Biomedical subjects

N K Mello

Publications and source records attributed to N K Mello.

At least 73 records · Page 4Linked to original sources

PubMed1995

Relationship between the discriminative stimulus effects and plasma concentrations of intramuscular cocaine in rhesus monkeys.

The relationship between the discriminative stimulus effects and plasma pharmacokinetics of cocaine was evaluated in six rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a FR30 schedule of food presentation. The same monkeys were tested in two procedures. In a cumulative dosing procedure, five cumulative doses of cocaine (0.013-1.3 mg/kg) were administered and discriminative stimulus effects were evaluated 10 min after the administration of each dose. Cocaine plasma concentrations were measured in separate sessions using the same doses and interdose intervals. In a single dosing procedure, the time-courses of the discriminative stimulus effects and plasma concentrations of cocaine were assessed after the administration of cocaine (0.4 mg/kg). A close correspondence between cocaine's discriminative stimulus effects and plasma concentrations was obtained in both procedures. Cocaine was virtually undetectable in plasma at doses that produced saline-appropriate responding (0.013 and 0.04 mg/kg), whereas increasing plasma concentrations were measured at doses that produced primarily cocaine-appropriate responding (0.13 mg/kg or higher). The time-course of the discriminative stimulus effects of cocaine was characterized by a rapid onset (within 1-3 min post-cocaine) and offset (within 20-60 min post-cocaine). Peak plasma levels were obtained at 10 min post-cocaine. No differences in plasma concentrations were found 10 min after the administration of a cumulative versus a single dose of cocaine 0.4 mg/kg (mean, 75.8 and 74.0 ng/ml, respectively). Cocaine plasma concentrations lasted longer than its discriminative stimulus effects. The results of the present study confirm that the cumulative dosing procedure used yields plasma concentrations of cocaine that are similar to the concentrations obtained after single cocaine dosing.

Animals↗

PubMed1995

Buprenorphine-induced alterations of cocaine's reinforcing effects in rhesus monkey: a dose-response analysis.

Buprenorphine reduces cocaine self-administration by rhesus monkeys, opiate- and cocaine-dependent men and polydrug abusers, but the mechanisms underlying these cocaine-opiate interactions are not well understood. In the present study, the effects of daily placebo or buprenorphine (0.1, 0.3 and 1.0 mg/kg) treatment on cocaine self-administration (0.001-0.3 mg/kg/inject) were examined in five cocaine-experienced rhesus monkeys. Saline and each of six cocaine doses were available in an irregular order. Responding for cocaine (or saline) and food was maintained on a second order FR4 (VR 16:5) schedule of reinforcement. During placebo treatment, the daily number of cocaine injections increased as the unit dose was increased and then decreased at higher doses. Cocaine doses that maintained the highest rates of responding during placebo treatment were more resistant to buprenorphine's effects. The typical increase in response rate during the first five cocaine injections of a session also was attenuated by buprenorphine. The ascending limb of the cocaine dose-response curve was shifted downward and approximately one log unit to the right during low-dose buprenorphine treatment (0.1 mg/kg/day). In contrast, individual response rates for food pellets were unaffected. We conclude that buprenorphine selectively decreases self-administration of some unit doses of cocaine at doses that have minimal effects on food-maintained responding.

Animals↗

PubMed1995

The concordance of pulsatile ultradian release of adrenocorticotropin and cortisol in male rhesus monkeys.

The ultradian release of ACTH and cortisol was investigated in six male rhesus monkeys (Macaca mulatta) with an intensive (2-min) blood-sampling procedure to investigate micropulsatile hormone secretory patterns. A sensitive and specific immunoradiometric assay was used to measure plasma ACTH concentrations. An objective pulse detection algorithm (Cluster) was used to assess the pulsatility of ACTH and cortisol release. The temporally coincident release of ACTH and cortisol was also examined. Venous blood samples were collected (over < 15 s) every 2 min for 120 min beginning at 1300 h. The number of ACTH peaks (3.2 peaks/h), interpulse intervals (19 +/- 2.4 min), and pulse amplitudes (9.7 +/- 1.6 pmol/L) in rhesus monkey were similar to corresponding measures of ACTH release in humans (3.3 peaks/h, 18 +/- 0.8 min, and 4.7 +/- 1.0 pmol/L, respectively). The number of cortisol peaks (2.3 peaks/h), interpulse interval (26 +/- 8.6 min), and other characteristics of pulsatile cortisol release were also determined. There was a 32.4% exact concordance of ACTH with cortisol peaks (11 of 34; P < 0.001). Fifty-six percent of ACTH peaks (19 of 34) were followed by a cortisol peak within 10 min (P < 0.02). There was a significant correlation between the ACTH and coincident cortisol pulse amplitudes (P < 0.0001). The amplitudes of ACTH peaks coincident with cortisol peaks at 0 min time lag were significantly higher than ACTH peaks not temporally coupled with cortisol peaks. Our data indicate that 1) high frequency, low amplitude micropulsatile ACTH secretion in rhesus monkeys is very similar to the high frequency ACTH rhythm in humans; 2) temporally concordant ACTH and cortisol release episodes may be amplitude coupled; and 3) an adequate incremental ACTH pulse amplitude may elicit a concurrent cortisol release episode from the adrenal cortex. These data suggest that the rhesus monkey is a potentially useful model for the study of neuroendocrine control of ACTH release.

Activity Cycles↗

PubMed1995

Effects of cocaine and corticotropin-releasing factor on pulsatile ACTH and cortisol release in ovariectomized rhesus monkeys.

Cocaine stimulates ACTH secretion by a corticotropin-releasing factor (CRF)-dependent mechanism in male rats, rhesus monkeys, and humans. To determine the generality of this effect, we examined the effects of acute cocaine administration on the pulsatile release of ACTH and cortisol in three ovariectomized (OVX) rhesus monkeys and compared its effects to stimulation with CRF. Venous blood samples were collected at 2-min intervals for 60 min before and after iv administration of cocaine (0.4 and 0.8 mg/kg) and CRF (1.0 and 10 micrograms/kg). Cluster analysis procedures were used to evaluate the pulsatile characteristics of ACTH and cortisol release. After placebo administration, an ACTH pulse frequency of 3 peaks/h was detected. After cocaine administration, plasma cocaine levels peaked at 92 +/- 3.0 and 201 +/- 60 ng/mL within 2 min. However, in contrast to normal intact males, cocaine did not stimulate the pulsatile release of ACTH in OVX females. Cocaine (0.4 mg/kg) decreased ACTH incremental peak height and valley levels compared with pre-cocaine values, and a higher dose of cocaine produced no changes in ACTH release. Bolus injection of a low dose of CRF (1.0 micrograms/kg, iv) significantly increased ACTH incremental peak height (P < 0.05), and a higher dose of CRF (10 micrograms/kg) increased ACTH peak amplitude, percentage increase in peak amplitude, area under the peaks, and incremental peak heights as well as ACTH valley level and nadir (10 micrograms/kg, iv) (P < 0.05). ACTH pulse frequency did not change after CRF or cocaine administration. Pulsatile release of cortisol was 2.7 peaks/h under placebo conditions and did not change after cocaine or CRF administration. Cortisol pulse amplitude was increased after low and high doses of CRF. High doses of CRF (10 micrograms/kg) also increased the mean level of cortisol valleys. In summary, we found that CRF but not cocaine stimulated pulsatile ACTH and cortisol release in OVX rhesus monkeys. The profound ACTH response to CRF challenge suggests that the CRF sensitivity and the ACTH release capacity of the anterior pituitary corticotroph cells were intact. The lack of stimulatory effects of cocaine on the hypothalamic-pituitary-adrenal axis in OVX monkeys, in contrast to normal male monkeys, may reflect the absence of gonadal steroids.

Adrenocorticotropic Hormone↗

PubMed1995

A primate model of polydrug abuse: cocaine and heroin combinations.

Abuse of cocaine-opiate combinations ("speedballs") reported clinically was simulated in a rhesus monkey model of simultaneous cocaine and heroin self-administration. The reinforcing effects of nine cocaine-heroin combinations (cocaine [0.001, 0.01 and 0.10 mg/kg per injection i.v.] and heroin [0.0001, 0.001 and 0.01 mg/kg per injection i.v.]) were evaluated for 10 days on a second-order fixed ratio of 4 (variable ratio of 16:S) schedule and compared with self-administration of cocaine and heroin alone. Dose-effect curves for cocaine-heroin combinations usually were similar to those for cocaine and heroin alone, and intermediate doses maintained equivalent high levels of drug self-administration. No toxic effects were observed. In drug discrimination studies, cocaine (0.004-1.3 mg/kg) substitution resulted in a dose-dependent generalization to the training dose (0.4 mg/kg i.m.) in all five monkeys. Heroin substitution (0.01-1.0 mg/kg i.m.) resulted in dose-dependent and complete generalization to cocaine in three of five monkeys. Heroin pretreatment (0.1-0.18 mg/kg i.m.) did not change the cocaine discrimination dose-effect curve. Pretreatment with an opiate antagonist, quadazocine (0.1 mg/kg i.m.), had no effect on the discriminative stimulus effects of cocaine but antagonized the cocaine-like discriminative stimulus effects of heroin. Pretreatment with a dopamine antagonist, flupenthixol (0.018 mg/kg), antagonized the discriminative stimulus effects of cocaine but did not affect the cocaine-like effects of heroin. These findings demonstrate the feasibility of maintaining self-administration of cocaine-heroin combinations and suggest that cocaine and heroin have similar reinforcing and discriminative stimulus effects in rhesus monkeys.

Animals↗

PubMed1995

Improved regional cerebral blood flow in chronic cocaine polydrug users treated with buprenorphine.

UNLABELLED: Chronic cocaine and polydrug abuse have been associated with regional abnormalities in cerebral perfusion. The authors have previously demonstrated that these abnormalities are partially reversible after drug addiction treatment with buprenorphine. This study was designed to separate the effect on cerebral perfusion of abstinence from drug use from that of buprenorphine directly. METHODS: Fifteen cocaine- and heroin-dependent men were studied with 99mTc-hexamethylpropyleneamine oxime (HMPAO) brain SPECT. The men, all part of an inpatient drug abuse treatment research program, were randomly assigned after detoxification to receive placebo or either 6 or 12 mg daily buprenorphine treatment. SPECT studies were performed at baseline, after maximum dosage was reached and after tapering off the study drug. Studies were compared visually with regard to the number and location of perfusion defects by reviewers blinded to treatment assignment. RESULTS: Subjects receiving buprenorphine had a significant reduction in the number of defects per study between baseline and maximum buprenorphine dose as compared with those receiving placebo (decrease of 4 +/- 5.4 versus increase of 4.8 +/- 4.7, p = 0.006). These differences were dose-related. Improvement with buprenorphine was temporary, with return to baseline after tapering off. CONCLUSION: Buprenorphine treatment, and not abstinence from drug use alone, leads to improvement in regional cerebral perfusion abnormalities in chronic cocaine- and heroin-dependent men.

Adult↗

PubMed1995

Role of delta opioid receptors in the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys.

The role of delta opioid receptors in the self-administration and discrimination of cocaine by rhesus monkeys was evaluated using the delta opioid antagonist naltrindole and the delta opioid agonist BW373U86 [(+/-)-4-((alpha R*)-alpha-((2S*,5R*)-4-Allyl-2,5-dimethyl-1- piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide dihydrochloride]. In the self-administration studies, monkeys were trained to respond for food (1 g banana pellets) or cocaine (0.032 mg/kg/injection, i.v.) under a second-order FR4(VR16:S) schedule of reinforcement during multiple daily food and drug sessions. Substitution of saline or other unit doses of cocaine (0.001-0.1 mg/kg/injection) for the maintenance dose of cocaine yielded typical inverted-U shaped dose-effect curves relating unit dose of cocaine to the number of saline or drug injections per day. The unit dose of cocaine available during drug sessions had little effect on food-maintained responding. In the drug discrimination studies, monkeys were trained to discriminate 0.4 mg/kg cocaine (i.m.) from saline in a two-lever, food-reinforced drug discrimination task. Cumulative dosing with cocaine (0.004-1.3 mg/kg) produced a dose-dependent generalization to the training dose of cocaine without consistently altering response rates. Initial experiments with naltrindole (0.1-3.2 mg/kg, i.v. or i.m.) produced effects in some monkeys suggesting that naltrindole may have antagonized the effects of cocaine under both procedures. In the drug self-administration studies, treatment with at least one dose of naltrindole for 10 consecutive days decreased self-administration of a unit dose of cocaine at the peak of the ascending limb of the cocaine dose-effect curve (0.01 mg/kg/injection) in three of four monkeys. In the drug discrimination studies, treatment with at least one dose of naltrindole shifted the cocaine dose-effect curve 1/2 log unit to the right in two of four monkeys. However, naltrindole did not alter the effects of cocaine in all monkeys under either procedure. Furthermore, in the monkeys in which naltrindole was effective, the cocaine-antagonist actions of naltrindole were not replicable and were not monotonically related to dose. When the delta agonist BW373U86 (0.001-0.032 mg/kg/inj, i.v.) was substituted for cocaine in one monkey in which naltrindole decreased cocaine self-administration, BW373186 was not self-administered. In addition, BW373U86 (0.0032-0.32 mg/kg, i.m.) neither generalized to cocaine nor potentiated the effects of cocaine in the drug discrimination procedure. These results suggest that delta opioid receptors play, at best, a minor and inconsistent role in the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys.

Animals↗

PubMed1995

The acute effects of cocaine on anterior pituitary hormones in ovariectomized rhesus monkeys.

Cocaine stimulates a rapid release of gonadotropins in intact rhesus males and females and human males and enhances synthetic luteinizing hormone-releasing hormone (LHRH), stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This report describes the effects of acute cocaine administration on basal and synthetic LHRH-stimulated anterior pituitary hormones [LH, FSH and prolactin (PRL)] in five ovariectomized female rhesus monkeys. Integrated blood samples were collected every 10 min for 40 min before i.v. administration of cocaine (0.4 or 0.8 mg/kg) or an equal volume of vehicle control solution and for 110 min after cocaine or placebo administration. Synthetic LHRH (100 micrograms i.v.) was administered 10 min after cocaine or placebo-cocaine injection. In contrast to previous observations in rhesus and human males and in early follicular and midluteal phase rhesus females, cocaine did not change basal levels of gonadotropins or PRL in long-term ovariectomized females. LHRH stimulated a significant and sustained increase in LH (P < .01) within 20 min and FSH (P < .05) within 40 min after placebo-cocaine administration. LHRH also stimulated significant increases in LH and FSH after 0.4 and 0.8 mg/kg cocaine administration. Significant increases in LH (P < .05) and FSH (P < .01) were measured 10 min sooner after 0.8 mg/kg cocaine than after placebo-cocaine, but cocaine did not significantly increase the magnitude or duration of LHRH-stimulated increases in gonadotropins in ovariectomized females as it did in follicular phase females. Basal PRL levels (3.6 +/- 0.2 and 5.5 +/- 0.7 ng/ml) did not change after administration of cocaine alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Antinociceptive effects of cocaine/opioid combinations in rhesus monkeys.

This study characterized the antinociceptive effects of cocaine alone and in combination with mu, delta, and kappa opioids in rhesus monkeys. The shaved tails of four rhesus monkeys were exposed to warm water (42, 46, 50, 54, and 58 degrees C), and tail withdrawal latencies (20 sec maximum) from each temperature were determined. The temperature that produced a tail withdrawal latency of 10 sec (T10) was interpolated, and drug-induced changes in the T10 value (delta T10) were calculated. Dose-dependent increases in delta T10 were produced by cocaine (0.032-1.8 mg/kg), the high efficacy mu agonist fentanyl (0.001-0.1 mg/kg), the intermediate efficacy mu agonist morphine (0.1-18 mg/kg), the low efficacy mu agonist nalbuphine (1-32 mg/kg), and the kappa agonist U69,593 (0.0032-0.1 mg/kg). The delta agonist BW373U86 (0.56 mg/kg) produced no effect. Relative maximum effects, determined from the maximum delta T10 values produced by each drug, were fentanyl > or = (5,7,8 beta)-N-methyl-N[2-(1-pyrrolidinyl)1-oxaspiro[4,5]dec-8- yl]benzeneacetamide > morphine > nalbuphine > or = cocaine > BW373U86. When individual doses of cocaine (0.1-1.8 mg/kg) and morphine (0.32-10.0 mg/kg) were combined, cocaine produced a dose-dependent increase in the effects of each dose of morphine, and the antinociceptive effects of most cocaine/morphine combinations were significantly greater than the antinociceptive effects of either cocaine or morphine alone. Cocaine (1.8 mg/kg) was also combined with nalbuphine (1.0, 10 mg/kg), fentanyl (0.001, 0.032 mg/kg), BW373U86 (0.56 mg/kg) and U69,593 (0.0032-0.056 mg/kg). Cocaine/nalbuphine combinations produced effects markedly greater than either drug alone.

Analgesics, Opioid↗

PubMed1994

In vivo proton magnetic resonance spectroscopy detection of human alcohol tolerance.

Alcohol tolerance was ascertained with in vivo proton magnetic resonance spectroscopy (MRS) in men who regularly consumed either large (10-20 drinks/week) or small (2-4 drinks/weeks) amounts of beverage alcohol. Brain ethanol concentrations were determined by MRS, and blood ethanol levels were measured by gas chromatography after controlled ethanol administration (0.8 g/kg). Brain-blood ethanol concentration ratios for heavy drinkers were significantly greater than ratios for occasional drinkers (P < 0.002). Inasmuch as ethanol tolerance covaries with the severity of dependence, MRS procedures may facilitate our understanding of alcohol tolerance and treatment of alcoholism.

Adult↗

PubMed1994

In vivo proton magnetic resonance spectroscopy of alcohol in rhesus monkey brain.

Brain alcohol was measured in rhesus monkeys (Macaca mulatta) by proton magnetic resonance spectroscopy (MRS) following acute nasogastric alcohol administration (0.8 g/kg). Monkeys were anesthetized with ketamine and xylazine. A 1.5 T whole body imager and a 3-inch surface coil were used to acquire TE 30 and 270 ms spectra from a 7.5 cc voxel localized with a stimulated echo (STEAM) sequence. Venous blood samples were collected during spectral acquisitions for gas chromatographic determination of temporally concordant blood alcohol levels (BALs). Acute alcohol administration did not alter the resonance areas of N-acetylaspartate/N-acetyl containing compounds (NAA), choline containing compounds, or total creatine. The NAA resonance was used as an internal standard to calculate approximate brain alcohol concentrations, which averaged 27 +/- 3% and 27 +/- 8% of temporally concordant BALs (T2-corrected TE 30 and TE 270 ms spectra, respectively). In addition to reconfirming results from prior studies finding incomplete detection of brain alcohol with MRS, these results demonstrate the feasibility of measuring brain alcohol in anesthetized nonhuman primates to examine relationships between alcohol exposure history and MRS-visibility of brain alcohol.

Animals↗

PubMed1994

Effects of dopamine on prolactin: interactions with cocaine self-administration by female rhesus monkeys.

The effects of dopamine on regulation of prolactin secretion were studied in female rhesus monkeys before cocaine exposure and again after 2 months to 2.7 years of daily cocaine self-administration. During chronic cocaine exposure, basal prolactin levels increased by 227 to 350% above drug-free control levels (P < .05). On each endocrine study day, three successive 80-min dopamine infusions (10 micrograms/kg/min i.v.) were alternated with 20-min interruptions of dopamine infusions to assess the degree of prolactin suppression and the magnitude of postdopamine prolactin increases. Dopamine significantly reduced prolactin below base-line levels within 60 to 80 min under all conditions (P < .05-.01). In four drug-naive follicular phase females, postdopamine increases in prolactin never exceeded predopamine base-line levels of 6.2 (+/- 1.8) ng/ml. After an average of 74 days of cocaine self-administration [3.7 (+/- 0.11) mg/kg/day], the postdopamine prolactin increases were significantly higher than during drug-free control conditions (P < .01) and reached hyperprolactinemic levels of 57.6 ng/ml. After an average of 300 days of cocaine self-administration [6.5 (+/- 0.06) mg/kg/day], postdopamine prolactin increases peaked at 339% above predopamine basal prolactin levels. After an average of 433 days of cocaine self-administration [6.45 (+/- 0.08) mg/kg/day] postdopamine prolactin increases remained significantly higher (P < .01) than during drug-free conditions. A similar pattern of postdopamine prolactin increases to hyperprolactinemic levels (ranging from 44.5 to 141.2 ng/ml) also were measured in two other females studied after 19 to 20 months of cocaine self-administration [6.21 (+/- 0.11) and 7.49 (+/- 0.17) mg/kg/day]. After 2.7 years of cocaine self-administration, one monkey developed persistent hyperprolactinemia and basal prolactin levels averaged 326 ng/ml after 89 days of cocaine abstinence. These data suggest that the prolactin secretory response to dopamine perturbation may provide a sensitive index of changes in dopaminergic regulation of prolactin during chronic cocaine exposure.

Animals↗

PubMed1994

Cocaine effects on pulsatile secretion of ACTH in men.

The effects of cocaine on pulsatile secretion of adrenocorticotropic hormone (ACTH) in men were studied under controlled clinical research ward conditions. Eight men with a Diagnostic and Statistical Manual of the American Psychiatric Association Version III, revised, diagnosis of concurrent cocaine and opioid dependence provided their informed consent for participation in this study. After an overnight fast, a challenge dose of cocaine (30 mg i.v.) or placebo was administered under single-blind conditions in a randomized order on 2 study days. Blood samples were collected at 2-min intervals for 76 min during base line and for an additional 76 min after i.v. administration of the challenge dose. Peak plasma cocaine levels of 313.8 +/- 46.5 ng/ml were detected within 2 min after cocaine administration. The cluster analysis program originally described by Veldhuis and Johnson (1986) was used to characterize ACTH pulsatile secretion (Iranmanesh et al., 1990). Acute cocaine administration (30 mg i.v.) significantly increased ACTH mean peak amplitude (P < .05), mean percent increase in peak amplitude, (P < .05), mean peak area (P < .04), total peak area (P < .04) and incremental peak height (P < .04). Mean ACTH valley levels (P < .02) and mean valley nadir (P < .02) were also significantly increased after cocaine administration. We postulate that cocaine stimulates the release of corticotropin releasing factor and that the cocaine-induced secretion of corticotropin releasing factor increases the amplitude of ACTH pulses, because ACTH pulse frequency was not altered by cocaine.

Adrenocorticotropic Hormone↗

PubMed1994

Buprenorphine effects on morphine- and cocaine-induced subjective responses by drug-dependent men.

The effects of daily buprenorphine treatment (4 or 8 mg/day, sublingual) on reports of subjective effects after single intravenous doses of morphine (10 mg), cocaine (30 mg), and saline placebo were studied on an inpatient clinical research ward in 26 men concurrently dependent on opioids and cocaine (DSM-III-R). Latency to detection and certainty of a drug effect, as well as drug quality (intensity, euphoria, and dysphoria), were studied before and after 10 to 12 days of buprenorphine maintenance. Saline was accurately identified by all 26 patients during the drugfree baseline and by 25 patients during buprenorphine maintenance conditions. All patients accurately identified morphine during the drugfree period before treatment with buprenorphine, but 18 (69%) of 26 patients were unable to detect morphine during buprenorphine maintenance and 2 misidentified morphine as cocaine. Six men (23%) accurately identified morphine and reported that the intensity and quality of morphine's effects were equivalent to drugfree conditions. Cocaine levels in plasma 5 minutes after intravenous cocaine injection were equivalent before and during buprenorphine treatment and averaged 282.8 +/- 43.6 and 295.2 +/- 28.8 ng/ml during 4 and 8 mg/day of buprenorphine maintenance, respectively. All patients accurately identified cocaine before and during buprenorphine maintenance, and there were no significant changes in latency to detection and certainty of a drug effect or reports of cocaine-induced intensity or euphoria during buprenorphine treatment. The concordance between responses to morphine and cocaine during inpatient buprenorphine maintenance and drug use during the first 4 weeks of outpatient buprenorphine treatment was also examined in 16 men. The effects of buprenorphine on individual responses to an acute intravenous dose of morphine or cocaine during the inpatient study did not reliably predict the frequency of heroin or cocaine self-administration during the first 4 weeks of daily outpatient buprenorphine maintenance.

Administration, Sublingual↗

PubMed1993

Naltrexone-buprenorphine interactions: effects on cocaine self-administration.

An opioid mixed agonist-antagonist analgesic, buprenorphine, significantly reduces cocaine self-administration by rhesus monkeys, but the relative contribution of buprenorphine's agonist and antagonist properties to this effect is unclear. This study examined the effects of concurrent treatment with naltrexone, a long-acting mu opioid antagonist, on buprenorphine's effects on cocaine and food self-administration by five rhesus monkeys. Cocaine (0.5 mg/kg per injection) and food self-administration (1 gm banana pellet) were maintained on a second order fixed ratio 4 (FR4) variable ratio (VR) 16:S schedule of reinforcement. Buprenorphine treatment alone (0.40 mg/kg/day) and in combination with ascending doses of naltrexone (0.05, 0.10, 0.20, and 0.40 mg/kg/day) was compared with naltrexone alone (0.40 mg/kg/day) and saline control treatment. Naltrexone was administered simultaneously or 20 minutes before buprenorphine administration. Each treatment condition was in effect for 10 days. Buprenorphine alone significantly reduced cocaine self-administration by an average of 53% in comparison to the saline treatment baseline (p < .01). When saline was substituted for buprenorphine, each monkey rapidly returned to its prebuprenorphine level of cocaine self-administration. Food self-administration in all conditions was equivalent to or significantly higher (p < .05) than food-maintained responding during the saline baseline. When buprenorphine and naltrexone were administered simultaneously, naltrexone significantly attenuated buprenorphine's suppressive effects on cocaine self-administration (p < .05 to .01). When naltrexone was administered 20 minutes before buprenorphine, there was a significant naltrexone dose-dependent (p < .01) decrease in buprenorphine's reduction of cocaine self-administration in comparison to the initial saline baseline. These data suggest that naltrexone antagonizes the partial mu agonist component of buprenorphine, which may be important for buprenorphine's effects on cocaine self-administration. Moreover, the addition of an opioid antagonist to reduce illicit diversion of buprenorphine might also compromise its effectiveness for treatment of dual dependence on cocaine and opiates.

Animals↗

PubMed1993

The effects of nalbuphine and butorphanol treatment on cocaine and food self-administration by rhesus monkeys.

This study was designed to determine whether opioid mixed agonist-antagonist analgesics other than buprenorphine also selectively reduce cocaine self-administration by rhesus monkeys. The effects of daily treatment with nalbuphine (0.1 to 3 mg/kg/day) or (0.254 to 7.62 mumol/kg/day), butorphanol (0.01 to 0.3 mg/kg/day) or (0.0209 to 0.628 mumol/kg/day), and saline on cocaine and food self-administration were each studied for 40 sessions over 10 consecutive days. Cocaine (0.05 or 0.10 mg/kg/inj) and food (1-gm banana pellets) self-administration were maintained on a fixed ratio 4 (variable ratio 16:S) schedule of reinforcement. Both nalbuphine and butorphanol reduced cocaine self-administration (p < 0.0001) but this effect was not selective since food self-administration also decreased in a dose-dependent manner (p < 0.0001). Nalbuphine administration (1 to 3 mg/kg/day) decreased cocaine injections to 40% to 60% below baseline (p < 0.01) and food pellets 30% to 68% below baseline (p < 0.01). Lower doses of nalbuphine (0.10 and 0.30 mg/kg) did not change cocaine- or food-maintained responding significantly. All doses of butorphanol (0.01 to 0.3 mg/kg/day) reduced cocaine injections to 16% to 58% below baseline (p < 0.01). Food self-administration decreased to 21% to 70% below baseline (p < 0.01) at butorphanol doses of 0.03 to 0.3 mg/kg/day). These data suggest that these opioid mixed agonist-antagonist analgesics may not be useful as pharmacotherapies for the treatment of cocaine abuse.

Analysis of Variance↗

PubMed1993

Pituitary volume in men with concurrent heroin and cocaine dependence.

Pituitary gland volume was measured in 16 men between the ages of 26-33 with magnetic resonance imaging. Eight male patients had a Diagnostic and Statistical Manual III-Revised, American Psychiatric Association Axis I diagnosis of concurrent opioid and cocaine dependence. The average duration of opioid and cocaine abuse was 7.8 +/- 2.0 and 6.9 +/- 1.4 yr, respectively. All patients were in good physical health as determined by physical examination, blood chemistry, hemogram and hormone analysis, and all tested negatively for the HIV antibody. No patient had any other Diagnostic and Statistical Manual III-Revised Axis I diagnosis or neurological disorder. Eight healthy males served as age-matched control subjects. None of the control subjects had any past or current history of substance abuse or any clinical indication for magnetic resonance imaging. Opioid and cocaine dependent men had significantly larger pituitary gland volumes (730.0 +/- 24.4 mm3) than control subjects (540.0 +/- 26.6 mm3) (P < 0.01). The significant increase in pituitary gland volume in men who abuse opiates and cocaine may be antecedent to detection of abnormal anterior pituitary hormone function.

Adult↗

PubMed1993

Acute effects of cocaine on anterior pituitary hormones in male and female rhesus monkeys.

The effects of acute cocaine administration (0.4 or 0.8 mg/kg) on anterior pituitary hormones were studied in four male and six female adult rhesus monkeys during the midluteal phase of the menstrual cycle (days 20-23). Progesterone levels averaged 15.7 +/- 3 and 10.6 +/- 2.8 ng/ml before low and high dose cocaine administration. Integrated plasma samples were collected every 10 min for 40 min before i.v. administration of cocaine, and 11 postcocaine samples were collected over 110 min. Cocaine (0.8 mg/kg) stimulated a significant increase in luteinizing hormone (LH) within 10 to 20 min (P < .01) and LH reached peak levels (59-60% above base line) within 30 min after cocaine administration in both males and females. Plasma cocaine levels averaged 289 +/- 23 and 346 +/- 73 ng/ml at 10 min after i.v. cocaine (0.8 mg/kg) administration in males and females, respectively. Follicle stimulating hormone levels were unchanged in midluteal females. Male testosterone increased by 50% above average base-line levels 50 min after the LH peak (80 min postcocaine). These data are consistent with our previous findings that cocaine increased LH and enhanced luteinizing hormone-releasing hormone-stimulated LH in early follicular females. The low dose of cocaine did not change basal levels of LH and follicle stimulating hormone in midluteal females and both LH and testosterone were unaffected in males. Cocaine plasma levels averaged 97.6 +/- 29 and 68.3 +/- 9.1 ng/ml at 10 min after 0.4 mg/kg of cocaine in males and females, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗