Biomedical subjects

Wendy J Lynch

Publications and source records attributed to Wendy J Lynch.

15 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

Dopamine beta-hydroxylase gene (DbetaH) -1021C-->T influences self-reported paranoia during cocaine self-administration.

BACKGROUND: Variation in the gene for dopamine beta-hydroxylase (DbetaH) has been reported to associate with cocaine-induced paranoia as assessed by retrospective self-report. This association has yet to be tested prospectively. METHODS: Visual analog scale (VAS) ratings of paranoia were obtained in 31 cocaine users during three cocaine self-administration sessions (8, 16, and 32 mg/70 kg). Pharmacogenetic interactions between cocaine and a putative functional polymorphism in DbetaH (-1021C-->T) were assessed. RESULTS: VAS self-ratings showed significant or trend-level interactions of genotype and time during each session (p = .004, .09 and .003, respectively) with TT homozygotes endorsing greater paranoia over time than either CT or CC individuals. Interactions were significant at all doses in African Americans (n = 19; p = .02, .04 and .05). No other demographic or experimental variable distinguished genotypic groups. CONCLUSIONS: Results indicate that individuals homozygous for the 'very low-activity' T allele at DbetaH -1021C-->T show an increased propensity to paranoia over time during cocaine self-administration.

Adult↗

PubMed2006

Self-reported paranoia during laboratory "binge" cocaine self-administration in humans.

Cocaine-induced paranoia (CIP) has been extensively studied by retrospective interviews; however, only limited efforts have been made to further characterize CIP by human laboratory methods. We examined CIP in 28 healthy cocaine-dependent volunteers, who participated in 2-h, intravenous cocaine self-administration sessions at 8, 16, and 32 mg/70 kg doses, including 18 in a placebo-controlled design. Self-reports of paranoia showed significant main effects of cocaine dose (p=0.0002) and time (p=0.0003), and were statistically distinguishable from placebo at the two highest doses (16 and 32 mg). These effects were accounted for by a subgroup of vulnerable subjects in whom self-reports were consistent across dose and test-retest sessions. Subjects with CIP did not differ from those without CIP with respect to demographic, cocaine use, or cocaine self-administration variables. In conclusion, self-reports of CIP in the human lab are frequently endorsed, dose-dependent, and though variable between subjects, reproducible within subjects. Such methods may facilitate our understanding of the vulnerability to CIP in humans.

Adolescent↗

PubMed2006

Sex differences in vulnerability to drug self-administration.

Recent evidence from both human and animal studies indicates that there are sex differences in all phases of the addiction process, including initiation and acquisition of use, patterns and levels of use, the progression to addiction, and relapse. This brief review summarizes a series of studies on sex differences in drug self-administration in rats on which the Wyeth Young Psychopharmacologist Award was based and relates these findings to human clinical data. Briefly, preclinical findings show that female rats acquire drug self-administration at a faster rate, work harder to obtain drug infusions, "binge" for longer initial periods of time and show a more diurnally dysregulated pattern of self-administration under extended-access conditions, and respond at higher levels under reinstatement testing conditions compared with male rats. Similar results have been reported in humans, suggesting a biological basis of sex differences in vulnerability to drug abuse. A number of biological mechanisms have been explored, and the results show that ovarian hormones play a critical role in modulating the reinforcing effects of drugs of abuse in females. Preclinical studies, in conjunction with human studies, should further inform a sex-specific model for differences in drug abuse, and such a model may be useful for developing prevention and treatment strategies for drug abuse.

Estrogens↗

PubMed2005

A paradigm to investigate the self-regulation of cocaine administration in humans.

INTRODUCTION: Current laboratory paradigms of human cocaine administration generally dictate the timing of drug access in ways that may limit assessing aspects of cocaine-taking behavior. Patient-controlled analgesia (PCA) methods, which allow individuals less restricted access to narcotic (i.e., opiate) analgesics, have proven safe and clinically effective for self-regulated treatment of pain. The current study assessed the feasibility, safety, and validity of a model of ad libitum cocaine self-administration, in which participants self-selected the timing of cocaine infusions, using PCA techniques. METHODS: Eight nontreatment seeking, otherwise medically healthy, experienced cocaine users participated in a double-blind, placebo-controlled, escalating-dose regimen of intravenous cocaine (0, 8, 16, and 32 mg per 70 kg) on 4 test days, during which time participants had 2 h of access to cocaine via manual presses of a corded PCA pump button under a fixed ratio 1: time-out 5-min schedule. RESULTS: Procedures were well-tolerated by participants, and no significant adverse events were noted. Measures of cocaine self-administration (e.g., number of responses and interinfusion intervals) indicated a significant main effect of cocaine dose, consistent with predicted dose-response relationships (i.e., decreasing responses and increasing interinfusion intervals with increasing injection dose). Participants appeared to regulate their cocaine intake in a carefully controlled manner, using considerably less cocaine (about half) that permitted by pump loading, PCA parameters, and session duration. CONCLUSIONS: Data from this study support the validity of our PCA paradigm. Moreover, results suggest the apparent feasibility and safety of allowing experienced users to self-select the timing of cocaine infusions to intervals as short as 5 min. Such procedures may enhance our ability to identify effective pharmacological treatments for cocaine addiction.

Adult↗

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↗

PubMed2004

Psychiatric correlates of gambling in adolescents and young adults grouped by age at gambling onset.

BACKGROUND: Gambling is a prevalent behavior, yet few studies have investigated its mental health correlates. Although early-onset engagement in behaviors with addictive potential has generally been associated with more severe problems, direct investigation of a nationally representative sample of gamblers grouped by age at onset of gambling has not been performed. OBJECTIVE: To identify differences in psychiatric correlates of gambling and gambling-related attitudes and behaviors in adolescents (aged 16-17 years) and in young adults (aged 18-29 years) with early-onset (before age 18 years) and adult-onset gambling. DESIGN: Logistic regression analysis. SETTING: Public access data set derived from random-digit-dialing telephone surveys. PATIENTS: The study analyzed data from adolescent (n = 235), early-onset adult (n = 151), and adult-onset (n = 204) past-year gamblers and adolescent (n = 299) and adult (n = 187) nongamblers in the Gambling Impact and Behavior Study. MAIN OUTCOME MEASURES: Gamblers and nongamblers were compared within each group on measures of sociodemographics and psychiatric health. Adolescent, early-onset adult, and adult-onset past-year gamblers were compared on measures of gambling attitudes and behaviors. RESULTS: Adolescent gamblers were more likely than adolescent nongamblers to report alcohol and drug use and abuse/dependence and depression. Elevated rates of alcohol and drug use and abuse/dependence were observed in early-onset adult gamblers vs adult nongamblers, and only elevated rates of alcohol use were observed in adult-onset gamblers vs adult nongamblers. Substantial differences in reasons for and patterns of gambling were observed among the 3 groups of gamblers. CONCLUSIONS: Adolescent-onset gambling is associated with more severe psychiatric problems, particularly substance use disorders, in adolescents and young adults. More research is needed to investigate the relationships and inform prevention and treatment strategies.

Adolescent↗

PubMed2004

Sex and estrogen influence drug abuse.

Evidence is accumulating that the etiology, epidemiology, consequences and mechanisms that underlie drug abuse are different in males and females. In this review, we present examples of sex differences in all phases of drug abuse, including acquisition, steady-state maintenance, escalation, dysregulation, withdrawal, relapse and treatment. Most reported findings are based on laboratory research in animals, but there are corroborating reports from human clinical and epidemiological studies. In all phases of drug abuse, females seem to be more sensitive to the rewarding effects of drugs than males, and estrogen is a major factor that underlies these sex differences.

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↗

PubMed2002

Biological basis of sex differences in drug abuse: preclinical and clinical studies.

The recent focus on drug abuse in women has brought attention to numerous differences between women and men. In this review, we discuss both preclinical and clinical findings of sex differences in drug abuse as well as mechanisms that may underlie these differences. Recent evidence suggests that the progression to dependence and abuse may differ between women and men; thus, different prevention and treatment strategies may be required. Similar sex differences in drug sensitivity and self-administration have been reported in laboratory animal studies. Females appear to be more vulnerable than males to the reinforcing effects of psychostimulants, opiates, and nicotine during many phases of the addiction process (e.g. acquisition, maintenance, dysregulation-escalation, relapse). Male and female animals differ in their behavioral, neurological, and pharmacological responses to drugs. Although the role of sex in the mechanisms of drug action remains unclear, preclinical and clinical studies indicate that ovarian hormones, particularly estrogen, play a role in producing sex differences in drug abuse. Future research is necessary to provide information on how to design more effective drug abuse treatment programs and resources that are sex specific.

Animals↗

PubMed2002

Patterns of cocaine self-administration in rats produced by various access conditions under a discrete trials procedure.

Frequency of drug access greatly affects the pattern and stability of cocaine self-administration. Previous research has shown that restricted drug availability produces remarkably consistent levels of daily cocaine intake, whereas increased or unlimited access produces more variable patterns of self-administration that may change over time. In the present study we used a discrete trials (DT) procedure to document how levels of access affect the pattern of cocaine intake. Rats that had been implanted with a chronically indwelling jugular cannula and trained to self-administer cocaine on an FR1 schedule were given access to cocaine during 10-min DT that were initiated throughout the day/night cycle for 21 days. Frequency of access (2, 3, 4 or 5 trials/h; 1.5 mg/kg/inj) and dose (1.0, 1.5, 2.0 and 2.5 mg/kg/inj, 3 trials/h) were investigated in separate groups of rats. When rats were presented with two or three trials an hour (1.5 mg/kg/inj), a highly regular and circadian pattern of intake was observed across weeks. Increasing the number of trials or increasing the unit dose resulted in a significant increase in average daily cocaine intake. Access to higher dose or higher frequency conditions produced a sustained drug-taking binge during the first few days on the schedule. Rats given access to five trials per hour typically responded at every opportunity for more than 48 h, then stabilized within a range of 80-100 mg/kg/day for the remainder of the experiment. To assess whether such high levels of cocaine intake had altered the motivation to respond, cocaine reinforced break-points were assessed on a progressive ratio schedule (0.32, 1.5 and 3.0 mg/kg/inj) in separate groups of animals before and 24 h after 5 days access on the DT procedure (5 trial/h). Sustained exposure to high levels of cocaine produced a shift in the dose-response curve to the right indicating tolerance to the reinforcing effects. This DT procedure provides a method to examine the behavioral and neurochemical effects of high cocaine intake over extended periods without toxicity.

Animals↗

PubMed2002

Changes in rat frontal cortex gene expression following chronic cocaine.

Alterations in gene expression caused by repeated cocaine administration have been implicated in the long-term behavioral aspects of cocaine abuse. The frontal cortex mediates reinforcement, sensory, associative, and executive functions and plays an important role in the mesocortical dopamine reinforcement system. Repeated cocaine administration causes changes in frontal cortex gene expression that may lead to changes in the behaviors subserved by this brain region. Rats treated non-contingently with a binge model of cocaine (45 mg/kg/day, i.p.) for 14 days were screened for changes in relative mRNA abundance in the frontal cortex by cDNA hybridization arrays. To confirm changes, immunoreactive protein was measured (via protein-specific immunoblots) in a second group of identically-treated animals. Protein levels of protein tyrosine kinase 2 (PYK2), activity-regulated cytoskeletal protein (ARC), as well as an antigen related to nerve growth factor I-B (NGFI-B-RA) were shown to be significantly induced after cocaine administration. Levels of NGFI-B mRNA were confirmed by real-time RT-PCR to be increased with cocaine administration. These observations are similar to previously reported cocaine-responsive changes in gene expression but novel to the frontal cortex. This study also validates the use of hybridization arrays for screening of neuronal gene expression changes and the utility of relative protein quantification as a post-hoc confirmation tool.

Animals↗

PubMed2002

Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: phenotype and sex differences.

RATIONALE: Rats selectively bred for high intake of a sweet saccharin solution (HiS) consume more ethanol than their low-saccharin intake (LoS) counterparts. The HiS phenotype may be a predictor of abuse of other drugs via other routes of administration. OBJECTIVE: HiS and LoS, male and female rats were tested for acquisition of IV cocaine and heroin self-administration under a fixed-ratio 1 (FR1) schedule, and cocaine-reinforced behavior was examined under a progressive-ratio (PR) schedule. METHODS: Four groups of rats (HiS males and females and LoS males and females) were trained to self-administer IV cocaine (0.2 mg/kg), and another four groups were trained to self-administer heroin (0.015 mg/kg) using an automated autoshaping procedure. Rats were allowed 30 days to reach a criterion whereby a mean of 100 (cocaine) or 20 (heroin) infusions were self-administered during 6-h sessions over 5 consecutive days. RESULTS: The HiS female rats acquired cocaine self-administration significantly more rapidly than the LoS rats, and females of both phenotypes met the acquisition criteria more rapidly than males. In both HiS and LoS cocaine groups a greater percentage of females (compared with males) met the acquisition criteria within 30 days. The only cocaine group in which 100% met the criterion was the HiS females. The female (compared with male) heroin groups showed a more rapid rate of acquisition, but there was no difference due to saccharin phenotype. In each of the four heroin groups 100% of all rats met the criteria within 30 days. Results of the PR schedule in the HiS females and males and LoS females indicated significantly higher break points in the HiS females (compared with HiS males), but there were no differences in females due to phenotype. CONCLUSION: Female rats selectively bred for higher saccharin intake show more rapid and successful acquisition of IV self-administration of a low dose of cocaine than those bred for low saccharin intake. Female rats (compared with males) consistently showed accelerated rates of acquisition and maintenance (PR) of cocaine self-administration and acquisition of heroin self-administration.

Analysis of Variance↗

PubMed2002

Repeated cocaine self-administration causes multiple changes in rat frontal cortex gene expression.

Repeated cocaine administration produces changes in gene expression that are thought to contribute to the behavioral alterations observed with cocaine abuse. This study focuses on gene expression changes in the frontal cortex, a component of reinforcement, sensory, associative, and executive circuitries. Changes in frontal cortex gene expression after repeated cocaine self-administration may lead to changes in the behaviors associated with this brain region. Rats self-administered cocaine for 10 days in a continuous access, discrete trial paradigm (averaging 100 mg/kg/day) and were examined for changes in relative frontal cortex mRNA abundance by cDNA hybridization arrays. Among the changes observed following array analysis, increased nerve-growth-factor-induced B (NGFI-B), adenylyl cyclase type VIII (AC VIII), and reduced cysteine-rich protein 2 (CRP2) mRNA were confirmed by quantitative RT-PCR. These changes share commonalities and exhibit differences with previous reports of gene expression changes in the frontal cortex after noncontingent cocaine administration.

Animals↗