Biomedical subjects

Jane Stewart

Publications and source records attributed to Jane Stewart.

At least 19 recordsLinked to original sources

PubMed2006

Dopamine has bidirectional effects on synaptic responses to cortical inputs in layer II of the lateral entorhinal cortex.

Dopaminergic modulation of neuronal function has been extensively studied in the prefrontal cortex, but much less is known about its effects on glutamate-mediated synaptic transmission in the entorhinal cortex. The mesocortical dopamine system innervates the superficial layers of the lateral entorhinal cortex and may therefore modulate sensory inputs to this area. In awake rats, systemic administration of the dopamine reuptake inhibitor GBR12909 (10 mg/kg, ip) enhanced extracellular dopamine levels in the entorhinal cortex and significantly facilitated field excitatory postsynaptic potentials (fEPSPs) in layer II evoked by piriform cortex stimulation. An analysis of the receptor subtypes involved in the facilitation of evoked fEPSPs was conducted using horizontal slices of lateral entorhinal cortex in vitro. The effects of 15-min bath application of dopamine on synaptic responses were bidirectional and concentration dependent. Synaptic responses were enhanced by 10 microM dopamine and suppressed by concentrations of 50 and 100 microM. The D(1)-receptor antagonist SCH23390 (50 microM) blocked the significant facilitation of synaptic responses induced by 10 microM dopamine and the D(2)-receptor antagonist sulpiride (50 microM) prevented the suppression of fEPSPs observed with higher concentrations of dopamine. We propose here that dopamine release in the lateral entorhinal cortex, acting through D(1) receptors, can lead to an enhancement of the salience of sensory representations carried to this region from adjacent sensory cortices.

Animals↗

PubMed2006

Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure.

BACKGROUND AND RATIONALE: The reinstatement model is widely used to study relapse to drug addiction. However, the model's validity is open to question. OBJECTIVE: We assess the reinstatement model in terms of criterion and construct validity. RESEARCH HIGHLIGHTS AND CONCLUSIONS: We find that the reinstatement model has adequate criterion validity in the broad sense of the term, as evidenced by the fact that reinstatement in laboratory animals is induced by conditions reported to provoke relapse in humans. The model's criterion validity in the narrower sense, as a medication screen, seems promising for relapse to heroin, nicotine, and alcohol. For relapse to cocaine, criterion validity has not yet been established primarily because clinical studies have examined medication's effects on reductions in cocaine intake rather than relapse during abstinence. The model's construct validity faces more substantial challenges and is yet to be established, but we argue that some of the criticisms of the model in this regard may have been overstated.

Alcoholism↗

PubMed2006

The effects of chronic buprenorphine on intake of heroin and cocaine in rats and its effects on nucleus accumbens dopamine levels during self-administration.

RATIONALE: Buprenorphine reduces both heroin and cocaine intake in opioid addicts, but the mechanisms remain unclear. OBJECTIVES: To determine the effects of chronic buprenorphine treatment on intake of heroin and/or cocaine and measure nucleus accumbens (NAc) dopamine (DA) levels during self-administration. METHODS: In experiment 1, plasma levels of buprenorphine were determined in rats with buprenorphine osmotic minipumps (3.0 mg/kg/day) using an ELISA. In experiment 2, rats self-administered (FR1) one dose of heroin [(0.025, 0.05, or 0.1 mg/kg/infusion (inf)] and one dose of cocaine (0.25, 0.5, or 1.0 mg/kg/inf) before and under sham or chronic buprenorphine treatment (1.5 or 3.0 mg/kg/day). In experiment 3, the effect of sham or chronic buprenorphine treatment (3.0) on heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration under FR5 and progressive ratio (PR) schedules was evaluated. In experiment 4, in vivo microdialysis sampling from the NAc was carried out during heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration (FR1) under sham or buprenorphine treatment (3.0). RESULTS: Buprenorphine levels in plasma were stable over time. Buprenorphine treatment had no effect on total heroin intake at any dose or under any schedule, whereas it suppressed cocaine intake at all doses and under all schedules. Buprenorphine enhanced basal levels of DA, attenuated the NAc DA response to heroin, and enhanced the DA response to cocaine. It is interesting to note that buprenorphine increased the latency to respond to drug-associated cues at the start of self-administration sessions. CONCLUSIONS: Chronic buprenorphine reduces cocaine, but not heroin, intake and possibly reduces drug seeking by reducing the salience of the drug-associated cues.

Animals↗

PubMed2006

The effects of long-term chronic buprenorphine treatment on the locomotor and nucleus accumbens dopamine response to acute heroin and cocaine in rats.

We have previously shown that chronic treatment with the partial mu-opioid receptor agonist, buprenorphine, blocks the nucleus accumbens dopamine response to an acute injection of heroin, whereas it potentiates the response to an acute injection of cocaine after 4-5 days of treatment. Here we studied the effects of chronic exposure to buprenorphine via osmotic minipumps for up to 28 days (1.5 or 3.0 mg/kg/day) on responses to acute injections of heroin and cocaine. Increases in locomotion induced by heroin (0.25 mg/kg, sc), given on the 5th, 15th or 25th day of treatment were unaffected by buprenorphine, whereas increases induced by cocaine (20 mg/kg, ip) were enhanced early in treatment but not on the 15th or 25th days. Using in vivo microdialysis we found that both the suppression of the dopaminergic response in the nucleus accumbens to heroin and the potentiation to cocaine seen early in treatment diminished over the 26-27 days, whereas basal dopamine levels remained elevated throughout. Therefore, although these studies do not explain the mechanism whereby buprenorphine reduces heroin and cocaine intake, they do indicate that there is little tolerance to the presence of chronic buprenorphine.

Animals↗

PubMed2006

d-Cycloserine facilitates extinction of a cocaine-induced conditioned place preference.

d-Cycloserine, a partial NMDA agonist, significantly accelerated extinction of a cocaine-induced conditioned place preference (CPP) when rats were given systemic injections immediately, but not 4h, after each extinction trial. Infusions directly into the basolateral amygdala had a similar effect. The facilitative effect of d-cycloserine on the extinction of appetitive conditioning is consistent with the idea of the formation of new learned associations during extinction.

Animals↗

PubMed2006

Prolonged rewarding stimulation of the rat medial forebrain bundle: neurochemical and behavioral consequences.

Extracellular dopamine levels were measured in the rat nucleus accumbens by means of in vivo microdialysis. Delivery of rewarding medial forebrain bundle stimulation at a low rate (5 trains/min) produced a sustained elevation of dopamine levels, regardless of whether train onset was predictable. When the rate of train delivery was increased to 40 trains/min, dopamine levels rose rapidly during the first 40 min but then declined toward the baseline range. The rewarding impact of the stimulation was reduced following prior delivery of stimulation at the high, but not the low, rate. These results support the idea that dopamine tone plays an enabling role in brain stimulation reward and is elevated similarly by predictable and unpredictable stimulation.

Animals↗

PubMed2006

Impact of basic FGF expression in astrocytes on dopamine neuron synaptic function and development.

Behavioural sensitization to amphetamine (AMPH) requires action of the drug in the ventral midbrain where dopamine (DA) neurons are located. In vivo studies suggest that AMPH sensitization requires enhanced expression of basic fibroblast growth factor (bFGF) in the nucleus of midbrain astrocytes. One idea is that the AMPH-induced increase in bFGF expression in astrocytes leads to enhanced secretion of this peptide and to long-term plasticity in DA neurons. To study directly the effects of astrocytic expression of bFGF on DA neurons, we established a cell-culture model of mesencephalic astrocytes and DA neurons. Immunolabelling showed that even in the absence of a pharmacological stimulus, the majority of mesencephalic astrocytes in culture express bFGF at a nuclear level. Arguing against the idea that bFGF was secreted, bFGF was undetectable in the extracellular medium (below 10 pg/mL). However, supplementing culture medium with exogenous bFGF at standard concentrations (20 ng/mL) led to a dramatic change in the morphology of astrocytes, increased spontaneous DA release, and inhibited synapse formation by individual DA neurons. RNA interference (siRNA) against bFGF mRNA, caused a reduction in DA release but produced no change in synaptic development. Together these data demonstrate that under basal conditions (in the absence of a pharmacological stimulus such as amphetamine) bFGF is not secreted even though there is abundant nuclear expression in astrocytes. The effects of bFGF seen here on DA neurons are thus likely to be mediated through more indirect glial-neuronal interactions, leading to enhanced DA release without a necessary change in synapse number.

Animals↗

PubMed2006

Cyclooxygenase inhibitors in urinary bladder cancer: in vitro and in vivo effects.

More than 14,000 people die from invasive transitional cell carcinoma (TCC) of the urinary bladder yearly in the United States. Cyclooxygenase (COX)-inhibiting drugs are emerging as potential antitumor agents in TCC. The optimal in vitro or in vivo systems to investigate COX inhibitor antitumor effects have not been defined. The purpose of this study was to determine COX-1 and COX-2 expression and antitumor effects of COX inhibitors in human TCC cell lines (HT1376, RT4, and UMUC3 cells) and xenografts derived from those cell lines. COX-2 expression (Western blot, immunocytochemistry) was high in HT1376, modest in RT4, and absent in UMUC3 cells in vitro. Similarly, COX-2 expression was noted in RT4 but not UMUC3 xenografts. COX-2 expression in HT1376 xenografts was slightly lower than that observed in vitro. None of four COX inhibitors evaluated (celecoxib, piroxicam, valeryl salicylate, and NS398) reduced TCC growth in standard in vitro proliferation assays at concentrations that could be safely achieved in vivo (< or =5 micromol/L). Higher celecoxib concentrations (> or =50 micromol/L) inhibited proliferation and induced apoptosis in all three cell lines. Celecoxib or piroxicam treatment in athymic mice significantly delayed progression of HT1376 xenografts, which express COX-2, but not UMUC3 xenografts that lack COX-2 expression. In conclusion, standard in vitro assays were not useful in predicting COX inhibitor antitumor effects observed in vivo. Athymic mice bearing TCC xenografts provide a useful in vivo system for COX inhibitor studies. Results of this study provide justification for further evaluation of COX inhibitors as antitumor agents against TCC.

Animals↗

PubMed2006

The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants.

OBJECTIVES: The objectives of this study were to delineate the etiologic profile and neurodevelopmental outcome of neonatal seizures in the current era of neonatal intensive care and to identify predictors of neurodevelopmental outcome in survivors. METHODS: Eighty-nine term infants with clinical neonatal seizures underwent neurologic examination, electroencephalography (EEG), neuroimaging, and extensive diagnostic tests in the newborn period. After discharge, all infants underwent regular neurologic evaluations and, at 12 to 18 months, formal neurodevelopmental testing. We tested the prognostic value of seizure etiology, neurologic examination, EEG, and neuroimaging. RESULTS: Etiology was found in 77 infants. Global cerebral hypoxia-ischemia, focal cerebral hypoxia-ischemia, and intracranial hemorrhage were most common. Neonatal mortality was 7%; 28% of the survivors had poor long-term outcome. Association between seizure etiology and outcome was strong, with cerebral dysgenesis and global hypoxia-ischemia associated with poor outcome. Normal neonatal period/early infancy neurologic examination was associated with uniformly favorable outcome at 12 to 18 months; abnormal examination lacked specificity. Normal/mildly abnormal neonatal EEG had favorable outcome, particularly if neonatal neuroimaging was normal. Moderate/severely abnormal EEG, and multifocal/diffuse cortical or primarily deep gray matter lesions, had a worse outcome. CONCLUSIONS: Mortality associated with neonatal seizures has declined although long-term neurodevelopmental morbidity remains unchanged. Seizure etiology and background EEG patterns remain powerful prognostic factors. Diagnostic advances have changed the etiologic distribution for neonatal seizures and improved accuracy of outcome prediction. Global cerebral hypoxia-ischemia, the most common etiology, is responsible for the large majority of infants with poor long-term outcome.

Brain↗

PubMed2005

Automatic and effortful emotional information processing regulates different aspects of the stress response.

There is increasing evidence that stress and self-regulation are important factors in the development and treatment of psychopathology. A key issue is to determine how cognitive-emotional systems modulate the stress response. We sought to determine whether effortful and automatic processing were differentially associated with subsequent mood and cortisol levels during a stressful challenge. We examined this question by having clinically anxious, depressed, and control participants perform a modified spatial cueing task with supraliminal and masked pictorial stimuli during a stressful challenge and control condition. The stressful challenge, relative to the control condition, lowered mood, but did not influence cortisol levels. In the full sample, disengagement from supraliminal dysphoric pictures was associated with subsequent mood ratings, whereas disengagement from masked pictures depicting threat was associated with subsequent cortisol levels. Effortful and automatic processing appears to regulate different aspects of the stress response.

Adaptation, Psychological↗

PubMed2005

The contribution of drug history and time since termination of drug taking to footshock stress-induced cocaine seeking in rats.

RATIONALE: There is reason to think that footshock stress-induced reinstatement of cocaine may be affected by the history of drug use and time since termination of drug taking. OBJECTIVES: Here, we assessed the contribution of daily access (hours per day) and duration (number of days) of cocaine self-administration to propensity to reinstate drug seeking following footshock stress at three time points following cocaine self-administration. METHODS: Rats were trained to self-administer cocaine (0.5 mg kg(-1) infusion(-1)) on a fixed ratio 1 schedule in one of four training combinations of hours per day and number of days [2/7, 2/21, 12/7, and 12/21 (h/day)]. Rats were then tested for the first time under extinction conditions at either day 1, 10, or 60 after termination of cocaine availability. Once extinction criterion was met (<15 lever presses in 1 h), rats were then tested for stress-induced reinstatement after 15 min of intermittent, inescapable footshock (0.8 mA, 0.5 s/shock, mean off period of 40 s). RESULTS: Rats that were given 12-h access to cocaine during training responded less in tests of extinction than those rats given 2-h access. Rats in all groups tested in extinction at days 10 and 60 showed higher responding than at day 1, suggesting an incubation of responding. In footshock stress-induced reinstatement tests, rats with greater exposure to cocaine showed a similar suppression of responding at day 1 and enhanced responding at day 60. As expected, rats that were given 12-h/21-day access to cocaine had the greatest intake of cocaine across the training phase with a slow escalation of hourly intake. CONCLUSION: Greater access to cocaine results in suppression of cocaine seeking following footshock stress at early time points and a progressive increase over time.

Anesthetics, Local↗

PubMed2005

Differential behavioral and neurochemical effects of cocaine after early exposure to methylphenidate in an animal model of attention deficit hyperactivity disorder.

We used a putative animal model of attention deficit hyperactivity disorder (ADHD), the SHR rat, to examine the effects of repeated exposure to methylphenidate (MPH; Ritalin) during the pubertal period on cocaine-induced conditioned place preference and dopamine (DA) levels in the nucleus accumbens (NAc) in adulthood. Our results indicate that early exposure to methylphenidate diminishes sensitivity to the incentive properties of cocaine in adulthood, but it does so without altering the response of the mesolimbic dopamine system.

Age Factors↗

PubMed2005

The central and basolateral nuclei of the amygdala exhibit opposite diurnal rhythms of expression of the clock protein Period2.

There is considerable evidence that circadian rhythms in mammals can be modulated by emotional state, but how emotional state modulates specific circadian outputs is poorly understood. We analyzed the expression of the circadian clock protein Period2 (PER2) in three regions of the limbic forebrain known to play key roles in emotional regulation, the central nucleus of the amygdala (CEA), the basolateral amygdala (BLA), and the dentate gyrus (DG). We report here that cells in all three regions exhibit daily rhythms in expression of PER2 that are under the control of the master clock, the suprachiasmatic nucleus (SCN). The rhythm in the CEA and the rhythms in the BLA and DG are diametrically opposite in phase and are differentially affected by adrenalectomy. Adrenalectomy completely abolished the PER2 rhythm in the CEA but had no effect on the PER2 rhythms in the BLA and DG. We previously reported a rhythm in PER2 expression in the oval nucleus of the bed nucleus of the stria terminalis that is identical in phase and sensitivity to adrenalectomy to that found in the CEA. Together, these findings show that key structures of the limbic forebrain exhibit daily oscillations in clock gene expression that are controlled not only by input from the SCN but, importantly, by hormonal and neurochemical changes that normally accompany motivational and emotional states. Thus, cells within these areas are strategically positioned to integrate the inputs from the SCN and emotional states to modulate circadian rhythms downstream from the SCN clock.

Adrenalectomy↗

PubMed2005

Patterns of opioid and cocaine co-use: a descriptive study in a Canadian sample of untreated opioid-dependent individuals.

This study examined prevalence and patterns of co-use of opioids and cocaine in regular users of illicit opioids (N = 729) recruited from 5 Canadian cities. Fifty-seven percent (n = 417) reported having used both opioids and cocaine in the month and week preceding the interview; of these, 73% (n = 304) were able to identify a typical pattern of daily co-use. In a typical day, injectors of opioids and cocaine (n = 119) and injectors of opioids who inhaled cocaine (n = 111) showed stable opioid use but variable cocaine use, which peaked at 21 hr. Overall, 30% of the individuals used both drugs exclusively in a sequential fashion, 35% reported taking opioids and cocaine within the same hour, and 35% reported taking them together at the same time or mixing them. These findings indicate that different individuals display different patterns of opioids and cocaine co-use.

Adolescent↗

PubMed2005

Rats maintained chronically on buprenorphine show reduced heroin and cocaine seeking in tests of extinction and drug-induced reinstatement.

Buprenorphine is being introduced as a maintenance therapy in opioid addiction, but it is not clear how buprenorphine will affect co-use of cocaine in opioid users. We examined the effects of chronic buprenorphine (BUP0: 0.0 mg/kg/day; BUP1.5: 1.5 mg/kg/day; BUP3: 3.0 mg/kg/day) on the locomotor activity effects of acute heroin (0.25 mg/kg, subcutaneously (s.c.)) and cocaine (20 mg/kg, intraperitoneally (i.p.)). Buprenorphine had no effect on the stimulatory effect of heroin, but potentiated the locomotor response to cocaine. To investigate further the interactions between buprenorphine (BUP1.5 and BUP3), heroin (0.125, 0.25 and 0.375 mg/kg, s.c.), and cocaine (10, 20 and 30 mg/kg, i.p.), we used in vivo microdialysis and high-performance liquid chromatography to analyze extracellular levels of dopamine (DA) in the nucleus accumbens (NAc). Buprenorphine attenuated the heroin-induced rise in NAc DA, but greatly potentiated the cocaine-induced rise. Finally, we examined the potential of the highest dose of buprenorphine (BUP3) to reduce heroin and cocaine seeking in the presence of drug-associated cues under extinction conditions and in tests for reinstatement induced by heroin (0.25 mg/kg, s.c.), cocaine (20 mg/kg, i.p.), and 15-min footshock stress (0.8 mA, 0.5 s/shock, 40 s mean OFF time) in rats trained to self-administer both drugs. Buprenorphine reduced heroin and cocaine seeking during extinction and following acute heroin and cocaine priming injections, but had no effect on stress-induced reinstatement. These results indicate that the suppression of responding following priming injections of drugs did not result from reduced motor activity, but possibly from a reduction in the salience of drug-associated cues induced by chronic buprenorphine treatment.

Analysis of Variance↗

PubMed2005

Estrogenic induction of spermatogenesis in the hypogonadal (hpg) mouse: role of androgens.

Testicular development is arrested in the hypogonadal (hpg) mouse due to a congenital deficiency of hypothalamic gonadotropin-releasing hormone synthesis. Previous studies have demonstrated that chronic treatment of these mice with estradiol induces testicular maturation and qualitatively normal spermatogenesis, but it is not known whether these are direct effects via estrogen receptors expressed in the testis, or indirect actions via the pituitary gland. The aim of the current studies was to determine whether the actions of estradiol require the presence of androgens. Sensitive assays revealed that chronic estradiol treatment produced time-dependent increases in pituitary FSH production but no increases in pituitary LH or testicular testosterone content could be detected. As a functional test of androgen dependence, hpg mice were treated for 70 days with estradiol plus Casodex (bicalutamide), an androgen receptor antagonist. Casodex treatment markedly attenuated both the estradiol-induced increase in testicular weight and the proliferation of the seminiferous epithelium, as revealed by morphometric analysis. However, it did not affect the estradiol-induced increase in pituitary FSH content, nor did it affect estradiol-induced increases in the weight of the seminal vesicles and epididymides. We conclude that increased FSH production is not sufficient to explain the increase in testicular development induced by estradiol in hpg mice; there is a requirement for functional androgen receptors for induction of testicular growth.

Androgen Antagonists↗

PubMed2005

Inhibin B as a potential biomarker of testicular toxicity.

Inhibin B is a glycoprotein produced predominantly by Sertoli cells which regulates pituitary FSH release by a negative feedback loop. The regulation of inhibin B is complex with changes in the pattern of secretion occurring during development, and many factors such as FSH, testosterone, Sertoli cell proliferation and germ cell complement likely to contribute to overall production. Systemic inhibin B concentrations seem to reflect the extreme ends of spermatogenic status with high levels of inhibin B observed in normal, fertile individuals and lower levels of inhibin B in individuals with severe damage to the testis as a result of germ cell depletion. Inhibin B has proved valuable in epidemiological studies exploring male infertility with data showing that inhibin B combined with FSH measurements has a higher positive predictive value for detecting male infertility than either alone. Inhibin B is proposed as a potential biomarker of testicular toxicity in rodent toxicity studies to compliment traditional endpoints. In pharmaceutical development, inhibin B might allow better linkage between animal study results and subsequent monitoring of testicular function in clinical trials. An international, intercompany project has been initiated to evaluate the overall suitability and limitations of inhibin B as a biomarker of testicular toxicity.

Adult↗

PubMed2005

Understanding of blood pressure by people with type 2 diabetes: a primary care focus group study.

BACKGROUND: For many people with type 2 diabetes most care is provided in primary care. While people with both diabetes and hypertension are at increased risk of complications, little is known about their understanding of blood pressure. AIM: To explore the understanding and beliefs about the importance of blood pressure held by people with type 2 diabetes. DESIGN OF STUDY: Framework analysis of qualitative research using focus groups. SETTING: Thirty-two participants were recruited from four general practices and a religious meeting group in Nottingham. Discussions took place in five community centres providing familiar surroundings for participants. METHOD: In order to get views expressed fully, white, Asian, and African-Caribbean participants met in five separate groups. Facilitators were fluent in the appropriate language and one member of the research team was present at all focus groups. RESULTS: Some participants, including those with raised blood pressure, were not aware of the increased importance of achieving good blood pressure control. No participants mentioned the increased risk of eye or kidney disease as a result of the combination of diabetes and raised blood pressure. Participants' perceptions regarding the control of blood sugar and blood pressure were different: blood sugar control was seen as their responsibility but blood pressure control was seen as the responsibility of the doctor. There was scepticism regarding the diagnosis of raised blood pressure, of targets and the management of blood pressure. There was also scepticism about the advice and education about diabetes given in primary care. CONCLUSIONS: People with type 2 diabetes require more knowledge of the increased risks they have from raised blood pressure, although this alone is unlikely to improve blood-pressure control. Strategies to increase the degree of control over and responsibility taken for the control of blood pressure need development and may require the specific development of participatory and negotiating skills among people with type 2 diabetes. Increasing the participation of these people in their own care will require doctors and nurses to work in a different way.

Aged↗