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Biomedical subjects

Jane Stewart

Publications and source records attributed to Jane Stewart.

At least 37 records · Page 2Linked to original sources
PubMed2004

A circadian rhythm in the expression of PERIOD2 protein reveals a novel SCN-controlled oscillator in the oval nucleus of the bed nucleus of the stria terminalis.

Circadian rhythms in mammals are regulated not only globally by the master clock in the suprachiasmatic nucleus (SCN), but also locally by widely distributed populations of clock cells in the brain and periphery that control tissue-specific rhythmic outputs. Here we show that the oval nucleus of the bed nucleus of the stria terminalis (BNST-OV) exhibits a robust circadian rhythm in expression of the Period2 (PER2) clock protein. PER2 expression is rhythmic in the BNST-OV in rats housed under a light/dark cycle or in constant darkness, in blind rats, and in mice, and is in perfect synchrony with the PER2 rhythm of the SCN. Constant light or bilateral SCN lesions abolish the rhythm of PER2 in the BNST-OV. Large abrupt shifts in the light schedule transiently uncouple the BNST-OV rhythm from that of the SCN. Re-entrainment of the PER2 rhythm is faster in the SCN than in the BNST-OV, and it is faster after a delay than an advance shift. Bilateral adrenalectomy blunts the PER2 rhythm in the BNST-OV. Thus, the BNST-OV contains circadian clock cells that normally oscillate in synchrony with the SCN, but these cells appear to require both input from the SCN and circulating glucocorticoids to maintain their circadian oscillation. Taken together with what is known about the functional organization of the connections of the BNST-OV with systems of the brain involved in stress and motivational processes, these findings place BNST-OV oscillators in a position to influence specific physiological and behavioral rhythms downstream from the SCN clock.

Adrenalectomy↗
PubMed2004

Sparing of behavior and basal extracellular dopamine after 6-hydroxydopamine lesions of the nigrostriatal pathway in rats exposed to a prelesion sensitizing regimen of amphetamine.

Repeated administration of amphetamine leads to enduring augmentation of its behavioral-activating effects, enhanced dopamine (DA) release in striatal regions, and morphological changes in DA target neurons. Here we show that exposure to a 2-week escalating-dose regimen of amphetamine prevents behavioral asymmetries of forelimb use and spontaneous (drug-independent) turning behavior following unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway made 7-14 days after termination of amphetamine treatment (Experiments 1-3). Exposure to three nonescalating injections of amphetamine 7 days before 6-OHDA lesions had no effect (Experiment 2). Prelesion amphetamine treatment led to normalization of basal extracellular levels of striatal DA as measured by microdialysis on days 11-14 and 25-28 after lesioning (Experiment 3). However, there were no significant differences between treatment groups in postmortem tissue levels of DA and its metabolites, indicating a dissociation between the DA depletion and the extracellular levels of DA as measured by microdialysis. Finally, rats exposed to the escalating amphetamine regimen had reduced lesion-induced loss of TH-IR cells in the ipsilateral DA cell body regions (Experiment 3). Thus, prelesion exposure to the escalating doses of amphetamine may render the cells resistant to the consequences of damage after subsequent 6-OHDA lesions, possibly by accelerating the development of compensatory changes in the DA neurons that typically accompany behavioral recovery. The potential role of amphetamine-induced endogenous neurotrophic factors in the behavioral sparing and normalization of basal extracellular DA levels observed after subsequent 6-OHDA lesions is discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Disentangling the sources of opioid withdrawal responses: comment on McDonald and Siegel (2004).

R. V. McDonald and S. Siegel (see record 2004-10475-001) present new evidence for the idea that opioid drug-opposite responses can become conditioned to cues of initial drug onset and that they could, therefore, play a role in the development of tolerance of some drug effects and a role in the elicitation of withdrawal-like symptoms in cases in which addicted individuals are exposed to small doses of the drug they normally consume. In this comment, some puzzling features of the data are discussed, and alternative explanations are suggested.

Animals↗
PubMed2004

Methadone maintenance reduces heroin- and cocaine-induced relapse without affecting stress-induced relapse in a rodent model of poly-drug use.

Although it is well established that methadone can be an effective treatment for opiate addiction, it is not clear how methadone maintenance affects cocaine use and cravings in individuals who self-administer both opiates and cocaine. In our attempt to explore the effect of methadone maintenance on the effects of cocaine, we first assessed the locomotor stimulatory effects of cocaine in rats maintained on methadone (0, 10, 20, or 30 mg/kg/day, via osmotic minipumps). Chronic methadone elevated baseline locomotion in a dose-dependent manner and did not reduce the direct stimulatory effects of cocaine (5 mg/kg). We then investigated the effects of the highest methadone maintenance dose (30 mg/kg/day) on heroin and cocaine seeking in extinction, and when it was precipitated by exposure to heroin, cocaine, or foot-shock stress in rats trained to self-administer both drugs in the same experimental context (heroin 0.05 mg/kg/inf; cocaine 0.5 mg/kg/inf, eight 3-h sessions each). In tests of reinstatement, rats responded selectively on the appropriate drug-associated lever after priming injections of heroin (0.25 mg/kg) or cocaine (20 mg/kg). Methadone maintenance blocked both cocaine- and heroin-induced reinstatement, but not stress-induced reinstatement, which was not lever selective. These results suggest that although methadone maintenance may not reduce the direct stimulatory effects of cocaine, it has the potential to reduce both spontaneous and cocaine-primed cocaine-seeking behavior.

Analysis of Variance↗
PubMed2004

Heroin and cocaine co-use in a group of injection drug users in Montréal.

OBJECTIVE: To describe the pattern of co-use of heroin and cocaine in individuals who were not receiving methadone maintenance treatment. DESIGN: Structured interviews. SETTING: Community hospital. PARTICIPANTS: Individuals (n = 1111) selected from a cohort of out-of-treatment injection drug users in Montréal, Que. OUTCOME MEASURE: Frequency (injections per day) and quantity (number of days of use) of heroin, cocaine and speedball (the simultaneous administration of heroin and cocaine) use reported in the month preceding the interview. RESULTS: About 50% of the sample reported using only cocaine intravenously (C group), about 8% reported using only heroin (H group) intravenously and about 15% reported using both heroin and cocaine (HC group) intravenously. Reported cocaine consumption was similar in the HC and C groups. Heroin was used on fewer days by the HC than by the H group, but the number of injections per day was similar. Speedball use, which was quantified independently from heroin and cocaine use, was reported almost exclusively by the HC group, and speedball was used less often than either heroin or cocaine alone. Finally, a similar proportion of individuals in the C and the HC groups consumed alcohol in the 24 hours preceding the interview, but a larger proportion of individuals in the HC group reported the use of marijuana. CONCLUSION: In a cohort of injection drug users in Montréal, cocaine was the most prevalent illicit drug. Furthermore, about 70% of the heroin users also injected cocaine, but not in the form of speedball. Thus, the sequential co-use of heroin and cocaine is highly prevalent in Montréal and deserves particular clinical attention.

Adolescent↗
PubMed2003

Effects of cocaine in rats exposed to heroin.

We investigated whether chronic exposure to heroin alters responses to cocaine in ways that might explain the use of cocaine by opioid addicts. To this end, the effects of cocaine (5 and 20 mg/kg) were assessed on locomotor activity of rats chronically exposed to heroin (0.0, 3.5, 7.0, and 14.0 mg/kg/day, over 14 days, via osmotic mini-pumps), or withdrawn from heroin (1 day, acute withdrawal, and 14 days, protracted withdrawal). Chronic heroin exposure, in itself, dose dependently increased locomotion and acute cocaine administration further elevated locomotor activity in a dose-dependent and additive manner. During acute withdrawal, there was a dose-dependent decrease in locomotion that was reversed by cocaine in a dose-dependent manner. During protracted withdrawal, spontaneous locomotion normalized, but rats previously exposed to heroin displayed cross-sensitization to cocaine as indicated by small, but significant, enhanced locomotor response to 5 mg/kg of cocaine, and enhanced intravenous self-administration of low doses of cocaine (0.13 mg/kg/infusion). In a separate study, we measured extracellular dopamine (DA) in the nucleus accumbens (Acb) using in vivo microdialysis before and after acute withdrawal from heroin. During chronic exposure to heroin, basal extracellular DA was elevated dose dependently, whereas in acute withdrawal, levels were not different from those in vehicle-treated rats. In response to cocaine, however, DA activity in the Acb was significantly lower in rats withdrawn from the highest dose of heroin.

Analysis of Variance↗
PubMed2003

Understanding polydrug use: review of heroin and cocaine co-use.

The use of cocaine by heroin-dependent individuals, or by patients in methadone or buprenorphine maintenance treatment, is substantial and has negative consequences on health, social adjustment and outcome of opioid-addiction treatment. The pharmacological reasons for cocaine use in opioid-dependent individuals, however, are poorly understood and little is known about the patterns of heroin and cocaine co-use. We reviewed anecdotal evidence suggesting that cocaine is co-used with opioid drugs in a variety of different patterns, to achieve different goals. Clinical and preclinical experimental evidence indicates that the simultaneous administration of cocaine and heroin (i.e. 'speedball') does not induce a novel set of subjective effects, nor is it more reinforcing than either drug alone, especially when the doses of heroin and cocaine are high. There is mixed evidence that the subjective effects of cocaine are enhanced in individuals dependent on opioids, although it is clear that cocaine can alleviate the severity of symptoms of withdrawal from opioids. We also reviewed preclinical studies investigating possible neurobiological interactions between opioids and cocaine, but the results of these studies have been difficult to interpret mainly because the neurochemical mechanisms mediating the motivational effects of cocaine are modified by dependence on, and withdrawal from, opioid drugs. Our analysis encourages further systematic investigation of cocaine use patterns among opioid-dependent individuals and in laboratory animals. Once clearly identified, pharmacological and neuroanatomical methods can be employed in self-administering laboratory animals to uncover the neurobiological correlates of specific patterns of co-use.

Central Nervous System↗
PubMed2002

A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats.

RATIONALE AND OBJECTIVE: It is well established that stress induces reinstatement of drug seeking in an animal model of relapse. Here we studied the role of the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) in foot-shock stress-induced reinstatement of cocaine seeking. METHODS: Groups of rats were trained to self-administer cocaine (0.5 mg/kg per infusion, i.v., 3 h/day for 9 days) and after ten drug-free days were exposed to extinction and reinstatement test sessions. Each 60 min of extinction was separated by a 30-min time-out period after which the lever and stimulus lights were reintroduced. Rats were given four 1-h extinction sessions on day 1 and then on subsequent days were given two to three 1-h extinction sessions that were followed by a 3-h test for reinstatement. Tests were run every 48 h. In one set of experiments, the effects of inactivation of the prelimbic (PL), infralimbic (IL) or OFC by tetrodotoxin (TTX, 5 ng/0.5 micro l per side) on reinstatement induced by foot shock (5 min, intermittent, 1 mA) or priming injections of cocaine (20 mg/kg, i.p.) were determined. In a second set, the effects of infusions of the D1-like and D2-like dopamine receptor antagonists (SCH 23390 and raclopride) were studied using the same methods. RESULTS: TTX infusions into the PL cortex blocked both foot shock and cocaine-induced reinstatement. TTX into OFC attenuated foot-shock-induced, but not cocaine-induced reinstatement. Infusions into IL were ineffective. Infusions of SCH 22390 (0.25 micro g/0.5 micro l per side) into either PL or OFC blocked foot-shock-induced reinstatement, but infusions into PL had no effect on cocaine-induced reinstatement. Raclopride (5 micro g/0.5 micro l per side) had no effect on foot-shock-induced reinstatement in either PL or OFC or on cocaine-induced reinstatement when infused into PL. Neither TTX nor SCH23390 infusions into PL or OFC had any effect on lever pressing for sucrose. CONCLUSIONS: These results suggest that the PL and OFC regions form part of the circuitry mediating the effects of foot shock stress on reinstatement of drug seeking and that the PL region may be a common pathway for cue, drug and foot-shock stress-induced reinstatement of drug seeking.

Animals↗
PubMed2002

Persistence and drug-induced reinstatement of a morphine-induced conditioned place preference.

Morphine induces a conditioned place preference (CPP) for a chamber associated with the drug. In the present set of experiments, we explored the persistence, extinction, and reinstatement of a morphine-induced CPP using an 'unbiased' apparatus with two distinct chambers separated by a smaller neutral zone. Rats were given four 45 min pairings of one chamber with morphine (Experiments 1 and 2: 1.0, 5.0, or 10.0 mg/kg, s.c.; Experiments 3A and 3B: 10.0 mg/kg, s.c.) and four pairings of the other chamber with saline on alternate days. Following conditioning, rats were given 15 min tests for chamber preference. In Experiment 1, rats showed a CPP following conditioning with all doses. In Experiment 2, in the same animals, the CPP was evident in subsequent tests given either 2 or 6 weeks following the initial test for preference. Furthermore, in the animals tested 2 weeks after the initial CPP test, the CPP was maintained for 12 weeks when tests were repeated every 2 weeks. Animals tested at 6 weeks were again tested after another 6-week delay and showed a clear preference for the previously morphine-paired chamber. In Experiment 3A, rats underwent place conditioning as above with 10.0 mg/kg morphine. Following extinction during which both chambers were paired with saline for 45 min on four occasions, the CPP was no longer evident. The CPP was reinstated by priming injections of 1.0 or 2.5 mg/kg morphine, but not 0.5 mg/kg in a 30 min test. Similar results were found in Experiment 3B, in which the CPP was reinstated following a priming injection of morphine (2.5 mg/kg) given immediately or 15 min before a 30 min test; no reinstatement was seen after injections of saline. These results show that a morphine-induced CPP is persistent over time and can be reinstated by morphine after extinction.

Analgesics, Opioid↗
PubMed2002

The reinstatement model of drug relapse: history, methodology and major findings.

RATIONAL AND OBJECTIVES: The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat reinstatement model provides a suitable preclinical model of relapse to drug taking. CONCLUSIONS: The data derived from studies using the reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce reinstatement in laboratory animals and those that provoke relapse in humans.

Animals↗
PubMed2002

Astrocytic basic fibroblast growth factor expression in dopaminergic regions after perinatal anoxia.

BACKGROUND: Perinatal anoxia leads to persistent behavioral and neurochemical alterations suggestive of sensitized dopaminergic function. Because astrocytic basic fibroblast growth factor (bFGF) activity in the midbrain dopaminergic cell body region is required for the development of enduring changes in dopaminergic function induced by stimulant drugs, we investigated the effects of intrauterine anoxia on astrocytic bFGF expression in dopaminergic regions at 2 weeks of age and after a stress manipulation in adults. METHODS: We examined bFGF immunoreactivity in dopaminergic regions of young and adult rats born by cesarean section, cesarean section + 15 min of intrauterine anoxia, or vaginally. bFGF immunoreactivity was also assessed before and after tail-pinch stress in adult animals exposed to the same perinatal interventions. RESULTS: Perinatal anoxia produced persistent decreases in basal bFGF immunoreactivity in the ventral tegmental area (VTA), but enhanced the effect of stress on VTA bFGF immunoreactivity. CONCLUSIONS: Perinatal anoxia has enduring effects on VTA bFGF immunoreactivity and influences adult neuroadaptations to stress. The mechanisms whereby perinatal anoxia alters dopaminergic function may be similar to those responsible for the development of sensitization to stimulant drugs and may involve bFGF.

Age Factors↗
PubMed2002

Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala.

Experiments in our laboratory have shown that central noradrenergic (NA) activation plays a major role in stress-induced reinstatement of drug seeking in rats. In the present experiments, we investigated the effects of blockade of beta-NA adrenoceptors in the bed nucleus of the stria terminalis (BNST) and in the region of the central nucleus of the amygdala (CeA) on footshock- and cocaine-induced reinstatement. Rats were trained to self-administer cocaine (0.5 mg/kg, i.v.) for 9 d and, after a 5-7 d drug-free period, were given extinction sessions followed by a test for footshock stress-induced (15 min of intermittent footshock, 0.8 mA) or cocaine-induced (20 mg/kg, i.p.) reinstatement. Before the test, different groups of rats were given bilateral infusions of one of four doses of a mixture of the beta(1)- and beta(2)-receptor antagonists betaxolol and ICI-118,551 (vehicle, 0.25, 0.5, and 1 nmol of each compound in 0.5 microliter) into either the BNST or CeA. We observed a dose-dependent reduction of stress-induced reinstatement after infusions into the BNST and a complete blockade of stress-induced reinstatement after infusions into the CeA at all doses tested. The same treatments did not block cocaine-induced reinstatement when given at either site. These data suggest that stress-induced NA activation in the BNST and in the region of the CeA is critical to relapse to drug seeking induced by stress but not to relapse induced by priming injections of cocaine, and we hypothesize that NA activity leads to activation of corticotropin-releasing factor neurons in these regions.

Adrenergic beta-Antagonists↗
PubMed2002

Modulation of the subjective and physiological effects of drugs by contexts and expectations--the search for mechanisms: comment on Alessi, Roll, Reilly, and Johanson (2002).

Contexts and expectations can change the subjective and physiological effects of psychotropic drugs. Learning and conditioning processes clearly contribute to some of these effects. It must be considered, however, that even the acute effects of drugs can be significantly altered by the context in which they are administered. The challenge is to determine the mechanisms operating to bring about these changes.

Anti-Anxiety Agents↗
PubMed2002

The consequences of different "lapses" on relapse to heroin seeking in rats.

Although human studies have shown that a lapse, the first violation of abstinence, often induces resumption of drug taking, or relapse, it is not known what aspect of a lapse is critical to relapse or whether this phenomenon can be studied in other species. Rats were trained to self-administer heroin accompanied by a discrete light stimulus. After extinction, different groups experienced different "lapses." Twenty-four hours later, all groups received a test for relapse. It was found that a lapse during which heroin was self-administered, or was presented in close temporal contiguity with lever pressing, induced subsequent heroin seeking. Simple exposure to heroin, or to heroin-related stimuli, during the lapse had little effect on responding in the test for relapse.

Analysis of Variance↗
PubMed2002

Stress and selective attention: the interplay of mood, cortisol levels, and emotional information processing.

The effects of a stressful challenge on the processing of emotional words were examined in college students. Stress induction was achieved using a competitive computer task, where the individual either repeatedly lost or won against a confederate. Mood, attention, and cortisol were recorded during the study. There were four findings: (1) Participants in the negative stressor condition were faster to shift attention away from negative words than positive or neutral words; (2) attentional shifts away from negative words were associated with stress-induced mood lowering; (3) participants in the negative stress condition with elevated scores on the Beck Depression Inventory were slow to disengage attention from all stimuli; and (4) elevated depression scores were associated with lower cortisol change from baseline during the experimental phase, and with higher cortisol levels during the recovery phase. These findings point to information-processing strategies as a means to regulate emotion, and to atypical features of cognitive and adrenocortical function that may serve as putative risk markers of depression.

Adolescent↗