Biomedical subjects

T E Robinson

Publications and source records attributed to T E Robinson.

At least 19 recordsLinked to original sources

PubMed2004

Drug-induced neurobehavioral plasticity: the role of environmental context.

Repeated administrations of addictive drugs produce long-lasting changes in brain and behavior. However, drug-induced neurobehavioral plasticity is not a mere function of the neuropharmacological actions of drugs, but the result of complex drug-environment interactions. In the present review we summarize results obtained in a series of studies using an animal model of drug-environment interaction, showing that environmental context and past drug history interact to modulate the effects of amphetamine, cocaine and morphine on behavior, gene expression and structural plasticity. These findings may help shed some light on the conditions necessary for addictive drugs to enduringly alter brain and behavior.

Amphetamine↗

PubMed2003

Environmental context and drug history modulate amphetamine-induced c-fos mRNA expression in the basal ganglia, central extended amygdala, and associated limbic forebrain.

The context in which amphetamine is administered modulates its ability to induce both behavioral sensitization and immediate early gene expression. When given in a novel test environment amphetamine produces greater levels of c-fos and arc mRNA expression in many brain regions relative to when it is given in the home cage. The purpose of the current study was to determine if environment and drug history interact to influence amphetamine-induced c-fos mRNA expression. Rats with a unilateral 6-hydroxydopamine lesion were treated for 7 days with saline or 0.5 mg/kg of d-amphetamine (i.v.) in a distinct and relatively novel test environment (Novel), or in their home cage (Home). Following a 10-12-day withdrawal period, a challenge injection of either saline or 0.5 mg/kg d-amphetamine was administered. In situ hybridization histochemistry was used to examine c-fos mRNA expression in several regions of the basal ganglia, the central extended amygdala, and limbic forebrain. In most brain regions amphetamine given in the Novel environment produced greater c-fos mRNA expression than when given it was given at Home, and drug history had no effect on amphetamine-induced c-fos mRNA expression. However, within the subthalamic nucleus, substantia nigra reticulata, and central nucleus of the amygdala prior experience with amphetamine in the Novel but not Home environment enhanced the effect of an amphetamine challenge injection on c-fos mRNA expression. In contrast, there was a decrease in c-fos mRNA expression in amphetamine-pretreated animals, regardless of environmental context, in the ventral portion of the far caudal striatum. Reexposure to an environment previously paired with amphetamine produced a conditioned increase in c-fos mRNA expression in portions of the caudate-putamen, the subthalamic nucleus, the nucleus accumbens shell and a conditioned decrease in c-fos mRNA expression in the central nucleus of the amygdala. We conclude that environmental context and drug history interact to alter the basal ganglia and central extended amygdala circuitry engaged by subsequent exposure to amphetamine, or exposure to an environment previously paired with amphetamine.

AIDS-Related Complex↗

PubMed2001

Environmental context modulates the ability of cocaine and amphetamine to induce c-fos mRNA expression in the neocortex, caudate nucleus, and nucleus accumbens.

We reported previously that environmental novelty enhances the acute psychomotor activating effects of amphetamine, its ability to induce behavioral sensitization, and its ability to induce c-fos mRNA in the striatum and other structures, relative to when amphetamine is given in the home cage. The purpose of the present experiment was 2-fold: to determine (1) whether environmental novelty has a similar effect on the ability of cocaine to induce c-fos mRNA, and (2) whether this effect is seen in neurologically-intact rats (in previous experiments we studied the intact hemisphere of rats with a unilateral 6-OHDA lesion). In the dorsal portion of the caudate putamen, core and shell of the nucleus accumbens, and in several cortical regions, both amphetamine (1.5 mg/kg) and cocaine (15 mg/kg) induced higher levels of c-fos mRNA expression when administered in a novel environment, relative to when they were administered in the home cage. The ability of environmental context to modulate psychostimulant drug-induced immediate early gene expression may be related to its ability to modulate forms of drug experience-dependent plasticity, such as behavioral sensitization.

Amphetamine↗

PubMed2001

Social defeat alters the acquisition of cocaine self-administration in rats: role of individual differences in cocaine-taking behavior.

RATIONALE: It is known that social defeat can modulate cocaine self-administration. However, it is unclear whether this psychosocial stressor affects drug-taking behavior to the same extent across all individual animals, particularly those with differing propensities to self-administer psychostimulants. OBJECTIVE: This study examined the effect of social defeat on cocaine self-administration in animals that differ in novelty-seeking behavior that predicts differences in drug self-administration. METHODS: Male Sprague-Dawley rats were first classified into high-responder (HR) and low-responder (LR) groups. HR and LR rats were categorized based on their locomotor activity in a novel environment, with HR rats exhibiting higher locomotor activity than LR rats. Then, male rats were exposed on four occasions to an aggressive Long Evans male rat over the course of 4 days. Control rats were not exposed to the social defeat. All rats were subsequently implanted with jugular catheters and 3 days later placed into the self-administration box to study the acquisition of cocaine self-administration (0.25 mg per infusion). RESULTS: HR non-defeated animals self-administered more cocaine than the LR non-defeated animals. Following social defeat, the acquisition of cocaine self-administration is significantly delayed in HR rats and enhanced in LR rats. CONCLUSION The unique patterns of responsiveness in the HR and LR animals suggest that social defeat plays a role of equalizer of individual differences in drug-taking behavior.

Animals↗

PubMed2001

Characterization of the TBX5 binding site and analysis of mutations that cause Holt-Oram syndrome.

Holt-Oram syndrome is caused by mutations in TBX5, a member of the T-box gene family. In order to identify DNA sequences to which the TBX5 protein binds, we have performed an in vitro binding site selection assay. We have identified an 8 bp core sequence that is part of the Brachyury consensus-binding site. We show that TBX5 binds to the full palindromic Brachyury binding site and to the half-palindrome, whereas Brachyury does not bind to the TBX5 site. Amino acids 1-237 of TBX5 are required for DNA binding. Analysis of the effects of specific substitution mutations that arise in Holt-Oram patients indicates that G80R and R237Q eliminate binding to the target site. DNA database analysis reveals that target sites are present in the upstream regions of several cardiac-expressed genes including cardiac alpha actin, atrial natriuretic factor, cardiac myosin heavy chain alpha, cardiac myosin heavy chain beta, myosin light chain 1A, myosin light chain 1V and Nkx2.5. Cell transfection studies demonstrate that TBX5 activates the transcription of an atrial natriuretic factor reporter construct and this effect is significantly reduced by deletion of the TBX5 binding site.

Abnormalities, Multiple↗

PubMed2001

Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex.

We studied the influence of cocaine use on the structure of neurons in brain regions that contribute to its rewarding effects by allowing rats to self-administer cocaine (0.33 mg/infusion) for 1 h a day for 1 month. Control animals were left undisturbed or allowed to work for food for the same period of time. After an additional 1 month drug-free period the brains were processed for Golgi-Cox staining. In rats that self-administered cocaine, but not rats that worked for food, there was a significant increase in dendritic branching and in the density of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens and on pyramidal cells in the prefrontal and parietal (but not occipital) cortex. There was also a 2.6-fold increase in the incidence of spines with multiple heads (branched spines) on medium spiny neurons. Finally, in the prefrontal cortex some of the apical dendrites of pyramidal cells appeared misshaped, having large bulbous structures on their terminal tips. We speculate that cocaine self-administration experience alters patterns of synaptic connectivity within limbocortical circuitry that is thought to contribute to cocaine's incentive motivational effects and may have neuropathological effects in frontal areas involved in decision making and judgment. Together, these two classes of drug-induced neuroadaptations may contribute to the development of addiction.

Animals↗

PubMed2001

Environmental novelty differentially affects c-fos mRNA expression induced by amphetamine or cocaine in subregions of the bed nucleus of the stria terminalis and amygdala.

The environmental context in which amphetamine or cocaine are administered modulates both their acute psychomotor activating effects and their ability to induce sensitization. Here we report that environmental context differentially affects patterns of amphetamine- and cocaine-induced c-fos mRNA expression in the bed nucleus of the stria terminalis (BST) and amygdala of male rats. In the medial amygdala and medial posterior BST, exposure to novelty resulted in a marked increase in c-fos mRNA. Amphetamine given at home did not induce c-fos mRNA, and when given in the novel environment, did not increase levels beyond that observed for novelty alone. In the basolateral and lateral amygdala, amphetamine or cocaine at home or exposure to novelty induced c-fos mRNA. When amphetamine or cocaine was given in a novel environment the c-fos mRNA response was significantly enhanced. In the central nucleus of the amygdala (CEA) and oval subnucleus of the BST (BSTov), amphetamine administration at home produced a robust increase in c-fos mRNA expression, whereas exposure to novelty had little effect. In contrast to other brain regions examined, the c-fos mRNA response to amphetamine in a novel versus home environment was significantly smaller. In both "home" and "novel" amphetamine groups, c-fos mRNA in the BSTov and CEA was predominantly expressed in enkephalin-containing cells; coexpression with corticotropin-releasing hormone was rare. These data suggest that the context in which psychostimulants are given powerfully and differentially alters the response of limbic structures that have been functionally implicated in drug reinforcement and emotional behaviors.

Amphetamine↗

PubMed2001

The ability of environmental context to facilitate psychomotor sensitization to amphetamine can be dissociated from its effect on acute drug responsiveness and on conditioned responding.

Doses of amphetamine or cocaine that fail to induce psychomotor sensitization when given to a rat in its home cage can produce robust sensitization if given immediately following placement into a relatively novel, distinct environment. A drug-associated context can serve as a conditioned stimulus, and therefore may promote robust sensitization by facilitating associative learning processes. We examined this hypothesis by habituating rats to the test environment for 1 or 6--8 hr prior to each drug injection, which degrades the ability of environmental context to serve as an effective conditioned stimulus. When 0.5 mg/kg of amphetamine was administered intravenously immediately after placement into a distinct environment there was a large acute psychomotor response (rotational behavior) on the first test day, and robust sensitization developed with repeated daily injections. When the same treatment was administered in the home cage, there was a small acute response and no sensitization developed. The enhanced acute response seen in the distinct environment was significantly attenuated by 1 hr of habituation to the test environment, and completely abolished by 6--8 hr of habituation. Also, as little as 1 hr of habituation completely prevented the development of a conditioned rotational response. In contrast, neither 1 nor 6--8 hr of habituation had any effect on the ability of amphetamine to induce robust behavioral sensitization. It is concluded that the ability of a distinct environment to facilitate sensitization to amphetamine can be dissociated from its effect on acute drug responsiveness and from the ability of drug-associated environmental stimuli to elicit a conditioned response. Possible mechanisms by which a distinct environment facilitates sensitization are discussed.

Akathisia, Drug-Induced↗

PubMed2001

Amphetamine and cocaine induce different patterns of c-fos mRNA expression in the striatum and subthalamic nucleus depending on environmental context.

In the dorsal striatum, there are two major populations of medium spiny projection neurons. One population is positive for dynorphin mRNA (DYN+), and these cells project preferentially to the substantia nigra, forming the so-called 'direct pathway'. A second population is positive for enkephalin mRNA (ENK+), and these cells influence the substantia nigra indirectly, via the globus pallidus and subthalamic nucleus. Psychostimulant drugs, such as amphetamine and cocaine, are reported to induce immediate early genes (IEGs) in only one subpopulation of dorsal striatal projection neurons, DYN+ cells. However, this apparent selectivity appears to be a function of environmental context. We found that when given in the animal's home cage, amphetamine and cocaine increased expression of the IEG, c-fos, almost exclusively in DYN+ cells. However, when given in a novel environment, amphetamine and cocaine increased c-fos mRNA in both DYN+ and ENK+ cells. Furthermore, amphetamine and cocaine increased c-fos mRNA expression in the subthalamic nucleus when administered in the novel environment, but not when given at home. We conclude that the neural circuitry engaged by psychostimulant drugs, and their ability to induce specific patterns of gene expression, are determined by the environmental context in which they are experienced. This may be related to the ability of environmental novelty to facilitate psychostimulant drug-induced neuroplasticity.

Amphetamine↗

PubMed2001

Incentive-sensitization and addiction.

The question of addiction concerns the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense of most other activities, and the inability to cease drug-taking, that is, the problem of relapse. In this paper we summarize one view of this process, the "incentive-sensitization" view, which we first proposed in 1993. Four major tenets of the incentive-sensitization view are discussed. These are: (1) potentially addictive drugs share the ability to alter brain organization; (2) the brain systems that are altered include those normally involved in the process of incentive motivation and reward; (3) the critical neuroadaptations for addiction render these brain reward systems hypersensitive ("sensitized") to drugs and drug-associated stimuli; and (4) the brain systems that are sensitized do not mediate the pleasurable or euphoric effects of drugs (drug "liking"), but instead they mediate a subcomponent of reward we have termed incentive salience (drug "wanting").

Behavior, Addictive↗

PubMed2001

Spirometer-triggered high-resolution computed tomography and pulmonary function measurements during an acute exacerbation in patients with cystic fibrosis.

OBJECTIVE: To evaluate a high-resolution computed tomography (HRCT) scoring system, clinical parameters, and pulmonary function measurements in patients with cystic fibrosis (CF) before and after therapy for a pulmonary exacerbation. STUDY DESIGN: Patients (n = 17) were evaluated by spirometer-triggered HRCT imaging, clinical parameters, and pulmonary function tests (PFTs) before and after treatment. HRCT scans were reviewed by 3 radiologists using a modified Bhalla scoring system. RESULTS: Bronchiectasis, bronchial wall thickening, and air trapping were identified in all subjects on initial evaluation. The initial total HRCT score correlated significantly with the Brasfield score (r = -.91, P <.001) and several PFT measures. After treatment, there were improvements in the acute change clinical score (ACCS) (P <.001), most pulmonary function measurements, and total HRCT score (P <.05). Bronchiectasis, bronchial wall thickening, and air trapping did not significantly change. Mucus plugging subcomponent HRCT score, slow vital capacity (SVC), forced expiratory volume in 1 second (FEV(1)), and forced vital capacity (FVC) (percent predicted) and reversible and total HRCT scores were most sensitive to change by effect size analysis. CONCLUSIONS: Improvements occurred with treatment in total and reversible HRCT scores, PFTs, and ACCS. Total and reversible HRCT scores and percent predicted SVC, FEV1, and FVC were the most sensitive to change. The greatest change was seen in the mucus plugging subcomponent HRCT score.

Adolescent↗

PubMed2001

An investigation of the cause of low variability on the fourth chromosome of Drosophila melanogaster.

The fourth chromosome of Drosophila melanogaster lacks meiotic recombination. There is also a lack of nucleotide variation on the chromosome. This lack of variation could have been caused by a recent selective sweep, by background selection, or by a combination of these two forces. It should be possible to differentiate between the two mechanisms by studying the frequencies of polymorphic sites on the chromosome: a selective sweep should have resulted in low-frequency polymorphisms, whereas higher frequency polymorphisms would indicate the action of background selection. We have analyzed retrotransposable element insertions on the fourth chromosome in 11 strains of D. melanogaster. The polymorphisms found have a range of frequencies, with the presence of some insertions with high frequencies suggesting that the lack of variation is the result of background selection. We summarize the data using two statistics: the number of sites shared by more than one of the sample of 11 chromosomes (internal sites) and the mean number of transposable element differences in presence or absence between the sampled chromosomes. Simulations indicate that a selective sweep occurring more than 15,000 (0.03N) generations ago cannot be ruled out from the number of internal sites, although the number of differences between the chromosomes suggests either background selection or a sweep occurring more than 60,000 (0.12N) generations ago. Our results show no homoplasies and are thus consistent with no recombination occurring on the chromosome. The difficulties of distinguishing between the models using polymorphism data are discussed.

Animals↗

PubMed2000

The role of contextual versus discrete drug-associated cues in promoting the induction of psychomotor sensitization to intravenous amphetamine.

The environmental context in which psychostimulant drugs are administered can have a large effect on both their acute psychomotor activating effects and their ability to induce the psychomotor sensitization associated with repeated drug administration. For example, the acute effects of amphetamine and the development of psychomotor sensitization to amphetamine and cocaine are enhanced when they are administered in a distinct and relatively novel test environment, relative to when they are given in the home cage, in the absence of any environmental stimuli predictive of drug administration. The experiments reported here were designed to further examine this phenomenon and to test the hypothesis that the ability of a distinct context to promote robust psychomotor sensitization is due to its ability to reliably signal (cue) drug administration. Specifically, we compared the ability of contextual cues (a distinct test environment) and discrete cues (light, tone and/or odor), which both reliably predict drug administration, to promote the induction of sensitization. The psychomotor stimulant effects (rotational behavior) of repeated intravenous infusions of 0. 5 mg/kg amphetamine were assessed in rats for whom drug treatments were signaled either: (1) by placement into a distinct test environment; (2) by presentation of discrete cues; or (3) rats for whom drug treatments were given in the home environment in the absence of any environmental cues. Amphetamine produced robust sensitization when given in association with placement into a distinct test environment. The same treatment failed to produce sensitization when the drug was given unsignaled in the animal's home cage. Most importantly, signaling drug administration by presenting discrete cues was not sufficient to promote the robust sensitization seen when treatments were given in a distinct test environment. These results confirm that the induction of psychomotor sensitization can be powerfully modulated by environmental context and further establish that, although contextual stimuli associated with a distinct test environment promote robust sensitization, discrete cues that merely predict drug administration do not have this property. Possible reasons for the difference in the ability of contextual versus discrete environmental cues to promote sensitization are discussed.

Amphetamine↗

PubMed2000

Modulation of morphine sensitization in the rat by contextual stimuli.

RATIONALE: The repeated administration of addictive drugs, such as amphetamine, cocaine, and morphine, produces a progressive enhancement (sensitization) of their psychomotor activating effects. We have previously shown that administration of amphetamine or cocaine in a distinct test environment promotes more robust psychomotor sensitization than if they are given at home. No information is available, however, on whether this environmental manipulation has a similar effect on sensitization to morphine, a drug that enhances dopamine (DA) release in the striatum indirectly by disinhibiting midbrain DA neurons. OBJECTIVES: The main goal of present study was to determine whether exposure to a distinct environmental context facilitates morphine sensitization. METHODS: As an index of psychomotor activation, we used rotational behavior in rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal DA system. There are inconsistencies in the literature regarding the ability of morphine to elicit rotational behavior. Therefore, in experiment 1 we determined the effect of 2.0, 3.0, 4.0, 6.0, and 8.0 mg/kg, IP, of morphine on rotational behavior. In experiment 2, we studied the effect of five consecutive IV infusions of saline or morphine (2.0 mg/kg) in rats treated either in their home cage or in a distinct and relatively novel test environment. After 5 days of withdrawal, all rats received an IV infusion of 2.0 mg/kg morphine (Morphine challenge). The following day all rats received an IV infusion of saline (Saline challenge). RESULTS: Morphine produced a dose-dependent increase in rotational behavior. Environmental novelty enhanced both the acute psychomotor response to morphine and its ability to induce psychomotor sensitization. Furthermore, a conditioned rotational response was seen only in animals treated in the novel environment. CONCLUSIONS: Environmental novelty can facilitate the development of sensitization to the psychomotor activating effects of major addictive drugs, such as amphetamine, cocaine, and morphine.

Analgesics, Opioid↗

PubMed2000

Environmental modulation of the response to amphetamine: dissociation between changes in behavior and changes in dopamine and glutamate overflow in the rat striatal complex.

RATIONALE: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens. OBJECTIVES: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow in the caudal portions of the caudate. METHODS: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine (0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate concentrations. RESULTS: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1-3) but did not alter amphetamine-induced DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate or aspartate efflux in the caudate (experiment 3). CONCLUSIONS: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context independent of its primary neuropharmacological actions in the striatal complex.

Amphetamine↗

PubMed2000

The psychology and neurobiology of addiction: an incentive-sensitization view.

The question of addiction specifically concerns (1), the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense of most other activities and (2), the inability to cease drug-taking; the problem of relapse. In this paper current biopsychological views of addiction are critically evaluated in light of the "incentive-sensitization theory of addiction", which we first proposed in 1993, and new developments in research are incorporated. We argue that traditional negative reinforcement, positive reinforcement, and hedonic accounts of addiction are neither necessary nor sufficient to account for compulsive patterns of drug-seeking and drug-taking behavior. Four major tenets of the incentive-sensitization view are discussed. These are: (1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems. (2) The brain systems that are changed include those normally involved in the process of incentive motivation and reward. (3) The critical neuroadaptations for addiction render these brain reward systems hypersensitive ("sensitized") to drugs and drug-associated stimuli. (4) The brain systems that are sensitized do not mediate the pleasurable or euphoric effects of drugs (drug "liking"), but instead they mediate a subcomponent of reward we have termed incentive salience (drug "wanting"). We also discuss the role that mesolimbic dopamine systems play in reward, evidence that neural sensitization happens in humans, and the implications of incentive-sensitization for the development of therapies in the treatment of addiction.

Animals↗

PubMed1999

What is the impact of transposable elements on host genome variability?

The spread of a transposable element family through a wild population may be of astonishing rapidity. At least three families of transposable genetic elements have recently invaded Drosophila melanogaster worldwide, including the P element. The mechanism has been a process of effectively replicative transposition, and, for the P element, has occurred notwithstanding the sterility induced by unrestricted movement. This element's invasion into D. melanogaster has been accompanied by the development of heterogeneity between P sequences, most of which now have internal deletions. Increasing evidence suggests that some deleted elements can repress P transposition, thereby protecting the host from the harmful effects of complete elements. Such repressing elements may rise to high frequencies in populations as a result of selection at the level of the host. We here investigate selective sweeps invoked by the spread of P sequences in D. melanogaster populations. Numerous high-frequency sites have been identified on the X chromosome, which differ in frequency between populations, and which are associated with repression of P-element transposition. Unexpectedly, sequences adjacent to high-frequency P-element sites do not show reduced levels of genetic diversity, and DNA variability is in linkage equilibrium with the presence or absence of a P element at the adjacent selected site. This might be explained by multiple insertions or through a selection for recombination analogous to that seen in 'hitchhiking'.

Alleles↗

PubMed1999

Morphine alters the structure of neurons in the nucleus accumbens and neocortex of rats.

Rats were given repeated injections of 10 mg/kg of morphine and were then left undisturbed for 24-25 days before their brains were processed for Golgi-Cox staining. Prior exposure to morphine decreased the complexity of dendritic branching and the number of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens and on pyramidal cells in the prefrontal and parietal cortex. It is suggested that some of the long-term behavioral consequences of repeated exposure to morphine may be due to its ability to reorganize patterns of synaptic connectivity in the forebrain.

Animals↗