19 results on '"Jane A, Taylor"'
Search Results
2. Targeted effects of ketamine on perceptual expectation during mediated learning in rats
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Leah M, Fleming, Frances-Julia B, Jaynes, Summer L, Thompson, Philip R, Corlett, and Jane R, Taylor
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Motivation ,Hallucinations ,Psychotic Disorders ,Animals ,Humans ,Learning ,Ketamine ,Rats - Abstract
While neural correlates of hallucinations are known, the mechanisms have remained elusive. Mechanistic insight is more practicable in animal models, in which causal relationships can be established. Recent work developing animal models of hallucination susceptibility has focused on the genesis of perceptual expectations and perceptual decision-making. Both processes are encompassed within mediated learning, which involves inducing a strong perceptual expectation via associative learning, retrieving that memory representation, and deciding whether this internally generated percept is predictive of an external outcome. Mediated learning in rodents is sensitive to many psychotomimetic manipulations. However, we do not know if these manipulations selectively alter learning of perceptual expectations versus their retrieval because of their presence throughout all task phases.Here, we used mediated learning to study the targeted effect of a psychotomimetic agent on the retrieval of perceptual expectation.We administered (R,S)-ketamine to rats selectively during the devaluation phase of a mediated learning task, when the representation of the expected cue is retrieved, to test the hypothesis that internally generated perceptual experiences underlie this altered mediated learning.We found that ketamine increased only mediated learning at a moderate dose in rats, but impaired direct learning at the high dose.These results suggest that ketamine can augment retrieval of perceptual expectations and thus this may be how it induces hallucination-like experiences in humans. More broadly, mediated learning may unite the conditioning, perceptual decision-making, and even reality monitoring accounts of psychosis in a manner that translates across species.
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- 2022
3. Phosphoproteomic analysis of cocaine memory extinction and reconsolidation in the nucleus accumbens
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Kathryn L. Stone, Matthew L. MacDonald, TuKiet T. Lam, Jane R. Taylor, Mary M. Torregrossa, and Angus C. Nairn
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Male ,Proteomics ,Cell signaling ,Self Administration ,Nucleus accumbens ,Biology ,Nucleus Accumbens ,Article ,Extinction, Psychological ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cocaine-Related Disorders ,0302 clinical medicine ,Recurrence ,medicine ,Animals ,Phosphorylation ,Pharmacology ,Motivation ,Basolateral Nuclear Complex ,Phosphoproteomics ,Association Learning ,Extinction (psychology) ,Amygdala ,Phosphoproteins ,030227 psychiatry ,Rats ,medicine.anatomical_structure ,Receptors, GABA-B ,Mental Recall ,Memory consolidation ,Cues ,Self-administration ,Neuroscience ,030217 neurology & neurosurgery ,Basolateral amygdala ,Signal Transduction - Abstract
RATIONALE: Environmental stimuli, or cues, associated with the use of drugs such as cocaine are one of the primary drivers of relapse. Thus, identifying mechanisms to reduce the motivational properties of drug cues is an important research goal. OBJECTIVES: The purpose of this study was to identify cellular signaling events in the nucleus accumbens (NAc) that are induced when a cocaine cue memory is either extinguished through repeated cue presentation in the absence of drug, or when the memory is reactivated and reconsolidated by a brief cue re-exposure. Signaling events specific to extinction or reconsolidation represent potential targets for pharmacotherapeutics that may enhance extinction or disrupt reconsolidation to reduce the likelihood of relapse. METHODS: Male Sprague-Dawley rats were trained to self-administer cocaine paired with an audiovisual cue. Following a period of self-administration, the memory for the cocaine-associated cue was either extinguished, reactivated, or not manipulated (control) 15 min before sacrifice. Tissue from the NAc was subsequently analyzed using mass spectrometry based phosphoproteomics to identify cellular signaling events induced by each condition. RESULTS: Extinction and reconsolidation of the cocaine cue memory produced both common and distinct changes in protein phosphorylation. Notably, there were no significant changes in protein phosphorylation that were modulated in the opposite direction by the two behavioral conditions. Comparison of NAc phosphoproteomic changes to previously identified changes in the basolateral amygdala (BLA) revealed that cue extinction increases phosphorylation at serine (S) 883 of the GABA(B) receptor subunit 2 and on S14 of syntaxin 1a in both regions, while no common regional signaling events were identified in the reconsolidation group. CONCLUSIONS: Phosphoproteomics is a useful tool for identifying signaling cascades involved in different memory processes and revealed novel potential targets for selectively targeting extinction versus reconsolidation of a cocaine cue memory. Furthermore, cross region analysis suggests that cue extinction may produce unique signaling events associated with increased inhibitory signaling.
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- 2018
4. Nicotinic acetylcholine receptors are required for the conditioned reinforcing properties of sucrose-associated cues
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Bo Söderpalm, Jane R. Taylor, Rosita Stomberg, Peter Olausson, and Elin Löf
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Male ,Sucrose ,Reinforcement Schedule ,Aconitine ,Pharmacology toxicology ,Mecamylamine ,Receptors, Nicotinic ,Pharmacology ,complex mixtures ,Article ,Rats sprague dawley ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Reward ,mental disorders ,medicine ,Animals ,Acetylcholine receptor ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Rats ,Nicotinic acetylcholine receptor ,Nicotinic agonist ,nervous system ,sense organs ,Cues ,Reinforcement, Psychology ,Neuroscience ,medicine.drug - Abstract
We recently demonstrated that blocking specific nicotinic acetylcholine receptors (nAChRs) abolishes the conditioned reinforcing properties of ethanol-associated cues in rat, suggesting nAChRs as promising pharmacological targets for prevention of cue-induced relapse.The present study investigated the involvement of nAChR subtypes in the conditioned reinforcing properties of stimuli associated with a natural reward (sucrose).Water-deprived rats were trained to associate a tone + light stimulus (CS) with the presentation of a 0.1 M sucrose solution for 10 consecutive days. On the subsequent day, the animals were tested on the stringent acquisition of a new instrumental response with conditioned reinforcement, following a systemic injection of the nonselective nAChR antagonist mecamylamine (MEC) or the selective α7 and α6/α3β2β3* nAChR antagonist methyllycaconitine (MLA). At testing, the rats were presented with two novel levers. Responding on the lever assigned as active (CR lever) resulted in a presentation of the CS alone, while pressing the inactive lever (NCR lever) had no programmed consequences.Control animals pressed the CR lever significantly more than the NCR lever, demonstrating that the CR had acquired conditioned reinforcing properties. Systemic MEC as well as MLA reduced the CR lever responses to the same level as for the NCR lever.These results demonstrate a role for the α7 and/or α6/α3β2β3* nAChRs in conditioned reinforcement to a natural reward and suggest neuronal nAChRs as common mediators of the impact of cues on incentive processes.
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- 2010
5. Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats
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Jane R. Taylor, Nii A. Addy, Amine Bahi, and Marina R. Picciotto
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Male ,medicine.medical_specialty ,Time Factors ,Calcineurin Inhibitors ,Motor Activity ,Pharmacology ,Biology ,Nucleus accumbens ,Article ,Rats, Sprague-Dawley ,Serine ,chemistry.chemical_compound ,Cocaine ,Internal medicine ,medicine ,Animals ,Phosphorylation ,Neurotransmitter ,Behavior, Animal ,Calcineurin ,Synapsin ,Synapsins ,Rats ,Endocrinology ,chemistry ,Cyclosporine ,Signal transduction ,Intracellular ,Signal Transduction - Abstract
Cocaine administration in rats increases locomotor activity as a result of underlying changes in neurotransmitter dynamics and intracellular signaling. The serine/ threonine phosphatase, calcineurin, is known to modulate several signaling proteins that can influence behavioral responses to cocaine.This study aimed to determine whether calcineurin plays a role in locomotor responses associated with acute and repeated cocaine exposure. Second, we examined cocaine-mediated changes in intracellular signaling to identify potential mechanism underlying the ability of calcineurin to influence cocaine-mediated behavior.Locomotor activity was assessed over 17 days in male Sprague-Dawley rats (n = 48) that received daily administration of cocaine (15 mg/kg, s.c.) or saline in the presence or absence of the calcineurin inhibitor, cyclosporine (15 mg/kg, i.p.). Non-cocaine-treated animals from this initial experiment (n = 24) also received an acute cocaine challenge on day 18 of testing.Daily cyclosporine administration potentiated the locomotor response to repeated cocaine 5 min after cocaine injection and attenuated the sustained locomotor response 15 to 40 min after cocaine. Furthermore, cyclosporine pretreatment for 17 days augmented the acute locomotor response to acute cocaine 5 to 30 min after cocaine injection. Finally, repeated exposure to either cocaine or cyclosporine for 22 days increased synapsin I phosphorylation at the calcineurin-sensitive Ser 62/67 site, demonstrating a common downstream target for both calcineurin and cocaine.Our results suggest that calcineurin inhibition augments locomotor responses to cocaine and mimics cocaine-mediated phosphorylation of synapsin I.
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- 2008
6. Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats
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Wendy J. Lynch, Barbara J. Caldarone, Drew D. Kiraly, Jane R. Taylor, and Marina R. Picciotto
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Male ,Dopamine and cAMP-Regulated Phosphoprotein 32 ,medicine.medical_specialty ,media_common.quotation_subject ,Blotting, Western ,Self Administration ,Biology ,Nucleus Accumbens ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Sex Factors ,Cocaine ,Dopamine Uptake Inhibitors ,Dopamine ,Internal medicine ,medicine ,Animals ,Receptors, AMPA ,Phosphorylation ,Neurotransmitter ,Protein kinase A ,media_common ,Pharmacology ,Behavior, Animal ,Addiction ,Glutamate receptor ,Cyclic AMP-Dependent Protein Kinases ,Rats ,Substance Withdrawal Syndrome ,Endocrinology ,chemistry ,Catecholamine ,Female ,sense organs ,Signal transduction ,Signal Transduction ,medicine.drug - Abstract
Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction.Given sex differences in the progression to cocaine addiction, we examined the possibility that the PKA pathway is differentially activated by cocaine in male and female rats.Rats were given 24-h access to cocaine (1.5 mg/kg) or saline for 7 days under a discrete trial procedure (four trials per hour). Rats were then retested on responding for cocaine under a progressive-ratio schedule after either 0 (no-delay retest) or 10 (10-day-delay retest) days of abstinence. Markers of PKA-regulated signaling in the striatum and nucleus accumbens were evaluated by Western blotting, including phosphorylation of DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 and glutamate receptor 1 (GluR1) at Ser 845.Compared to males, females had higher levels of DARPP-32 phosphorylated at the PKA site in the striatum. Increased phosphorylation of DARPP-32 at the PKA site was also seen in the nucleus accumbens of females compared to males, particularly among controls and rats tested after a 10-day abstinence period. DARPP-32 phosphorylation was also increased as a consequence of cocaine when tested after a 0-day abstinence period in male rats but not female rats.These findings indicate sex differences in PKA-regulated signaling in drug-naïve controls. Furthermore, these data suggest that regulation of PKA signaling by cocaine is differentially influenced in male and female rats as a consequence of cocaine exposure and cocaine abstinence period.
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- 2006
7. Repeated nicotine exposure enhances responding with conditioned reinforcement
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Peter Olausson, J. David Jentsch, and Jane R. Taylor
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Male ,Nicotine ,NICOTINE EXPOSURE ,media_common.quotation_subject ,Pharmacology toxicology ,Drug Administration Schedule ,Nucleus Accumbens ,Developmental psychology ,Smoking behavior ,medicine ,Animals ,Drug Interactions ,Rats, Wistar ,Reinforcement ,media_common ,Pharmacology ,Adrenergic Uptake Inhibitors ,Behavior, Animal ,Addiction ,Ganglionic Stimulants ,Rats ,Amphetamine ,Conditioning, Operant ,Psychology ,Reinforcement, Psychology ,medicine.drug ,Clinical psychology - Abstract
Stimuli associated with a reinforcer (e.g., an addictive drug) can acquire conditioned reinforcing effects. Clinical observations indicate that smoking depends strongly upon conditioned reinforcement (i.e., cues support smoking behavior); however, little is known about the effects of repeated nicotine exposure on these processes.This study investigated the consequences of prior repeated nicotine exposure on responding with conditioned reinforcement and on the potentiation of conditioned reinforcement by intra-NAc amphetamine infusion.Rats received repeated saline or nicotine injections (0.35 mg/kg; 15 days) and were, following 3 days of withdrawal, trained to associate a tone + light stimulus with water reinforcement for 10 days. Animals were subsequently tested on acquisition of a new instrumental response with conditioned reinforcement (i.e., 14 days after the final nicotine injection). In additional experiments, animals received an infusion of amphetamine (10 microg per side) prior to the conditioned reinforcement test.Prior repeated nicotine exposure produced a behaviorally specific enhancement of responding with conditioned reinforcement. Furthermore, repeated nicotine pretreatment also augmented the potentiation of conditioned reinforcement by intra-NAc amphetamine.These findings demonstrate that prior repeated nicotine exposure augments the control over behavior by a conditioned reinforcer. Such long-lasting alterations in incentive motivational processes produced by repeated nicotine exposure may depend on drug-induced neuroadaptations in dopamine-regulated signaling within limbic-striatal brain regions that could underly persistent and compulsive aspects of addiction.
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- 2004
8. Nicotine enhances responding with conditioned reinforcement
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Jane R. Taylor, J. David Jentsch, and Peter Olausson
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Male ,Nicotine ,medicine.medical_treatment ,Conditioning, Classical ,Neutral stimulus ,Mecamylamine ,Pharmacology ,Discrimination Learning ,Rats, Sprague-Dawley ,medicine ,Animals ,Nicotinic Agonists ,Reinforcement ,Dose-Response Relationship, Drug ,Alkaloid ,Antagonist ,Drug Synergism ,Rats ,Stimulant ,Nicotinic acetylcholine receptor ,Anesthesia ,Psychology ,Reinforcement, Psychology ,medicine.drug - Abstract
The mesolimbic dopamine system has been implicated in the primary reinforcing properties of drugs of abuse as well as in enhanced responding with conditioned reinforcement produced by psychomotor stimulant drugs. Despite clinical observations that nicotine self-administration (i.e. smoking) depends strongly upon conditioned reinforcement (i.e. cues support smoking behavior), little is known about whether nicotine directly affects motivational processes.In these experiments, we investigated whether acute nicotine would influence responding with conditioned reinforcement and the degree to which pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine would modify any nicotine-induced behavioral effects.After subjects had been trained to associate an initially neutral stimulus with water reward, they received acute nicotine (43,25-350 micro g/kg SC; -5 min) or saline injections and were tested on the acquisition of a new response for conditioned reinforcement paradigm. In separate experiments, the effect of pretreatment with the nicotinic acetylcholine receptor antagonist mecamylamine (300 or 1000 micro g/kg SC; -20 min) alone, or in combination with nicotine (350 micro g/kg SC; -5 min), on conditioned reinforcement was also examined.Acute nicotine injection produced a selective enhancement of responding with conditioned reinforcement (i.e. on the CR lever), without producing non-selective increases in overall responding. The effect of nicotine (350 micro g/kg SC; -5 min) was selectively blocked by mecamylamine (300 micro g/kg).These findings demonstrate that acute exposure to nicotine augments the control over behavior by a conditioned reinforcer, suggesting that nicotine may enhance motivational processes.
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- 2004
9. Enhanced responding for conditioned reward produced by intra-accumbens amphetamine is potentiated after cocaine sensitization
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Jane R. Taylor and Brian A. Horger
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Male ,medicine.medical_treatment ,Dopamine Agents ,Motor Activity ,Pharmacology ,Nucleus accumbens ,Stimulus (physiology) ,Nucleus Accumbens ,Rats, Sprague-Dawley ,Cocaine ,Dopamine Uptake Inhibitors ,Reward ,Conditioning, Psychological ,Basal ganglia ,medicine ,Animals ,Reinforcement ,Amphetamine ,Sensitization ,Classical conditioning ,Drug Synergism ,Rats ,Stimulant ,medicine.anatomical_structure ,Psychology ,Neuroscience ,medicine.drug - Abstract
The mesolimbic dopamine (DA) system has been implicated in conditioned reward (CR), locomotor sensitization, and the reinforcing properties of psychomotor stimulants. Stimuli with formerly motivationally neutral properties that gain incentive properties by their predictive association with primary reinforcers are termed conditioned, or secondary, reinforcers. In these experiments, we investigated whether cocaine sensitization could potentiate augmented responding for CR produced by intra-accumbens amphetamine. After subjects were trained on the CR paradigm for 14 days, they received a regimen of cocaine sensitization or saline injections. On 2 test days, 8-10 days later, subjects were given amphetamine (6 microg/0.5 microl) or saline infusions into the nucleus accumbens (NAc) and responding for CR was measured using the "acquisition of a new response" paradigm. Responding on one novel lever resulted in the delivery of the conditioned stimulus (conditioned reinforcer, or CR lever), whereas responding on the other lever resulted in no CR stimulus presentation (NCR lever). Animals sensitized to cocaine showed increased responding on the CR lever after intra-NAc saline and potentiated CR lever responding after intra-NAc amphetamine. No differences in responding between the cocaine- and saline-treated groups on the NCR lever after the challenge were found. Locomotor sensitization under these conditions was confirmed in a separate group of subjects. These findings show that prior exposures to cocaine results in changes that potentiate the ability of intra-NAc amphetamine to enhance CR. Repeated stimulant drug use may induce long-term neuronal adaptations that result in increased sensitivity to the behavioral, or incentive motivational, effects of stimulant drugs.
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- 1999
10. Learning to forget: manipulating extinction and reconsolidation processes to treat addiction
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Jane R. Taylor and Mary M. Torregrossa
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Psychotherapist ,Time Factors ,Substance-Related Disorders ,media_common.quotation_subject ,Pharmacology toxicology ,Craving ,Article ,Extinction, Psychological ,Memory ,medicine ,Secondary Prevention ,Animals ,Humans ,media_common ,Pharmacology ,Secondary prevention ,Motivation ,Addiction ,Extinction (psychology) ,Abstinence ,Behavior, Addictive ,Treatment strategy ,Memory consolidation ,medicine.symptom ,Cues ,Psychology ,Cognitive psychology - Abstract
Finding effective long-lasting treatments for drug addiction has been an elusive goal. Consequently, researchers are beginning to investigate novel treatment strategies including manipulations of drug-associated memories. When environmental stimuli (cues) become associated with drug use, they become powerful motivators of continued drug use and relapse after abstinence. Reducing the strength of these cue–drug memories could decrease the number of factors that induce craving and relapse to aid in the treatment of addiction. Enhancing the consolidation of extinction learning and/or disrupting cue–drug memory reconsolidation are two strategies that have been proposed to reduce the strength of cues in motivating drug-seeking and drug-taking behavior. Here, we review the latest basic and clinical research elucidating the mechanisms underlying consolidation of extinction and reconsolidation of cue–drug memories in the hopes of developing pharmacological tools that exploit these signaling systems to treat addiction.
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- 2012
11. Antidepressant-like properties of oral riluzole and utility of incentive disengagement models of depression in mice
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Shannon L. Gourley, Gerard Sanacora, Jonathan W. Espitia, and Jane R. Taylor
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Male ,Transgene ,Administration, Oral ,Pharmacology ,Neuroprotection ,Article ,Mice ,medicine ,Animals ,Disengagement theory ,Depression (differential diagnoses) ,Brain-derived neurotrophic factor ,Motivation ,Riluzole ,Dose-Response Relationship, Drug ,Depression ,Brain-Derived Neurotrophic Factor ,Antidepressive Agents ,Mice, Inbred C57BL ,Disease Models, Animal ,Excitatory Amino Acid Transporter 2 ,Knockout mouse ,Antidepressant ,Psychology ,Neuroscience ,medicine.drug - Abstract
The neuroprotective agent riluzole has antidepressant-like properties in humans, but its mechanisms of action are unclear. Despite the increasing utility of transgenic and knockout mice in addressing such issues, previous studies aimed at characterizing biochemical mechanisms have been conducted in rats.We sought to optimize an oral riluzole administration protocol with antidepressant-like consequences in C57BL/6 mice, a common background strain in genetically modified mice.Riluzole (6-60 μg/ml) was dissolved in tap water and replaced regular drinking water for up to 3 weeks; sensitivity to tail suspension, forced swimming, and the locomotor response to extinction training in a model of "incentive disengagement" were tested. Peripheral and central effects of long-term 60-μg/ml treatment were also evaluated.Riluzole had dose-dependent antidepressant-like effects in the forced swim test, and like chronic fluoxetine, exerted antidepressant-like actions in an adaptation of the "incentive disengagement" model at the highest concentration tested. This 60-μg/ml concentration also restored hippocampal brain-derived neuroptrophic factor (BDNF) expression after chronic corticosteroid exposure and increased glutamate glial transporter 1 (GLT-1, or EAAT2) expression without significantly affecting baseline locomotor activity, thymus and adrenal gland weights, or blood serum corticosterone. The lowest 6-μg/ml concentration increased locomotor activity, potentially consistent with an anxiolytic-like effect.Riluzole's therapeutic potential for treating mood disorders may involve GLT-1 and BDNF, and we suggest this protocol could be used to further characterize its precise long-term biochemical mechanisms of action in animal models of depression.
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- 2010
12. Potentiation of the effects of reward-related stimuli by dopaminergic-dependent mechanisms in the nucleus accumbens
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M. Cador, Trevor W. Robbins, and Jane R. Taylor
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Male ,Dextroamphetamine ,medicine.drug_class ,Dopamine ,Pharmacology ,Nucleus accumbens ,Nucleus Accumbens ,Norepinephrine ,Neurochemical ,Reward ,medicine ,Animals ,Oxidopamine ,Injections, Intraventricular ,Brain Chemistry ,Dose-Response Relationship, Drug ,Chemistry ,Dopaminergic ,Classical conditioning ,Rats, Inbred Strains ,Long-term potentiation ,Receptor antagonist ,Corpus Striatum ,Rats ,Catecholamine ,Conditioning, Operant ,Caudate Nucleus ,Neuroscience ,medicine.drug - Abstract
Three experiments examined the behavioural, pharmacological and neural specificity of the previously reported potentiation of responding with conditioned reinforcement following intra-accumbensd-amphetamine, by studying the effects of intraaccumbens dopamine (DA) and noradrenaline, using an acquisition of a new response procedure. In experiment 1, the effects of intra-cerebral DA infusions (5, 20, 50 µg/2 µl) were compared in four conditions: (i) intra-accumbens DA following positive pairing of the conditioned stimulus (CS) and water during training; (ii) as (i) but also following a systemic dose of the DA receptor antagonist alpha-flupenthixol; (iii) intra-accumbens DA following random pairing of the CS and water during training; and (iv) as (i) but with intra-caudate rather than intra-accumbens DA. The results showed that only with intra-accumbens DA in the positive pairing condition was there a significant dose-dependent increase in responding. In experiment 2, the effects of a higher range of doses (20, 100, 200 µg) and smaller infusion volume (5, 25, 50 µg/l µl) of intra-accumbens DA were studied, in comparison with a similar range of doses (5, 25, 50 µg/l µl) of intra-accumbens noradrenaline (NA). Only DA produced a selective, dose-dependent increase in responding with conditioned reinforcement. In experiment 3 neurotoxic lesions of the dorsal noradrenergic bundle (DNAB) using 6-hydroxydopamine producing profound (about 90%) depletion of cortical and nucleus accumbens NA levels had no effect on the increased responding with conditioned reinforcement produced by intra-accumbensd-amphetamine (3, 10, 30 µg/l µl). The results are discussed in terms of the neurochemical mediation of the potentiation of the effects of conditioned reinforcers byd-amphetamine and the role of DA-dependent mechanisms of the nucleus accumbens in reward-related processes.
- Published
- 1991
13. Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues
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Bo Söderpalm, J. Michael McIntosh, Jane R. Taylor, Peter Olausson, Rosita Stomberg, Andrea deBejczy, and Elin Löf
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Male ,Dopamine ,Microdialysis ,Self Administration ,Nicotinic Antagonists ,Pharmacology ,Nucleus accumbens ,Mecamylamine ,Receptors, Nicotinic ,Rats, Sprague-Dawley ,mental disorders ,medicine ,Animals ,Nicotinic Agonists ,Nicotinic Antagonist ,Rats, Wistar ,Ethanol ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Dopaminergic ,Ventral Tegmental Area ,Dihydro-beta-Erythroidine ,Rats ,Ventral tegmental area ,medicine.anatomical_structure ,Nicotinic agonist ,nervous system ,Conditioning, Operant ,Cues ,Conotoxins ,Neuroscience ,Reinforcement, Psychology ,Acetylcholine ,medicine.drug - Abstract
Cues associated with alcohol can elicit craving, support drug-seeking and precipitate relapse.We investigated the possible involvement of nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area (VTA) in the conditioned reinforcing properties of ethanol-associated stimuli in the rat.First, using in vivo microdialysis, we analyzed the effect of VTA perfusion of the nonselective nAChR antagonist mecamylamine (MEC) or the selective alpha4beta2* nAChR antagonist dihydro-beta-erythroidine (DHbetaE) on the nucleus accumbens (nAc) dopaminergic response to the presentation of an ethanol-associated conditioned stimulus (CS). Second, rats were trained to associate a tone+light CS with the presentation of 10% ethanol and were subsequently tested on the acquisition of a new instrumental response with conditioned reinforcement (CR) after local VTA infusion of MEC, DHbetaE, or alpha-Conotoxin MII (alpha-CtxMII, a selective alpha3beta2* and alpha6* nAChR antagonist).The ethanol-associated CS elevated nAc dopamine, an effect that was blocked by VTA perfusion of MEC but not DHbetaE. Systemic administration of MEC or local VTA infusion of MEC or alpha-CtxMII selectively blocked ethanol-associated CR, whereas systemic DHbetaE had no effect.We hypothesize a novel mechanism by which alcohol-associated cues promote drug-seeking behavior via activation of dopamine-stimulating alpha-CtxMII-sensitive nAChRs in the VTA. Pharmacological manipulations of selective nAChRs may thus be possible treatment strategies to prevent cue-induced relapse.
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- 2007
14. Assessment of cognitive function in the heterozygous reeler mouse
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Dilja D. Krueger, Jessica L. Howell, Jane R. Taylor, Angus C. Nairn, Britni F. Hebert, and Peter Olausson
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Serial reaction time ,Psychosis ,Heterozygote ,Time Factors ,Perseveration ,Cell Adhesion Molecules, Neuronal ,Prefrontal Cortex ,Spatial Behavior ,Mice, Transgenic ,Nerve Tissue Proteins ,Reversal Learning ,Motor Activity ,Impulsivity ,Hippocampus ,Article ,Mice ,Mice, Neurologic Mutants ,Reeler ,Cognition ,Memory ,medicine ,Animals ,Attention ,Reelin ,Maze Learning ,Pharmacology ,Extracellular Matrix Proteins ,biology ,Behavior, Animal ,Serine Endopeptidases ,Cognitive flexibility ,medicine.disease ,Disease Models, Animal ,Reelin Protein ,Schizophrenia ,Impulsive Behavior ,biology.protein ,Schizophrenic Psychology ,medicine.symptom ,Psychology ,Neuroscience - Abstract
The heterozygous reeler mouse has been proposed as a genetic mouse model of schizophrenia based on several neuroanatomical and behavioral similarities between these mice and patients with schizophrenia. However, the effect of reelin haploinsufficiency on one of the cardinal symptoms of schizophrenia, the impairment of prefrontal-cortex-dependent cognitive function, has yet to be determined. Here, we investigated multiple aspects of cognitive function in heterozygous reeler mice that are known to be impaired in schizophrenic patients. Heterozygous reeler mice were assessed for (1) cognitive flexibility in an instrumental reversal learning task, (2) impulsivity in an inhibitory control task, (3) attentional function in a three-choice serial reaction time task, and (4) working memory in a delayed matching-to-position task. No differences were found between heterozygous reeler mice and wild-type littermate controls in any prefrontal-related cognitive measures. However, heterozygous reeler mice showed deficits in the acquisition of two operant tasks, consistent with a role for reelin in certain forms of learning. These findings suggest that heterozygous reeler mice may not be an appropriate model for the core prefrontal-dependent cognitive deficits observed in schizophrenia, but may model more general learning deficits that are associated with many psychiatric disorders.
- Published
- 2006
15. beta2-Subunit-containing nicotinic acetylcholine receptors are involved in nicotine-induced increases in conditioned reinforcement but not progressive ratio responding for food in C57BL/6 mice
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Peter Olausson, Darlene H. Brunzell, Jessica R. Chang, Brandon Schneider, Marina R. Picciotto, and Jane R. Taylor
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Male ,medicine.medical_specialty ,Nicotine ,Reinforcement Schedule ,Conditioning, Classical ,Drinking ,Receptors, Nicotinic ,chemistry.chemical_compound ,Food Preferences ,Mice ,Internal medicine ,medicine ,Animals ,Reinforcement ,Saccharin ,Acetylcholine receptor ,Pharmacology ,Mice, Knockout ,Motivation ,Alkaloid ,Classical conditioning ,Association Learning ,Tobacco Use Disorder ,Associative learning ,Mice, Inbred C57BL ,Endocrinology ,Nicotinic agonist ,chemistry ,Conditioning, Operant ,Psychology ,Neuroscience ,medicine.drug - Abstract
Nicotine administration potentiates conditioned reinforcement in rats, an effect that persists for weeks after chronic exposure. Little is known regarding the nicotinic receptor subtypes that may mediate this effect.The purpose of this study was to determine whether beta2-subunit-containing nicotinic acetylcholine receptors (beta2*nAChRs) are necessary for lasting effects of nicotine on conditioned and primary reinforcement in mice.Beta2 knockout (beta2KO) and wild-type (WT) mice received 14 days of nicotine exposure (NIC, 200 microg/ml in 2% saccharin) or saccharin alone (SAC) in their drinking water. Five days later, mice received paired presentations of a conditioned stimulus (CS) with water unconditioned stimulus (US) or explicitly unpaired presentations of the CS and US during Pavlovian discriminative approach training. Training was followed by two conditioned reinforcement tests. Mice were subsequently tested for food-reinforced responding in the absence of explicit cues followed by a progressive ratio test.During conditioned reinforcement testing, only mice in the paired condition showed increased responding in the CS-reinforced aperture over inactive apertures. WT-NIC mice showed enhanced conditioned reinforcement compared to WT-SAC animals. beta2KO-SAC mice showed elevated conditioned reinforcement compared to WT-SAC subjects, but beta2KO-NIC and beta2KO-SAC mice did not differ in responding with conditioned reinforcement. Prior nicotine exposure did not alter food-reinforced responding but resulted in elevated break points for food in both genotypes.These data show that nicotine exposure enhances conditioned reinforcement in mice and indicate that beta2*nAChRs are necessary for nicotine-dependent enhancement of incentive aspects of motivation but not motivation for primary reinforcement measured by progressive ratio responding.
- Published
- 2005
16. A comparison of the effects of clonidine and CNQX infusion into the locus coeruleus and the amygdala on naloxone-precipitated opiate withdrawal in the rat
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Laurie J. Punch, Jane R. Taylor, and John D. Elsworth
- Subjects
Male ,medicine.medical_specialty ,N-Methylaspartate ,Glutamine ,Narcotic Antagonists ,Glutamic Acid ,Clonidine ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Norepinephrine ,Internal medicine ,medicine ,Animals ,Pharmacology ,6-Cyano-7-nitroquinoxaline-2,3-dione ,Kindling ,business.industry ,Naloxone ,Central nucleus of the amygdala ,Amygdala ,Rats ,Substance Withdrawal Syndrome ,Endocrinology ,chemistry ,Opioid ,CNQX ,Morphine ,Locus coeruleus ,Locus Coeruleus ,Opiate ,business ,Adrenergic alpha-Agonists ,Excitatory Amino Acid Antagonists ,Morphine Dependence ,medicine.drug - Abstract
Both the locus coeruleus (LC) and the amygdala have been implicated in aspects of opiate dependence and withdrawal. The LC is known to be one of the most sensitive sites for precipitating withdrawal behaviors after local opiate antagonist infusions in morphine-dependent subjects. The amygdala is also known to mediate antagonist-induced withdrawal behaviors and aversive motivational states. The goal of the present study was to evaluate directly the ability of noradrenergic agonists and glutamatergic antagonists to attenuate naloxone-precipitated withdrawal behaviors when infused into the LC or the central nucleus of the amygdala (CeA). The alpha-2-noradrenergic agonists clonidine or ST-91 were infused into the CeA to compare the effects of noradrenergic activation in the CeA to the attenuation of withdrawal previously observed in rats infused with clonidine into the LC, since the LC and CeA are known to contain co-localized opiate and noradrenergic receptors. The effects of microinfusions of the non-NMDA excitatory amino acid antagonist 6-cyano-2,3-dihydroxy-7-nitroquinoxaline (CNQX) were also infused into the LC and CeA since opiate withdrawal is associated with increased glutamatergic transmission. Intra-CeA clonidine or ST-91 (2.4 microg/0.5 microl or 1.0 microl) produced significant reductions primarily in the occurrence of irritability. Conversely, intra-CeA or intra-LC infusions of CNQX (2.5 microg/0.5 microl) significantly attenuated naloxone-precipitated withdrawal, an effect similar to the attenuation previously observed after intra-LC clonidine infusions. These data demonstrate the specific behavioral effects of altering glutamatergic and noradrenergic neurotransmission in the LC or CeA during naloxone-precipitated opiate withdrawal. Elucidation of the neuroanatomical circuitry involved in opiate withdrawal should increase our understanding of the neuroadaptations associated with drug dependence and subsequent withdrawal behavior.
- Published
- 1998
17. Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens
- Author
-
Trevor W. Robbins and Jane R. Taylor
- Subjects
Male ,medicine.medical_specialty ,Dextroamphetamine ,Microinjections ,Caudate nucleus ,Stimulus (physiology) ,Nucleus accumbens ,Nucleus Accumbens ,Thalamus ,Internal medicine ,medicine ,Animals ,Amphetamine ,Reinforcement ,Pharmacology ,Behavior, Animal ,Brain ,Classical conditioning ,Rats, Inbred Strains ,Rats ,Endocrinology ,Conditioning, Operant ,Septal Nuclei ,Caudate Nucleus ,Stimulus control ,Psychology ,Neuroscience ,medicine.drug - Abstract
Stimulant drugs have been shown to enhance the control over behaviour exerted by stimuli previously correlated with primary reinforcers, termed conditioned reinforcers (CR). Experiment 1 examined the possible neuroanatomical specificity of the enhancement of conditioned reinforcement following intracerebral injections of d-amphetamine. Thirsty rats were trained to associate a light with water. In the test phase, water was no longer presented but the light (CR) was intermittently produced by responding on one of two novel levers. Rats with bilateral guide cannulae aimed at the nucleus accumbens, posterior caudate nucleus, or medio-dorsal nucleus of the thalamus received four counterbalanced microinfusions of d-amphetamine (10, 20, 30 micrograms/2 microliters) or vehicle (control) over 4 test days. There was a dose-dependent selective increase in responding on the lever that produced the light (CR) with intra-accumbens d-amphetamine infusions. Quantitatively similar, but much more variable effects were found with intra-caudate infusions and no effects following intra-thalamic d-amphetamine. Experiment 2 provided evidence that the enhanced control over responding by a CR with intra-accumbens d-amphetamine is behaviourally specific. Three groups of rats received a compound tone--plus--light stimulus that was positively, negatively or randomly correlated with water during training. Intra-accumbens d-amphetamine produced selective increases in responding only if the contingent stimulus had been positively correlated. The results suggest that the nucleus accumbens may play an important role in d-amphetamine's enhanced control over behaviour exerted by conditioned reinforcers.
- Published
- 1984
18. Clonidine infusions into the locus coeruleus attenuate behavioral and neurochemical changes associated with naloxone-precipitated withdrawal
- Author
-
E. J. Garcia, D.E. Redmond, Jane R. Taylor, Robert H. Roth, Steven J. Grant, and John D. Elsworth
- Subjects
Male ,Agonist ,medicine.medical_specialty ,medicine.drug_class ,Stimulation ,Hippocampus ,Clonidine ,Injections ,Methoxyhydroxyphenylglycol ,Neurochemical ,Naloxone ,Internal medicine ,medicine ,Animals ,Premovement neuronal activity ,Brain Chemistry ,Pharmacology ,Behavior, Animal ,business.industry ,Body Weight ,Rats, Inbred Strains ,Rats ,Substance Withdrawal Syndrome ,Endocrinology ,Morphine ,Locus coeruleus ,Locus Coeruleus ,business ,medicine.drug - Abstract
Clonidine, an alpha-2-adrenergic agonist, suppresses signs of opiate withdrawal in animals and in man. Electrical or chemical stimulation of the nucleus locus coeruleus (LC) increases noradrenergic activity and brain concentration of the noradrenergic metabolite MHPG, and produces many signs of opiate withdrawal. Thus, clonidine's ability to attenuate withdrawal might be due to the reduction of noradrenergic neuronal activity originating in the LC, but additional alpha-2-adrenergic receptors throughout the body and other mechanisms may also play a role. The present study explored the neuroanatomical and pharmacological selectivity of alpha-2-adrenergic receptors of the LC in the anti-withdrawal action of clonidine. Experiment 1 tested the hypothesis that behavioral and biochemical measures of naloxone-precipitated withdrawal from morphine would be blocked by infusions of clonidine (0.6 or 2.4 micrograms/microliters) into the LC. Significant reductions were observed in the occurrence of diarrhea, ptosis, weight loss and wet-dog shakes. Clonidine also reversed the naloxone-precipitated increase in hippocampus MHPG concentration. In experiment 2 subjects received an LC infusion or IP injection of a non-lipophilic alpha-2-agonist (ST-91), which does not penetrate the blood-brain barrier, or of clonidine into the dorsal parabrachial nucleus (DPB) to test the selectivity of the effects of clonidine infusions into the LC. ST-91 infusions into the LC reduced several of the observed withdrawal signs and increased others (e.g., jumping). Although peripheral injections of ST-91 attenuated some of the checked signs associated with naloxone-precipitated withdrawal, the frequency of wet-dog shakes was not reduced. ST-91 infusions into the LC, but not systemic ST-91 administration, prevented the withdrawal-induced increase in hippocampus MHPG concentration. Clonidine infused lateral to the LC into the DPB did not significantly attenuate withdrawal or reduce hippocampus MHPG levels. These results provide behavioral and biochemical evidence to support the suggestion that clonidine significantly attenuates naloxone-precipitated withdrawal through an interaction with noradrenergic neurons located in the vicinity of the LC.
- Published
- 1988
19. 6-Hydroxydopamine lesions of the nucleus accumbens, but not of the caudate nucleus, attenuate enhanced responding with reward-related stimuli produced by intra-accumbens d-amphetamine
- Author
-
Trevor W. Robbins and Jane R. Taylor
- Subjects
Male ,medicine.medical_specialty ,Dextroamphetamine ,Dopamine ,Caudate nucleus ,Nucleus accumbens ,Nucleus Accumbens ,Injections ,Hydroxydopamines ,Norepinephrine ,Reward ,Internal medicine ,medicine ,Animals ,Amphetamine ,Oxidopamine ,Pharmacology ,Hydroxydopamine ,Dopaminergic ,Rats, Inbred Strains ,Ascorbic acid ,Rats ,Apomorphine ,Endocrinology ,Anesthesia ,Conditioning, Operant ,Septal Nuclei ,Caudate Nucleus ,Psychology ,medicine.drug - Abstract
Intra-accumbens d-amphetamine enhances responding for reward-related stimuli (conditioned reinforcers, CRs), whereas intra-caudate d-amphetamine has only weak and variable effects (Taylor and Robbins 1984). The present experiment further examined the involvement of the nucleus accumbens and the role of dopamine (DA) in this effect. Thirsty rats were trained to associate a flash of a light and movement of a dipper (CR) with water. After implantation of permanent guide cannulae aimed at the nucleus accumbens, they were assigned to one of four groups, receiving either bilateral 6-OHDA (4 mg/ml free base in 2 μ1 0.1% ascorbic acid/0.9% saline) or sham (vehicle) infusions into the nucleus accumbens or the caudate nucleus. In the test phase, two novel levers were available. Responding on one lever (CR lever) produced the light and dipper stimuli without water presentation, whereas responding on the other (NCR lever) had no effect. All four groups received four counterbalanced intra-accumbens infusions of d-amphetamine (3, 10, 20 μg/2 μl) or vehicle. On the 5th test day, subjects were pretreated subcutaneously with apomorphine (0.1 mg/kg). Intra-accumbens d-amphetamine in both sham-lesioned groups produced a dose-dependent increase in responding on the CR lever, but no significant change on the NCR lever. No selective increases in responding on either lever were found in animals with 6-OHDA-induced depletion of DA (>80%) in the nucleus accumbens following intra-accumbens d-amphetamine; however, in subjects with DA depletion of the posterior caudate nucleus (>80%), increases in responding on the CR lever were observed to be similar in magnitude to those of both the sham-lesioned groups. Following systemic administration of apomorphine, only rats in the nucleus-accumbens-lesioned group continued to respond, preferring the CR lever, thus suggesting the involvement of DA receptors in these effects. These results indicate that enhanced responding for CR following administration of psychomotor stimulant drugs is critically dependent on dopaminergic activation of the nucleus accumbens, rather than the caudate nucleus.
- Published
- 1986
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