypic culture.

Tumour invasion is a dynamic process occurring in three dimensions and involving interactions between both tumour and stromal cells. Experimental analysis of squamous carcinoma cell invasion has often used the organotypic gel culture system, which is generated by plating tumour cells on to a synthetic stroma composed of a collagen gel embedded with fibroblasts. Unfortunately, quantitation of invasion in these organotypic gels has relied largely on subjective pathological opinion, which may be influenced by different patterns of tumour cell infiltration. Therefore a computer-assisted digital image analysis system that assesses invasion objectively and provides a numerical 'Invasion Index' was developed. The Invasion Index, by combining depth and pattern of invasion in a single value, establishes a quantitative value that allows assessment of the influences of positive and negative regulation of tumour invasion. These data demonstrate that the organotypic gel system is a robust, accurate, and reproducible method for measuring tumour cell invasion. They also show that the Invasion Index can be used after organotypic gels have been implanted in mice for up to 6 weeks. Illustrative examples of how various factors influence the invasion of squamous carcinoma cells in three dimensions both in vitro and in vivo are provided.

Animals↗

PubMed2004

Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells.

The development of an altered stromal microenvironment is a common feature of many tumours including squamous cell carcinoma (SCC), and there is increasing evidence that these changes in the stroma, which include increased expression of proteases and cytokines, may actually promote tumour progression. A common finding is that stromal fibroblasts become 'activated' myofibroblasts, expressing smooth muscle actin and secreting cytokines, proteases and matrix proteins. We show that myofibroblasts are commonly found in the stroma of oral SCC and are often concentrated at the invasive margin of the tumour. Using oral SCC cells and primary oral fibroblasts, we demonstrate that tumour cells directly induce a myofibroblastic phenotype, and that this transdifferentiation is dependent on SCC-derived TGF-beta1. In turn, myofibroblasts secrete significantly higher levels of hepatocyte growth factor/scatter factor compared with fibroblast controls, and this cytokine promotes SCC invasion through Matrigel, a mixture of basement membrane proteins. This is the first time that this double paracrine mechanism has been demonstrated between squamous carcinoma cells and fibroblasts, and emphasises that cancer invasion can be promoted indirectly by the release of tumour-induced host factors from stroma.

Carcinoma, Squamous Cell↗

PubMed2002

Binding of TGF-beta1 latency-associated peptide (LAP) to alpha(v)beta6 integrin modulates behaviour of squamous carcinoma cells.

The integrin alpha(v)beta6 is not detectable on normal keratinocytes in vivo but expression is increased significantly in oral squamous cell carcinoma where this heterodimer has been shown to play a role in cell migration, invasion and protease expression. Although regarded initially as a fibronectin receptor, alpha(v)beta6 may bind to arginine-glycine-aspartic acid sequences in other matrix molecules including tenascin and vitronectin. Interestingly, alpha(v)beta6 has also been shown to have high affinity for the TGF-beta1 latency associated peptide and to participate in the activation of the TGF-beta1 latent complex. Since TGF-beta1 is present in squamous carcinomas, it is possible that latency associated peptide may modulate malignant keratinocyte behaviour independently from the classical TGF-beta signalling pathways through its interaction with integrins. We show here that when latency associated peptide is immobilised onto a surface, it acts as an alpha(v)beta6-specific ligand for oral squamous carcinoma cells promoting adhesion and haptotactic migration in addition to alpha(v)beta6-dependent increase in pro-MMP-9 expression. In contrast, even very low concentrations of soluble latency associated peptide (0.1 microg ml(-1)) inhibited alpha(v)beta6-dependent adhesion, migration and invasion. Thus alpha(v)beta6-dependent processes of oral squamous cell carcinoma, is likely to be modulated, not only by the local concentration of latency associated peptide in the stroma, but also whether it is immobilised in the matrix or released as a soluble protein.

Antigens, Neoplasm↗

PubMed2002

Further characterization of preproenkephalin mRNA-containing cells in the rodent globus pallidus.

The globus pallidus (external pallidum of primates) is an essential nucleus within basal ganglia circuitry, in part because it receives at least one-half of striatal efferent projections. Neurons of the globus pallidus can be divided into subpopulations based on anatomical, physiological, and chemical features. Globus pallidus neurons project to several structures (the striatum, subthalamic nucleus, entopeduncular nucleus, and substantia nigra pars reticulata), have one of two alternative waveforms (positive/negative versus negative/positive), contain either the calcium binding protein parvalbumin or the neuropeptide precursor preproenkephalin mRNA and show differential immediate early gene responses to dopamine receptor agonists and antagonists. The objective of the present study was to characterize in greater detail the preproenkephalin mRNA-containing pallidal neurons using Sprague-Dawley rats. In situ hybridization for preproenkephalin mRNA was combined with immunocytochemical detection of: (i) the neuron-specific nuclear protein, NeuN, (ii) FluoroGold-labeled pallidostriatal and pallidosubthalamic cells, or (iii) Fos induced by either systemic combined D1-class/D2-class dopamine receptor agonists or a D2-class receptor antagonist. These experiments demonstrated that a substantial population (42%) of globus pallidus neurons contains preproenkephalin mRNA, and that globus pallidus neurons retrogradely labeled after FluoroGold injections into the striatum are more frequently preproenkephalinergic, compared to the population of pallidosubthalamic neurons. Furthermore, systemic administration of a D2 receptor antagonist, eticlopride, induced Fos immunoreactivity predominantly in globus pallidus neurons expressing preproenkephalin mRNA, while combined administration of D1 and D2 receptor agonists induced Fos predominantly in pallidal neurons lacking preproenkephalin mRNA.These results support the conclusion that preproenkephalin mRNA identifies one of the two major subpopulations of pallidal neurons. This preproenkephalin mRNA-expressing pallidal subpopulation preferentially targets the striatum and is more readily activated in its immediate early gene expression by D2 receptor antagonists than by dopamine receptor agonists. This projection provides a pallidal substrate for the dopaminergic regulation of striatal information processing.

Animals↗

PubMed2001

AlphaVbeta6 integrin promotes invasion of squamous carcinoma cells through up-regulation of matrix metalloproteinase-9.

The integrin alphaVbeta6 is a fibronectin receptor, which is not detectable on normal epithelium but is neo-expressed in oral epithelial dysplasia and oral squamous-cell carcinoma (SCC), suggesting a role in promoting malignant behaviour and tumour progression. We used transfection and retroviral infection to create a panel of SCC cell lines expressing various levels of alphaVbeta6 to examine this possibility. We found that increased expression of alphaVbeta6 in malignant keratinocytes up-regulates MMP-9 and MMP-2 expression and promotes invasion in an MMP-9-dependent manner. Our results suggest a possible mechanism for the involvement of alphaVbeta6 in squamous carcinoma in vivo.

Animals↗

PubMed2001

The role of the globus pallidus D2 subfamily of dopamine receptors in pallidal immediate early gene expression.

The globus pallidus plays an important role in basal ganglia circuitry, representing the first relay nucleus of the 'indirect pathway' of striatal efferents. In contrast to the well-characterized actions of dopamine on striatal neurons, the functional role of the dopamine innervation of globus pallidus is less well understood. Previous research showed that systemic administration of either a dopamine D2 receptor antagonist or combined dopamine D1 and D2 receptor agonists induces Fos, the protein product of the immediate early gene c-fos, in neurons of globus pallidus [Ruskin and Marshall (1997) Neuroscience 81, 79-92]. To determine whether the ability of the D2 receptor antagonist, sulpiride, to induce Fos in rat pallidal neurons is mediated by D2-like receptors in striatum or globus pallidus, intrastriatal or intrapallidal sulpiride infusions were conducted. The diffusion of intrastriatal sulpiride was estimated by measuring this antagonist's competition for N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-induced D2 receptor inactivation. The phenotype of the striatal neurons expressing Fos after intrastriatal infusion was assessed by combining Fos immunocytochemistry with D2 receptor mRNA in situ hybridization. Intrastriatal infusions of (-)-sulpiride (10-200 ng) dose-dependently increased the number of striatal cells expressing Fos; and the Fos-immunoreactive striatal cells were D2 receptor mRNA-expressing, the same population in which systemic D2 receptor antagonists induce Fos. Intrastriatal infusions of high (5 microg), but not low (10-200 ng), (-)-sulpiride doses also induced Fos in globus pallidus cells but the sulpiride appeared to spread to the globus pallidus. Direct intrapallidal infusions of (-)-sulpiride (50-100 ng) dose-dependently induced Fos in globus pallidus with minimal influence on striatum or other basal ganglia structures. Using sensitive in situ hybridization conditions, prominent labeling of D2 receptor mRNA was evident in globus pallidus. D2 receptor mRNA was densest in a lateral 200 microm wide band that follows the curvature of the pallidal/striatal boundary. Cellular analysis revealed silver clusters associated with D2 receptor mRNA labeling over globus pallidus neurons that were immunoreactive for neuron-specific nuclear protein. These results strongly suggest that the dopaminergic innervation of globus pallidus, acting through D2-like receptors internal to this structure, can control gene expression in pallidal neurons.

Animals↗

PubMed2001

Expression of the alphavbeta6 integrin promotes migration and invasion in squamous carcinoma cells.

The integrin alphavbeta6 is a fibronectin receptor whose expression is not detectable on normal oral epithelium but is increased significantly in healing and in oral epithelial dysplasia and oral squamous cell carcinoma, suggesting it may promote changes associated with tumor development. To study whether alphavbeta6 may drive invasive behavior we have used transfection and retroviral infection to create a panel of epithelial cell lines expressing various levels of alphavbeta6. We report that increased expression of alphavbeta6 in malignant keratinocytes promotes invasion and leads to an increased capacity for migration towards fibronectin. alphavbeta6 expression may have a significant role in contributing to the malignant behavior of epithelial cells.

Antigens, Neoplasm↗

PubMed2001

alpha v beta 6 Integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytes.

The integrin alpha v beta 6 is a fibronectin receptor that is undetectable on normal keratinocytes in situ, but is increased significantly in wound healing and in culture-established keratinocytes, suggesting that it may promote changes associated with cell motility. Using normal human oral keratinocytes we have shown that cultured cells express relatively high levels of alpha v beta 6 and this integrin has a functional role in both cell adhesion and migration towards fibronectin. We provide experimental evidence that the increased expression of alpha v beta 6 by normal human oral keratinocytes results in coordinate changes, which promote a more migratory phenotype. Thus increased expression of alpha v beta 6 results in a fibronectin-dependent increase in pro-matrix metalloproteinase 9, matrix metalloproteinase 9 activity increases normal human oral keratinocyte migration, and this may be further dependent on plasmin activation. The results suggest a key role for alpha v beta 6 in these processes and indicate a coordinated link between alpha v beta 6 expression and upregulation of matrix metalloproteinase 9. It appears that alpha v beta 6 may function in normal human oral keratinocyte migration through matrix-metalloproteinase-9-dependent and -independent mechanisms.

Antigens, Neoplasm↗

PubMed2001

beta(3)A-integrin downregulates the urokinase-type plasminogen activator receptor (u-PAR) through a PEA3/ets transcriptional silencing element in the u-PAR promoter.

Migration of cells requires interactions with the extracellular matrix mediated, in part, by integrins, proteases, and their receptors. Previous studies have shown that beta(3)-integrin interacts with the urokinase-type plasminogen activator receptor (u-PAR) at the cell surface. Since integrins mediate signaling into the cell, the current study was undertaken to determine if in addition beta(3)-integrin regulates u-PAR expression. Overexpression of beta(3)-integrin in CHO cells, which are avid expressers of the receptor, downregulated u-PAR protein and mRNA expression. The u-PAR promoter (-1,469 bp) that is normally constitutively active in CHO cells was downregulated by induced beta(3)-integrin expression. A region between -398 and -197 bp of the u-PAR promoter was critical for beta(3)-integrin-induced downregulation of u-PAR promoter activity. Deletion of the PEA3/ets motif at -248 bp substantially impaired the ability of beta(3)-integrin to downregulate the u-PAR promoter, suggesting that the PEA3/ets site acts as a silencing element. An expression vector encoding the transcription factor PEA3 caused inhibition of the wild-type but not the PEA3/ets-deleted u-PAR promoter. The PEA3/ets site bound nuclear factors from CHO cells specifically, but binding was enhanced when beta(3)-integrin was overexpressed. A PEA3 antibody inhibited DNA-protein complex formation, indicating the presence of PEA3. Downregulation of the u-PAR promoter was achieved by the beta(3)A-integrin isoform but not by other beta(3)-integrin isoforms and required the cytoplasmic membrane NITY(759) motif. Moreover, overexpression of the short but not the long isoform of the beta(3)-integrin adapter protein beta(3)-endonexin blocked u-PAR promoter activity through the PEA3/ets binding site. Thus, besides the physical interaction of beta(3)-integrin and u-PAR at the cell surface, beta(3) signaling is implicated in the regulation of u-PAR gene transcription, suggesting a mutual regulation of adhesion and proteolysis receptors.

Amino Acid Sequence↗

PubMed2000

The integrins alpha3beta1 and alpha6beta1 physically and functionally associate with CD36 in human melanoma cells. Requirement for the extracellular domain OF CD36.

Lateral association between different transmembrane glycoproteins can serve to modulate integrin function. Here we characterize a physical association between the integrins alpha(3)beta(1) and alpha(6)beta(1) and CD36 on the surface of melanoma cells and show that ectopic expression of CD36 by CD36-negative MV3 melanoma cells increases their haptotactic migration on extracellular matrix components. The association was demonstrated by co-immunoprecipitation, reimmunoprecipitation, and immunoblotting of surface-labeled cells lysed in Brij 96 detergent. Confocal microscopy illustrated the co-association of alpha(3) and CD36 in cell membrane projections and ruffles. A requirement for the extracellular domain of CD36 in this association was shown by co-immunoprecipitation experiments using surface-labeled MV3 melanoma or COS-7 cells that had been transiently transfected with chimeric constructs between CD36 and intercellular adhesion molecule 1 (ICAM-1) or with a truncation mutant of CD36. CD36 is known to engage in signal transduction and to localize to membrane microdomains or rafts in several cell types. Toward a mechanistic explanation for the functional effects of CD36 expression, we demonstrate that in fractionated Triton X-100 lysates of the MV3 cells stably transfected with CD36, CD36 was greatly enriched with the detergent-insoluble fractions that represent plasma membrane rafts. Significantly, when these fractionated lysates were reprobed for endogenous beta(1) integrin, it was found that a 4-fold increase in the proportion of the mature protein was contained within the detergent-insoluble fractions when extracted from the CD36-transfected cells compared with MV3 cells transfected with vector only. These results suggest that in melanoma cells CD36 expression may induce the sequestration of certain integrins into membrane microdomains and promote cell migration.

Animals↗

PubMed2000

In vivo therapy of malignant melanoma by means of antagonists of alphav integrins.

Integrin alphavbeta3 (vitronectin receptor) has been implicated in human malignant melanoma progression and angiogenesis as a receptor that provides survival signals. However, little is known about the therapeutic potential of antagonists of alphavbeta3. In this report, we characterize the activities of 2 antagonists of alphavbeta3 integrins: a human specific monoclonal antibody (MAb), 17E6, and a cyclic RGD peptide that blocked cell adhesion and induced detachment of previously substrate-attached cells in vitro. In vivo, alphavbeta3 antagonists behaved as anti-tumor drugs in a dose- and time-dependent manner. Moreover, different therapeutic treatments proved to be effective even in the therapy of established macroscopic tumor masses, thus supporting the use of these antagonists in clinical therapy. Using a panel of 6 human melanomas and 5 carcinomas, MAb 17E6 efficiently blocked the in vivo tumor growth of melanomas expressing alphavbeta3 as xenografts but did not affect the alphavbeta3-negative (although alphav integrin-positive) tumors. This demonstrated that alphavbeta3 is a pivotal integrin for the growth of human melanomas. Furthermore, since MAb 17E6 does not recognize murine alphavbeta3, the effect is due only to the direct anti-tumor activity and not to the well-known anti-angiogenic activity of alphav-integrin antagonists. Taken together, our results confirm the essential role of alphavbeta3 integrin in the growth of human malignant melanoma in vivo and provide strong evidence of the therapeutic potential of alphav-integrin antagonists for the treatment of such tumors.

Animals↗

PubMed2000

Dopamine D1 receptors synergize with D2, but not D3 or D4, receptors in the striatum without the involvement of action potentials.

The widespread biological actions of the neurotransmitter dopamine (DA) are mediated by two classes of receptor, the D(1) class (D(1) and D(5)) and the D(2) class (D(2), D(3), and D(4)), which interact synergistically in many paradigms, such as DA agonist-stimulated motor behavior and striatal c-fos expression. Understanding the mechanism(s) of this interaction has been impeded by a controversy regarding the cellular localization of D(1) and D(2) class receptors. To address this issue from a functional point of view, we elicited striatal Fos by combined administration of a D(1) class and a D(2) class agonist either in the presence or absence of the fast sodium channel blocker tetrodotoxin (TTX). Striatal Fos elicited by direct D(1)/D(2) stimulation was not reduced by TTX. By contrast, TTX greatly attenuated the Fos response evoked by cocaine or GBR 12909. In separate experiments using antagonists that distinguish among members of the D(2) class of receptors, amphetamine-stimulated Fos and motor behavior were attenuated dose-dependently by the selective D(2) antagonist L-741,626, but not by the selective D(3) antagonist U99194A or the D(4)-selective antagonist L-745,870. Because Fos expression in the paradigms that were used occurs in enkephalin-negative striatonigral neurons, which show limited coexpression of D(1) and D(2) receptors, the present findings taken together suggest the intriguing possibility that D(1)/D(2) synergism may be mediated by D(1) and D(2) receptors residing on separate striatal neurons and interacting in a manner that is not dependent on action potentials.

Action Potentials↗

PubMed2000

Substantia nigra glutamate antagonists produce contralateral turning and basal ganglia Fos expression: interactions with D1 and D2 dopamine receptor agonists.

Experiments measuring behavior and immediate-early gene expression in the basal ganglia can reveal interactions between dopamine (DA) and glutamate neurotransmission. Nigrostriatal DA projections influence two striatal efferent pathways that, in turn, directly and indirectly influence the activity of the substantia nigra pars reticulata (SNr). This report tests the interactions between striatal DA receptors and nigral glutamate receptors on basal ganglia function by examining both contralateral turning and Fos immunoreactivity in striatum and pallidum following unilateral intranigral microinfusions of glutamate antagonists given to intact and 6-OHDA-lesioned rats. The NMDA antagonist AP5 (1 microg), or the AMPA/kainate antagonist DNQX (0.015-1.5 microg), injected into the SNr (0.5 microl) elicited contralateral turning as well as both striatal and pallidal Fos expression. Moreover, intranigral DNQX elicited more turning and greater numbers of Fos-positive striatal neurons in 6-OHDA-lesioned animals than in unlesioned controls, suggesting that the 6-OHDA injection induces functional changes in nigral glutamate transmission. In 6-OHDA-lesioned rats, systemic injections of the DA D1 receptor agonist SKF38393 (0.5 mg/kg, i.p.) increased striatal Fos expression due to intranigral DNQX. In contrast, the D2 agonist quinpirole (0.1 mg/kg, i.p.) decreased striatal Fos expression but increased the pallidal Fos arising from intranigral AP5. In additional experiments, both intact and 6-OHDA-lesioned rats were given simultaneous intranigral and intrastriatal infusions and turning and pallidal Fos expression were measured. 6-OHDA-lesioned rats given 5 microg of intrastriatal quinpirole exhibited both turning and pallidal Fos that was significantly increased by intranigral AP5. These results indicate that the opposing influences of D2 agonists and endogenous nigral glutamate transmission are mediated by striatal D2 receptors. Finally, the behavioral effects of intranigral glutamate antagonism can be dissociated from the effects on striatal or pallidal immediate-early gene expression.

Animals↗

PubMed2000

Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment.

To examine neuronal activation associated with incentive motivation for cocaine, cocaine-seeking behavior (operant responding without cocaine reinforcement) and Fos expression were examined in rats exposed to saline and cocaine priming injections and/or a self-administration environment. Rats were first trained to self-administer cocaine or received yoked saline administration ("control"). They then received 21 daily exposures to either the self-administration environment ("extinction") or a different environment ("no extinction") without cocaine available. Extinction training, used to decrease incentive motivation for cocaine elicited by the self-administration environment, decreased cocaine-seeking behavior elicited by both the environment and the cocaine priming injection. Exposure to the self-administration environment enhanced Fos expression in the no extinction group relative to control and extinction groups in the anterior cingulate, basolateral amygdala, hippocampal CA1 region, dentate gyrus, nucleus accumbens shell and core, and central gray area, regardless of whether or not priming injections were given. The priming injections enhanced Fos expression in the ventral tegmental area, caudate putamen, substantia nigra pars reticulata, entorhinal cortex, central amygdala, lateral amygdala, arcuate nucleus, and central gray area, regardless of group. Thus, these changes likely reflect an unconditioned effect from either cocaine or injection stress. The priming injections also enhanced Fos expression in the anterior cingulate, but only in cocaine-experienced groups, suggesting that this enhancement reflects an experience-dependent motivational effect of the priming injections. The results suggest that different neural circuits may be involved in the incentive motivational effects of cocaine-paired environmental stimuli versus priming injections and that the anterior cingulate may be part of a common pathway for both.

Animals↗

PubMed2000

Repeated administration of methamphetamine damages cells in the somatosensory cortex: overlap with cytochrome oxidase-rich barrels.

Multiple injections of methamphetamine (mAMPH) cause degeneration of neurons in rat primary somatosensory cortex (Par1). These degenerating cells can be labeled histochemically with the fluorochrome dye, Fluoro-Jade (FJ). This area of Par1 also contains the representation of the mystacial vibrissae. Neurons in this area of Par1 receiving projections derived from the vibrissae are arranged in discrete functional units ("barrels"), which are revealed by cytochrome oxidase (CO) histochemistry. Here, rats given mAMPH (four injections of 4 mg/kg, sc, 2-h intervals between injections) showed FJ-positive neurons in Par1 that were located predominantly near the perimeter of the CO-dense barrels. Thus, the Par1 neurons damaged by multiple administration of mAMPH are located within whisker barrels.

Animals↗