Biomedical subjects

Mary Jeanne Kreek

Publications and source records attributed to Mary Jeanne Kreek.

At least 19 recordsLinked to original sources

PubMed2007

Effects of acute "binge" cocaine on mRNA levels of mu opioid receptor and neuropeptides in dopamine D1 or D3 receptor knockout mice.

In humans, elevations of mu opioid receptor (MOP-r) binding potential (BP) in the frontal cortex (FC) are associated with cocaine craving during early abstinence. In rats, decreases in dopaminergic (DAergic) transmission in the medial FC are associated with increased cocaine-seeking behavior. DA D1 or D3 receptor homozygous knockout (D1-/- or D3-/-) mice offer the opportunity to test the roles of these specific receptors in regulating MOP-r gene expression in response to cocaine. In the present studies, we found an increase in basal MOP-r mRNA levels in the FC of both D1-/- and D3-/- mice compared to wild type controls, with no change in the nucleus accumbens (NAc) core or caudate-putamen (CPu). Acute "binge" cocaine (3 x 15 mg/kg for 2.5 h) returned FC MOP-r mRNA levels in D1-/- or D3-/- mice to those in wild type controls. In the NAc core, the MOP-r mRNA levels after acute "binge" cocaine were decreased in D1-/- mice while increased in D3-/- mice. In the CPu, however, the MOP-r mRNA levels after acute "binge" cocaine were increased in D1-/- mice while decreased in D3-/- mice. We also found a decrease in basal orexin mRNA levels in the lateral hypothalamus of the D3-/- mice, which was unaltered by acute "binge" cocaine. Together, our findings suggest that: (1) both D1 and D3 receptors are involved in FC MOP-r gene regulation; and (2) D1 and D3 receptors play opposite roles in the effects of cocaine on MOP-r gene regulation differentially in the NAc core or CPu.

Animals↗

PubMed2007

Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients: a cross-sectional study.

AIMS: To determine and evaluate QTc intervals in electrocardiograms (ECGs) of former heroin addicts, currently in methadone maintenance treatment (MMT), as previous reports suggest that methadone may prolong QTc intervals, thus possibly increasing the risk for Torsade de pointes (TdP). DESIGN: Cross-sectional study. SETTING: Between January 2003 and September 2004, patients on a steady dose of methadone for at least 2 weeks were studied. PARTICIPANTS: This study is a subset of 153 patients, of whom 151 patients participated in a study of high methadone doses and serum levels. A total of 138 patients in MMT for a minimum of 100 days up to 10.7 years, receiving 40-290 mg/day methadone dose, participated. MEASUREMENTS: Patients had an ECG at the time when blood was drawn for determination of serum methadone levels at around 24 hours after the last oral methadone dose. Corrected-QT intervals (QTc) were calculated using the Bazett formula. FINDINGS: Of 138 patients studied, 98 (71%) were male. Mean QTc interval was 418.3 +/- 32.8 milliseconds (ms). Mean methadone dose was 170.9 +/- 50.3 mg/day and mean serum methadone level was 708.2 +/- 363.1 ng/ml. Methadone dose and serum levels did not correlate with QTc. Three patients had QTc intervals above 500 ms ('prolonged'). After 2 +/- 0.4 years of follow-up, two patients died; they were two of three patients with very prolonged QTc. Causes of death were not attributed to cardiac origin. An additional 19 patients had QTc intervals of between 450 and 499 ms ('possibly prolonged'). None of these QTc > or = 450 ms patients had any cardiac problems. Methadone doses of all 22 patients were > 120 mg/day. CONCLUSIONS: Methadone maintenance is generally safe; however, the possible toxicity of high dose (> 120 mg/day) should be monitored for QTc.

Adolescent↗

PubMed2006

Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans.

This study focused on the in vivo effects of the kappa-opioid hallucinogen salvinorin A, derived from the plant Salvia divinorum. The effects of salvinorin A (0.0032-0.056 mg/kg i.v.) were studied in a neuroendocrine biomarker assay of the anterior pituitary hormone prolactin in gonadally intact, adult male and female rhesus monkeys (n = 4 each). Salvinorin A produced dose- and time-dependent neuroendocrine effects, similar to the synthetic high-efficacy kappa-agonist U69,593 ((+)-(5alpha,7 alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiniyl)-1-oxaspiro[4.5]dec-8yl]-benzeneacetamide), but of shorter duration than the latter. Salvinorin A was approximately equipotent to U69,593 in this endpoint (salvinorin A ED50, 0.015 mg/kg; U69,593 ED(50), 0.0098 mg/kg). The effects of i.v. salvinorin A were not prevented by a small dose of the opioid antagonist nalmefene (0.01 mg/kg s.c.) but were prevented by a larger dose of nalmefene (0.1 mg/kg); the latter nalmefene dose is sufficient to produce kappa-antagonist effects in this species. In contrast, the 5HT2 receptor antagonist ketanserin (0.1 mg/kg i.m.) did not prevent the effects of salvinorin A. As expected, the neuroendocrine effects of salvinorin A (0.0032 mg/kg i.v.) were more robust in female than in male subjects. Related studies focused on full-length cloning of the coding region of the rhesus monkey kappa-opioid receptor (OPRK1) gene and revealed a high homology of the nonhuman primate OPRK1 gene compared with the human OPRK1 gene, including particular C-terminal residues thought to be involved in receptor desensitization and internalization. The present studies indicate that the hallucinogen salvinorin A acts as a high-efficacy kappa-agonist in nonhuman primates in a translationally viable neuroendocrine biomarker assay.

Amino Acid Sequence↗

PubMed2006

The nociceptin/orphanin FQ receptor agonist Ro 64-6198 reduces alcohol self-administration and prevents relapse-like alcohol drinking.

Effects of the opioid receptor like-1 (ORL-1) receptor agonist Ro 64-6198 (0.1, 0.3, and 1.0 mg/kg intraperitoneally (i.p.)) on operant ethanol self-administration and activation of self-administration by ethanol deprivation were studied in male Wistar rats. Acute administration of Ro 64-6198 caused a dose-dependent reduction of ethanol self-administration. In comparison, the opioid antagonist naltrexone (0.1, 0.3, and 1.0 mg/kg i.p.) inhibited ethanol self-administration at all doses tested. Ethanol deprivation for 10 days significantly increased ethanol self-administration during the first 2 days after deprivation. Daily pretreatment with Ro 64-6198 (0.3 mg/kg) or naltrexone (0.3 mg/kg) during the last 3 days of ethanol deprivation abolished the deprivation-induced increase in ethanol intake. Thus, stimulation of the ORL-1 receptors by Ro 64-6198 reduced the acute reinforcing effects of ethanol and prevented relapse-like behavior in the ethanol-deprivation model in a similar manner as a blockade of opioid receptors by naltrexone. Ro 64-6198 at 0.1 and 0.3 mg/kg doses did not alter self-administration of 0.2% saccharin solution, indicating an apparent selectivity of this compound in modification of ethanol reward. These findings add further support to the idea that Ro 64-6198 and potentially other synthetic ORL-1 receptor agonists are as effective as naltrexone in blocking the actions of ethanol important for its addictive potential in animal experiments, and therefore may have therapeutic value in the treatment of alcoholism.

Alcohol Drinking↗

PubMed2006

Altered levels of basal cortisol in healthy subjects with a 118G allele in exon 1 of the Mu opioid receptor gene.

The mu opioid receptor is centrally involved in the development of the addictive diseases. It also modulates the stress responsive hypothalamic-pituitary-adrenal axis. Receptors encoded by the variant 118G polymorphism in exon 1 of the mu opioid receptor gene have a threefold increase in beta-endorphin binding and beta-endorphin is three times more potent in receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels. Humans with this variant have increased stress response following opioid antagonism. Here, we study basal levels of adrenocorticotropic hormone and cortisol in subjects with this variant. In all, 59 healthy adults were genotyped and had morning levels of adrenocorticotropic hormone and cortisol measured following intravenous administration of saline placebo. Subjects with a 118G allele had significantly greater levels of cortisol than subjects with the prototype gene. Groups did not differ in levels of adrenocorticotropic hormone. A planned comparison revealed significantly greater cortisol in females with at least one copy of the 118G allele compared to females with the prototype gene. There was no significant effect of gender alone, nor was there a significant interaction between gender and genotype, on ACTH or cortisol. Subjects with at least one copy of the 118G allele have increased basal levels of cortisol, which may influence the susceptibility to and treatment of the stress responsive dyscrasia.

Adrenocorticotropic Hormone↗

PubMed2006

Gender differences in cardiovascular and corticoadrenal response to stress and drug cues in cocaine dependent individuals.

RATIONALE: Extensive research suggests that gender may affect neuroendocrine and cardiovascular arousal mechanisms underlying biological responses to stress. OBJECTIVE: To examine the impact of gender on response to stress and to drug-cue exposure in treatment-seeking cocaine abusers. METHODS: Fifty recently abstinent cocaine dependent individuals (25F/25M), who were matched on cocaine use history, were exposed to a brief guided-imagery procedure that involved imagining a recent personal stressful situation, a personal drug-related situation and neutral-relaxing situation, one imagery per session, presented in random order. Subjective craving and anxiety, cardiovascular measures and plasma adrenocorticotrophic hormone (ACTH), cortisol and prolactin were assessed. RESULTS: Males showed significantly higher levels of ACTH, cortisol, and SBP, both at baseline and following all three imagery conditions. Females showed significantly higher basal heart rate and prolactin, although no gender differences were observed following imagery. No gender differences were seen in subjective anxiety or cocaine craving. CONCLUSIONS: Results indicate significant gender differences in baseline sensitivity and subsequent variations in hypothalamus-pituitary-adrenal (HPA) and cardiovascular response to imagery challenge. Such gender-specific responses could have implications for the development of pharmacological treatments that address stress and drug-cue-related relapse in cocaine-abusing individuals.

Adrenocorticotropic Hormone↗

PubMed2006

Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes.

BACKGROUND: Cocaine dependence is associated with high rates of relapse. Stress and drug cue exposure are known to increase cocaine craving and stress arousal, but the association between these responses and cocaine relapse has not been previously studied. OBJECTIVE: To examine whether stress-induced and drug cue-induced cocaine craving and hypothalamic-pituitary-adrenal axis responses evoked in the laboratory are associated with subsequent cocaine relapse. DESIGN: Prospective study design assessing cocaine relapse and drug use during a 90-day follow-up period after discharge from inpatient treatment and research. Data were analyzed by Cox proportional hazards regression and multiple regression. SETTING: Inpatient treatment and research unit in a community mental health center. PATIENTS: Forty-nine treatment-seeking cocaine-dependent individuals. MAIN OUTCOME MEASURES: Time to cocaine relapse, number of days of cocaine use, and amount of cocaine used per occasion in the follow-up phase. RESULTS: Greater stress-induced, but not drug cue-induced, cocaine craving was associated with a shorter time to cocaine relapse. Stress-induced corticotropin and cortisol responses predicted higher amounts of cocaine use per occasion in the 90-day follow-up. CONCLUSIONS: These results demonstrate that stress-related increases in cocaine craving and hypothalamic-pituitary-adrenal axis responses are each associated with specific cocaine relapse outcomes. The findings support the use of stress-induced drug craving and associated hypothalamic-pituitary-adrenal axis responses to evaluate cocaine relapse propensity. Furthermore, treatments that address stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses could be of benefit in improving relapse outcomes in cocaine dependence.

Adrenocorticotropic Hormone↗

PubMed2006

Association analysis of polymorphisms in serotonin 1B receptor (HTR1B) gene with heroin addiction: a comparison of molecular and statistically estimated haplotypes.

OBJECTIVES: 5-Hydroxytryptamine (serotonin)-1B receptors (HTR1B) may play an important role in psychiatric disorders and drug and alcohol dependence. In this study we report on genotype, molecular haplotype and statistically estimated haplotype analyses of previously identified polymorphisms in positions -261T>G, -161A>T, 129C>T, 861G>C and 1180A>G of the HTR1B gene in ethnically diverse populations (African-Americans, Caucasians, Hispanics and Asians) including 235 former heroin addicts and 161 control subjects from New York City. The objectives were to test for an association of molecular and statistically estimated haplotypes and genotypes in HTR1B gene with heroin addiction and to compare results provided by molecular and statistically estimated haplotyping methods. METHODS: Genotype analysis was performed using a standard TaqMan protocol. Molecular haplotype analysis of the subset of polymorphisms consisting of -261T>G, -161A>T and 129C>T was performed using a protocol specially designed by our group, using fluorescent PCR. This is based on use of allele-specific primers complementary to flanking polymorphisms and a fluorescently labeled sequence-specific TaqMan probe set complementary to an internal polymorphism of the haplotype region. Every individual's statistically inferred haplotype pair agreed with the individual's haplotype pair determined by molecular haplotyping. RESULTS AND CONCLUSION: A point-wise significant association of haplotype pairs containing allele G at position 1180 with protective effect from heroin addiction in Caucasians was found. A point-wise nominally significant association of allele 1180G with a protective effect from heroin addiction was found in Caucasians. Statistically significant differences across four ethnic groups in control subjects for allelic frequencies of -261T>G and -161A>T were found.

Black or African American↗

PubMed2006

Glucocorticoid negative feedback in methadone-maintained former heroin addicts with ongoing cocaine dependence: dose-response to dexamethasone suppression.

Combined cocaine and illicit opiate use is common. This study aimed to test the hypothesis that cocaine dependence in former heroin-addicted patients maintained on methadone treatment is associated with enhanced glucocorticoid negative feedback. Multiple dose dexamethasone suppression tests, using a conventional 2.0 mg dose, and two lower doses, 0.5 mg and 0.125 mg, were performed in 10 methadone-maintained former heroin addicts with ongoing cocaine dependence (C-MM), 10 stabilized methadone-maintained former heroin addicts with no ongoing drug or alcohol use (MM), and 22 normal volunteers (NV). At 9 hours, there was no difference in plasma adrenocorticotropin hormone (ACTH) and/or cortisol levels among groups on the baseline day, as well as after the two lower doses of dexamethasone. At 17 hours, C-MM and MM had significantly lower plasma ACTH and/or cortisol levels than NV. However, C-MM did not significantly differ from MM in their hormonal levels. When the hormonal responses to dexamethasone are expressed as magnitude of lowering from baseline, there was no significant difference at any dose among groups. Therefore, C-MM exhibited a normal glucocorticoid negative feedback in the morning. Using the standard interpretation of dexamethasone suppression testing based on the examination of the actual hormonal levels rather than the difference from baseline condition, C-MM appear to have glucocorticoid effects similar to MM, yet were both greater than NV in the late afternoon. Thus, further studies are needed to know whether altered glucocorticoid negative feedback is related to chronic cocaine exposure, or is the result of former heroin addiction and/or its long-term treatment with methadone.

Adrenocorticotropic Hormone↗

PubMed2006

High methadone dose significantly reduces cocaine use in methadone maintenance treatment (MMT) patients.

AIM: To evaluate whether effective methadone treatment affects cocaine use. METHODS: 421 consecutive patients admitted to a methadone maintenance clinic in Israel (1993-2002) were prospectively studied. Patients' urine samples were analyzed for cocaine during months 1 and 13. RESULTS: On admission 55(13.1%) of 421 patients had urine positive for cocaine and 366 had negative. Of the 55 cocaine-positive patients, 45(81.8%) stayed in treatment at least one year, as did 267(73%) of cocaine-negative. After one year (n=312) 31 of 45 cocaine users stopped and 25 of 267 started. Methadone dose was highest in 31 patients who stopped cocaine (176.1+/-42.1 mg/ day), followed by 14 who did not stop (161.4+/-37.5 mg/day), and 25 who started during treatment (122.9+/-48.7 mg/day), or 242 who never used cocaine (119.5+/-48.4 mg/day) (ANOVA, F=15.6, p<0.0005). CONCLUSIONS: High methadone dose may reduce cocaine use in patients addicted to both heroin and cocaine.

Adolescent↗

PubMed2006

Antidepressant treatment patterns in a novel methadone maintenance clinic targeting young adults an observational study.

This observational study examined the antidepressant treatment patterns of a novel New York City methadone maintenance treatment program (MMTP), founded for the treatment of adolescents and now targeting young adults and older patients with special problems. The goal of the study was to investigate demographic or clinical characteristics that were associated with prescribing patterns, as well as whether antidepressant use was associated with sobriety. The method of data collection was a thorough chart review. Antidepressant treatment was significantly associated with gender, education, marital status, and relapse. However, after controlling for demographic and clinical characteristics, antidepressant treatment was not significantly associated with a reduction in relapse risk. Further research is needed to explore these relationships, as well as their generalizability to adult methadone clinics, and to examine the underlying factors that lead to similarities and distinctions in antidepressant prescribing practices between various types of clinics (i.e., general outpatient vs. methadone maintenance).

Adolescent↗

PubMed2006

Adolescent and young adult heroin patients: drug use and success in methadone maintenance treatment.

This study examined the impact of methadone maintenance treatment on an inclusive group of adolescent and young adult opiate-dependent patients, ages 15-23, admitted over a 6-year period, during their first year in the program. Retention in treatment was the primary outcome variable, and at 12 months, 48% were still in treatment. The findings were: (a) a stepwise discriminant function analysis revealed that patients who consistently used heroin were at a greater risk of leaving treatment within the first 12 months; (b) the use of cocaine was an indicator of higher levels of heroin use in those who reached the one-year mark; (c) among patients who stayed in treatment for one year, there was a significant reduction in heroin use, a trend toward a reduction in cocaine use, and no significant impact on benzodiazepine use; and (d) the group that stayed in treatment was slightly younger than the group that left before the first year ended. There were no gender or ethnic differences between the two groups. Suggestions for interventions that might improve treatment outcome are presented.

Adolescent↗

PubMed2006

On blending practice and research: the search for commonalities in substance abuse treatment.

There has been a growing interest in the substance abuse treatment field in bringing together the treatment and research communities. While dialogues about logistical and philosophical issues are important, the development of shared core concepts could potentially be quite helpful in facilitating communication and creating common treatment and research goals. It is the contention of this paper that all psychosocial and, potentially, pharmacological treatments ideally address, in part or in full, three aspects of the self--the capacity to regulate emotional and behavioral expression, the ability to engage in future-oriented, goal-directed behavior, and the development of nonaddict and/or recovery-oriented identities. Examples from the research and treatment literature are provided.

Alcoholism↗

PubMed2006

Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal.

In this study, we investigated the effects of acute morphine administration, chronic intermittent escalating-dose morphine administration and spontaneous withdrawal from chronic morphine on mRNA levels of mu opioid receptor (MOP-r), and the opioid peptides pro-opiomelanocortin (POMC) and preprodynorphin (ppDyn) in several key brain regions of the rat, associated with drug reward and motivated behaviors: lateral hypothalamus (lat.hyp), nucleus accumbens (NAc) core, amygdala, and caudate-putamen (CPu). There was no effect on MOP-r mRNA levels in these brain regions 30 min after either a single injection of morphine (10 mg/kg, i.p.) or chronic intermittent escalating-dose morphine (from 7.5 mg/kg per day on day 1 up to 120 mg/kg per day on day 10). Activation of the stress-responsive hypothalamic-pituitary-adrenal axis by 12 h withdrawal from chronic morphine was confirmed; both POMC mRNA levels in the anterior pituitary and plasma adrenocorticotropic hormone levels were significantly elevated. Under this withdrawal-related stress condition, there was an increase in MOP-r mRNA levels in the lat.hyp, NAc core, and CPu. Recent studies have demonstrated a novel role for the lat.hyp orexin (or hypocretin) activation in both drug-related positive rewarding, and withdrawal effects. Around 50% of lat.hyp orexin neurons express MOP-r. Therefore, we also examined the levels of lat.hyp orexin mRNA, and found them increased in morphine withdrawal, whereas there was no change in levels of the lat.hyp ppDyn mRNA, a gene coexpressed with the lat.hyp orexin. Our results show that there is an increase in MOP-r gene expression in a region-specific manner during morphine withdrawal, and support the hypothesis that increased lat.hyp orexin activity plays a role in morphine-withdrawal-related behaviors.

Adrenocorticotropic Hormone↗

PubMed2005

Pharmacokinetics of the plant-derived kappa-opioid hallucinogen salvinorin A in nonhuman primates.

Salvinorin A, a potent hallucinogen isolated from the leaves of Salvia divinorum, has gained popularity among adolescents in the USA. No detailed study of the pharmacokinetics has been conducted in vivo. The present study investigates the in vivo pharmacokinetics of salvinorin A (0.032 mg/kg, i.v. bolus) in rhesus monkeys (n=4, 2 male, 2 female). The elimination t(1/2) was rapid (56.6+/-24.8 min) for all subjects. Pharmacokinetic differences (distribution t(1/2), elimination t(1/2), and AUC) were observed between males and females, suggesting potential sex differences in its pharmacologic effects. Salvinorin B, the presumed major metabolite, is observed to accumulate ex vivo; however, in this study it never reached the limit of detection.

Animals↗

PubMed2005

Steady-dose and escalating-dose "binge" administration of cocaine alter expression of behavioral stereotypy and striatal preprodynorphin mRNA levels in rats.

This study examined the effects of chronic (14-day) steady-dose and escalating-dose "binge" pattern cocaine administration on striatal preprodynorphin (ppDyn) mRNA levels and behavioral stereotypies. Animals in the steady-state and escalating groups received cocaine in a "binge" pattern (three equal injections starting 30 min following the start of the daily light cycle, separated by 1 h). The dose of cocaine in the "steady-dose" group was 15 mg/kg/injection and remained constant throughout the study. The escalating group received 15 mg/kg/injection on days 1-3, 20 mg/kg/injection on days 4-6, 25 mg/kg/injection on days 7-9 and 30 mg/kg/injection thereafter, for a maximum daily dose of 90 mg/kg. Levels of ppDyn mRNA were determined by solution hybridization. Cocaine significantly affected body weight. Both steady-dose and escalating-dose "binge" cocaine administration resulted in expression of behavioral stereotypy and induced intense, rapid head movements which were dose- and time-dependent. Cocaine, independent of dose, increased ppDyn mRNA levels in the caudate putamen (CPu), but not in the nucleus accumbens (NAc). These data suggest that the ppDyn response to cocaine in the CPu is not dose-dependent or that it has reached a maximal level at the 45 mg/kg daily dose.

Analysis of Variance↗

PubMed2005

Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine self-administration, and mu-opioid receptor mRNA expression in the rat brain.

Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/kg, i.p.) CPP. In contrast, methadone maintenance (30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.

Analysis of Variance↗

PubMed2005

Persistent upregulation of mu-opioid, but not adenosine, receptors in brains of long-term withdrawn escalating dose "binge" cocaine-treated rats.

There is evidence showing that the opioid and adenosine systems play an important role in cocaine addiction; fewer studies have examined their roles in cocaine withdrawal. To determine whether cocaine and/or chronic withdrawal from cocaine alters the specific components of the opioid and adenosine systems, we carried out quantitative autoradiographic mapping of mu-opioid, A1 and A2A adenosine receptors in the brains of rats treated with an escalating dose "binge" cocaine administration paradigm and of rats chronically withdrawn from cocaine. Male Fischer rats were injected with saline or cocaine (15 x 3 mg/kg/day for 4 days, 20 x 3 mg/kg/day for 4 days, 25 x 3 mg/kg/day for 4 days and 30 x 3 mg/kg/day for 2 days) at 1-h intervals for 14 days. Similarly treated rats were withdrawn from that paradigm for 14 days. A significant increase in [(3)H]DAMGO binding to mu-receptors was detected in the frontal and cingulate cortex, as well as in the caudate putamen, of long-term withdrawn rats after an escalating dose "binge" cocaine administration paradigm and in chronic cocaine-treated rats. No significant cocaine-induced change was found in A1 or A2A receptor binding in any region analyzed. These results reconfirm that mu-opioid (MOP) receptors undergo upregulation in response to chronic escalating dose "binge" cocaine administration. This upregulation was shown for the first time to persist at least 14 days into withdrawal after escalating "binge" cocaine.

Adenosine↗