Biomedical subjects

Jane R Taylor

Publications and source records attributed to Jane R Taylor.

At least 19 recordsLinked to original sources

PubMed2006

Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats.

RATIONALE: Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction. OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Animals↗

PubMed2006

The striatal-enriched protein tyrosine phosphatase gates long-term potentiation and fear memory in the lateral amygdala.

BACKGROUND: Formation of long-term memories is critically dependent on extracellular-regulated kinase (ERK) signaling. Activation of the ERK pathway by the sequential recruitment of mitogen-activated protein kinases is well understood. In contrast, the proteins that inactivate this pathway are not as well characterized. METHODS: Here we tested the hypothesis that the brain-specific striatal-enriched protein tyrosine phosphatase (STEP) plays a key role in neuroplasticity and fear memory formation by its ability to regulate ERK1/2 activation. RESULTS: STEP co-localizes with the ERKs within neurons of the lateral amygdala. A substrate-trapping STEP protein binds to the ERKs and prevents their nuclear translocation after glutamate stimulation in primary cell cultures. Administration of TAT-STEP into the lateral amygdala (LA) disrupts long-term potentiation (LTP) and selectively disrupts fear memory consolidation. Fear conditioning induces a biphasic activation of ERK1/2 in the LA with an initial activation within 5 minutes of training, a return to baseline levels by 15 minutes, and an increase again at 1 hour. In addition, fear conditioning results in the de novo translation of STEP. Inhibitors of ERK1/2 activation or of protein translation block the synthesis of STEP within the LA after fear conditioning. CONCLUSIONS: Together, these data imply a role for STEP in experience-dependent plasticity and suggest that STEP modulates the activation of ERK1/2 during amygdala-dependent memory formation. The regulation of emotional memory by modulating STEP activity may represent a target for the treatment of psychiatric disorders such as posttraumatic stress disorder (PTSD), panic, and anxiety disorders.

Acoustic Stimulation↗

PubMed2006

Assessment of cognitive function in the heterozygous reeler mouse.

RATIONALE: 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. OBJECTIVE: Here, we investigated multiple aspects of cognitive function in heterozygous reeler mice that are known to be impaired in schizophrenic patients. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Animals↗

PubMed2006

DeltaFosB in the nucleus accumbens regulates food-reinforced instrumental behavior and motivation.

Alterations in motivation have been implicated in the pathophysiology of several psychiatric disorders, including substance abuse and depression. Repeated exposure to drugs of abuse or stress is known to persistently induce the transcription factor deltaFosB in the nucleus accumbens (NAc) and dorsal striatum, effects hypothesized to contribute to neuroadaptations in dopamine-regulated signaling. Little is known, however, about the specific involvement of deltaFosB in dysregulation of appetitively motivated behaviors. We show here that inducible overexpression of deltaFosB in NAc and dorsal striatum of bitransgenic mice, or specifically in the NAc core of rats by use of viral-mediated gene transfer, enhanced food-reinforced instrumental performance and progressive ratio responding. Very similar behavioral effects were found after previous repeated exposure to cocaine, amphetamine, MDMA [(+)-3,4-methylenedioxymethamphetamine], or nicotine in rats. These results reveal the powerful regulation of motivational processes by deltaFosB, and provide evidence that drug-induced alterations in gene expression via induction of deltaFosB within the NAc core may play a critical role in the impact of motivational influences on instrumental behavior.

Animals↗

PubMed2006

Bidirectional behavioral plasticity of memory reconsolidation depends on amygdalar protein kinase A.

Reconsolidation-the stabilization of a memory after retrieval-is hypothesized to be a critical and distinct component of memory processing, the disruption of which results in memory impairment. In the rat, we found that activation of amygdalar protein kinase A (PKA) was sufficient to enhance memory only when it was retrieved; in contrast, PKA inhibition impaired reconsolidation. This study demonstrates both a selective enhancement and an impairment of memory reconsolidation dependent on amygdalar PKA.

Acoustic Stimulation↗

PubMed2005

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.

RATIONALE: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Animals↗

PubMed2005

Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat.

Thalamic projections to prefrontal cortex are important for executive aspects of attention. Using two-photon imaging in prefrontal brain slices, we show that nicotine and the wakefulness neuropeptide hypocretin (orexin) excite the same identified synapses of the thalamocortical arousal pathway within the prefrontal cortex. Although it is known that attention can be improved when nicotine is infused directly into the midlayer of the prefrontal cortex in the rat, the effects of hypocretin on attention are not known. The overlap in thalamocortical synapses excited by hypocretin and nicotine and the lack of direct postsynaptic effects prompted us to compare their effects on a sustained and divided attention task in the rat. Similar to nicotine, infusions of hypocretin-2 peptide into the prefrontal cortex significantly improved accuracy under high attentional demand without effects on other performance measures. We show for the first time that hypocretin can improve attentional processes relevant to executive functions of the prefrontal cortex.

Action Potentials↗

PubMed2005

Protein kinase A as a therapeutic target for memory disorders: rationale and challenges.

cAMP-dependent protein kinase A (PKA) signaling has a key role in memory processes and has been identified as a potential therapeutic target for memory disorders. The activation of PKA signaling is crucial for the consolidation of long-term memories dependent on the hippocampus and/or the amygdala, By contrast, initial studies indicate that cAMP-PKA activation might impair the working memory and executive functions of the prefrontal cortex. Furthermore, PKA activation in the nucleus accumbens might increase sensitivity to addiction. These complexities must be heeded when designing medications aimed at altering PKA activity. PKA might be most practical as a therapeutic target in disorders with global alterations in cAMP-PKA activity due to genetic or environmental factors.

Age Factors↗

PubMed2005

Neonatal isolation stress potentiates cocaine seeking behavior in adult male and female rats.

Little is known with regard to how sex and stress might interact as vulnerability factors in cocaine abuse. In this study, we compared the effects of neonatal isolation stress on cocaine self-administration under extended access conditions and on subsequent responding in a cue-induced reinstatement paradigm in adult male and female rats. Pups from each litter were subjected to either neonatal isolation (1 h/day) or brief daily handling from postnatal day 2 through 12. Adults rats were then trained to self-administer cocaine, and once they acquired lever responding for cocaine under a fixed ratio 1 schedule, they were given 24-h access to intravenous cocaine infusions (1.5 mg/kg) that were available in discrete trials (4, 10 min trials/h) for 7 consecutive days. At 10 days after the last discrete trial session, responding was assessed during six to eight 1-h extinction sessions that were followed by a 1-h cue-induced reinstatement session. Results revealed that females took more cocaine than did males over the 7-day discrete trial self-administration period and tended to respond at higher levels during the initial extinction sessions. Although intake did not differ between handled control rats and isolated rats under extended access conditions, stress effects were observed under subsequent extinction and cue-induced reinstatement testing conditions with isolated rats responding at higher levels during both phases. Notably, stress seemed to obscure sex differences in extinction responding such both isolated males and females responded at high levels. These findings demonstrate robust and enduring effects of neonatal isolation stress on cocaine seeking behavior in adult male and female rats.

Animals↗

PubMed2005

Decreased motivation following cocaine self-administration under extended access conditions: effects of sex and ovarian hormones.

We have previously shown that following extended access to cocaine, females, but not males, show marked increases in motivation to obtain cocaine, and we have hypothesized that such changes may contribute to long-term compulsive aspects of addiction that result in a persistent vulnerability to relapse. Here, we investigate the effects of extended cocaine access on short-term motivational changes in both male and female rats. An additional goal was to determine whether estrogen modulates motivation to self-administer cocaine in female rats following extended access to cocaine. A discrete trial procedure was used that allowed rats 24-h access to cocaine infusions (1.5 mg/kg) that were available in discrete trials (four, 10-min trials/h) for 7 consecutive days. Motivation to obtain cocaine was assessed by responding under a progressive ratio schedule, and preference for sucrose (1%) vs water was assessed using a two-bottle, 24-h test. Each was assessed prior to and immediately following discrete trial cocaine self-administration. Results showed that following discrete trial cocaine self-administration, both males and females showed a decrease in preference for sucrose, but only females showed a reduction in levels of responding for cocaine under the progressive ratio schedule, suggesting a sex difference in motivation that was specific to cocaine. Subsequent studies with ovariectomized rats showed that estrogen replacement blocked the decrease in motivation to obtain cocaine infusions. Together, these findings suggest that there is a dissociation between sex and the short- vs long-term alteration in motivation to use cocaine. The mechanisms that may underlie these observed sex differences, including the role of estrogen, are discussed.

Animals↗

PubMed2005

Blockade of melanocortin transmission inhibits cocaine reward.

Melanocortins and the melanocortin-4 receptor (MC4-R) are enriched in the nucleus accumbens, a brain region that has been implicated in the rewarding action of cocaine and other drugs of abuse. In the present study we use a number of rat behavioral models to show that infusion of a melanocortin peptide antagonist into the nucleus accumbens blocks the reinforcing, incentive motivational, and locomotor sensitizing effects of cocaine. We also show that locomotor responses to repeated cocaine exposure are completely blocked in MC4-R null mutant mice and reduced in Agouti mice that overexpress an endogenous inhibitor of melanocortins in the brain. The results also demonstrate that cocaine administration increases the expression of MC4-R in the nucleus accumbens and striatum, and that MC4-R is co-localized with prodynorphin in medium spiny neurons in the nucleus accumbens. Together, these findings indicate that the behavioral actions of cocaine are dependent on activation of MC4-R, and suggest that upregulation of this receptor by drug exposure may contribute to sensitization of these behavioral responses. Modulation of cocaine reward is a novel action of the melanocortin-MC4-R system and could be targeted for the development of new medications for cocaine addiction.

Agouti Signaling Protein↗

PubMed2004

Natural reward-related learning in rats with neonatal ventral hippocampal lesions and prior cocaine exposure.

RATIONALE: Psychostimulant injections in rats have been shown to alter future performance in natural reward conditioning. These effects may represent a persistent impact of drugs on neurocircuits that interface cognitive and motivational processes, which may be further altered in neuropsychiatric conditions that entail increased addiction vulnerability. OBJECTIVE: This study investigated whether a rat model of schizophrenia with cocaine addiction vulnerability shows altered natural reward conditioning with or without prior cocaine exposure. METHODS: Adult rats with SHAM or neonatal ventral hippocampal lesions were given cocaine (15 mg/kg per day for 5 days) or saline injections, followed 7 days later by natural reward-conditioned learning. Over ten daily sessions, water-restricted rats were assessed for durations of head entries into a magazine during random water presentations, a conditioning stimulus phase predictive of the water reward, and an "inappropriate" phase when conditioning stimuli were absent and reward presentation would be delayed. RESULTS: Over repeated sessions, lesioned and SHAM rats showed similar reductions in total magazine entry durations, with similar increases in the allocations of entry times during the water presentation. However, lesioned rats, especially those exposed to cocaine, demonstrated reduced allocations of magazine entry times during the conditioning stimulus phase, and increased allocations during the inappropriate phase. CONCLUSIONS: Intact natural reward motivation accompanied by deficient learning of complex contingencies to guide efficient reward approach may represent a form of impulsivity as an addiction vulnerability trait marker in an animal model of schizophrenia.

Animals↗

PubMed2004

Animal modeling dual diagnosis schizophrenia: sensitization to cocaine in rats with neonatal ventral hippocampal lesions.

BACKGROUND: Increased substance disorder comorbidity in schizophrenia may reflect greater vulnerability to addictive processes because of inherent neurocircuit dysfunction in the schizophrenic brain. METHODS: To further explore this hypothesis, we used neonatal ventral hippocampal lesions (NVHL) as a rat model of schizophrenia and assessed locomotor sensitization to cocaine (15 mg/kg) in adulthood. RESULTS: The NVHL animals showed greater activity in response to an initial cocaine injection compared with sham and saline-treated groups. With daily cocaine injections over 7 days, NVHL rats showed elevated locomotor sensitization curves with greater fluctuations in the intersession changes in activity between days 4 and 7. In a single session 4 weeks later, NVHL compared with SHAM rats showed maintenance of cocaine-associated hyperactivity, as if superimposed on long-term sensitization effects present in both groups. CONCLUSIONS: In a neurodevelopmental model of schizophrenia, the locomotor effects of cocaine were augmented on initial and repeated doses, with emergence of irregularity in sensitization-related changes in activity in the short term and perseverance of augmented effects in the long term. Altered patterns of behavioral sensitization, as a possible correlate of greater addiction vulnerability, can occur as a by-product of neural systems dysfunction responsible for major psychiatric syndromes.

Animals↗

PubMed2004

Locomotor sensitization to cocaine in rats with olfactory bulbectomy.

Olfactory bulbectomy in rats has been suggested as a comprehensive animal model of affective disorders associated with an array of behavioral changes, responsivity to chronic antidepressant treatment, and alterations in limbic structures thought to be critical in the pathophysiology of affective disorders. Recent work showing increased motivational responsivity to amphetamine suggests that olfactory bulbectomy could also be a useful animal model of dual diagnosis disorders. To further investigate this possibility, we studied locomotor activity in olfactory bulbectomized rats 14 days postsurgery in response to novelty and upon acute and repeated injections of cocaine (15/mg/kg) or saline. Consistent with prior studies, lesioned animals showed greater locomotor activity in response to a novel environment and significantly heightened locomotor activation upon initial cocaine exposure. Over 7 days of repeated cocaine injections, lesioned animals also showed a presensitized pattern of activity, with a loss of incremental increases in locomotion observed in control animals. Daily saline injections produced no group differences in pre- or postinjection activity, while cocaine-treated bulbectomized rats demonstrated a decline in their daily preinjection activity. These results suggest that neural alterations caused by olfactory bulbectomy produce altered behavioral response patterns to repeated doses of cocaine, and support the study of olfactory bulbectomy as a useful neurobehavioral model for understanding substance use disorder comorbidity in mental illness.

Animals↗

PubMed2004

Loss of glutamatergic pyramidal neurons in frontal and temporal cortex resulting from attenuation of FGFR1 signaling is associated with spontaneous hyperactivity in mice.

Fibroblast growth factor receptor (FGFR) gene products (Fgfr1, Fgfr2, Fgfr3) are widely expressed by embryonic neural progenitor cells throughout the CNS, yet their functional role in cerebral cortical development is still unclear. To understand whether the FGF pathways play a role in cortical development, we attenuated FGFR signaling by expressing a tyrosine kinase domain-deficient Fgfr1 (tFgfr1) gene construct during embryonic brain development. Mice carrying the tFgfr1 transgene under the control of the Otx1 gene promoter have decreased thickness of the cerebral cortex in frontal and temporal areas because of decreased number of pyramidal neurons and disorganization of pyramidal cell dendritic architecture. These alterations may be, in part, attributable to decreased genesis of T-Brain-1-positive early glutamatergic neurons and, in part, to a failure to maintain radial glia fibers in medial prefrontal and temporal areas of the cortical plate. No changes were detected in cortical GABAergic interneurons, including Cajal-Retzius cells or in the basal ganglia. Behaviorally, tFgfr1 transgenic mice displayed spontaneous and persistent locomotor hyperactivity that apparently was not attributable to alterations in subcortical monoaminergic systems, because transgenic animals responded to both amphetamine and guanfacine, an alpha2A adrenergic receptor agonist. We conclude that FGF tyrosine kinase signaling may be required for the genesis and growth of pyramidal neurons in frontal and temporal cortical areas, and that alterations in cortical development attributable to disrupted FGF signaling are critical for the inhibitory regulation of motor behavior.

Adrenergic alpha-Agonists↗

PubMed2004

Repeated nicotine exposure enhances responding with conditioned reinforcement.

RATIONALE: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adrenergic Uptake Inhibitors↗

PubMed2004

Repeated, intermittent delta(9)-tetrahydrocannabinol administration to rats impairs acquisition and performance of a test of visuospatial divided attention.

The residual neuropsychological effects of marijuana abuse in man indicate a dysfunction of the attentional/executive systems. Moreover, experimental investigations suggest that repeated, intermittent (subchronic) Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient of marijuana, alters neurotransmission in the frontal cortex of rats and humans, a key neural site mediating attention and executive functions. In the present studies, the acquisition and performance of a test of visuospatial attention (the lateralized reaction time task) after subchronic THC administration (10.0 mg/kg twice daily for 14 days) was examined. Rats previously administered THC showed impairments in this self-paced version of the classic multiple-choice serial reaction time task, which persisted 14 days after the final drug administration. Longer time points were not examined. These attentional impairments were transiently reversible with an acute amphetamine (0.5 mg/kg) challenge. These behavioral data demonstrate that chronic THC administration to rats induces an attentional deficit, similar to that observed in humans who abuse marijuana. Finally, amphetamine's ability to reverse the attentional impairments provides indirect evidence that monoaminergic deficits may be linked to the cognitive dysfunction.

Animals↗

PubMed2004

Sex differences in the behavioral effects of 24-h/day access to cocaine under a discrete trial procedure.

Although more men than women are addicted to cocaine, it has been suggested that women may have an accelerated transition to addiction, and that once addicted they may be more vulnerable to relapse. Here we investigate the effects of extended access to cocaine under a 24-h/day discrete trial procedure on patterns of intake and subsequent motivation to use cocaine as assessed by responding under a progressive-ratio schedule in male and female rats. Rats were initially trained to self-administer cocaine (1.5 mg/kg/infusion) under a fixed-ratio 1 schedule until acquisition occurred, and then responding was assessed under a progressive schedule for three sessions. Subsequently, rats had 24-h access to intravenous cocaine infusions (1.5 mg/kg) that were available in discrete trials (4, 10 min trials/h) for 7 consecutive days. At 10 days after the last discrete trial session, responding was reassessed under a progressive-ratio schedule for three additional sessions to investigate changes in motivation to obtain cocaine. Prior to cocaine self-administration under the 24-h access discrete trial procedure, males and females did not differ on cocaine self-administration under the fixed-ratio or progressive-ratio schedules. However, sex differences emerged under the 24-h access discrete trial procedure with females self-administering higher levels of cocaine, for longer initial periods of time, and showing a greater disruption in the diurnal control over intake than did males. Additionally, following a 10-day forced abstinence period, females responded at higher levels under the progressive-ratio schedule to obtain cocaine infusions than did males. These findings suggest that extended access to cocaine under the discrete trial cocaine self-administration procedure produces sex-dependent patterns of intake and sex-specific changes in motivation to obtain cocaine as measured by progressive-ratio responding.

Animals↗