Biomedical subjects

N K Mello

Publications and source records attributed to N K Mello.

At least 37 records · Page 2Linked to original sources

PubMed1999

Cocaine pharmacokinetics in men and in women during the follicular and luteal phases of the menstrual cycle.

Preclinical and clinical studies suggest that females may be less vulnerable to cocaine's toxic effects than males. The pharmacokinetics of intravenous cocaine (0.2 and 0.4 mg/kg) were measured in 12 men and 22 women with a history of cocaine abuse, matched with respect to age and body mass index (BMI). Women were studied during the follicular and the luteal phases of the menstrual cycle. There were no differences between men and women in pharmacokinetic measures [peak plasma cocaine levels (Cmax), elimination half-life (T 1/2 min), area under the curve (AUC)] or cardiovascular or subjective effects "high" measures. Heart rate increases were cocaine dose-related (p < .01-.02) and also did not differ between men and women. Cocaine's pharmacokinetic and pharmacodynamic effects were similar in men and women, and in women during the follicular and mid-luteal phases of the menstrual cycle.

Adult↗

PubMed1999

Effects of flupenthixol and quadazocine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys.

The simultaneous i.v. administration of heroin and cocaine, called "speedball," is often reported clinically, and identification of effective pharmacotherapies for polydrug abuse is a continuing challenge. This study compared the effects of treatment using combinations of dopamine and opioid antagonists with each antagonist alone on speedball self-administration by rhesus monkeys. Speedballs (0.01 mg/kg/inj cocaine and 0.0032 mg/kg/inj heroin) and food (1 g banana pellets) were available in four daily sessions on a second-order schedule of reinforcement [FR4 (VR16:S)]. Monkeys were treated for 10 days with saline or ascending 1:10 dose combinations of the dopamine antagonist flupenthixol and the opioid antagonist quadazocine. The combination of flupenthixol (0.018 mg/kg/day) + quadazocine (0.18 mg/kg/day) significantly reduced speedball self-administration in comparison to the saline treatment baseline (p < .05), whereas, the same doses of each antagonist alone had no significant effect on speedball-maintained responding. Treatment with 0.018 mg/kg/day flupenthixol + 0.18 mg/kg/day quadazocine produced a 3-fold rightward shift in the speedball (3:1 cocaine-heroin combination) dose-effect curve. Food-maintained responding was similar during treatment with saline and with flupenthixol + quadazocine combinations. These findings suggest that medication mixtures designed to target both the stimulant and opioid component of the speedball combination, may be an effective approach to polydrug abuse treatment.

Animals↗

PubMed1999

Effects of kappa opioid agonists on the discriminative stimulus effects of cocaine in rhesus monkeys.

This study examined the effects of the kappa opioid agonists U50,488 and ethylketocyclazocine (EKC) on cocaine discrimination in rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline. Administration of U50,488 and EKC alone produced primarily saline-appropriate responding. Kappa agonist pretreatments produced variable effects on cocaine discrimination across monkeys, attenuating the discriminative stimulus effects of cocaine in some monkeys, but either having no effect on cocaine discrimination or enhancing the discriminative stimulus effects of cocaine in other monkeys. The effects of kappa agonists on cocaine discrimination were reversed by pretreatment with the opioid antagonist naloxone (1.0 mg/kg). These results indicate that kappa agonists do not consistently block the discriminative stimulus effects of cocaine in rhesus monkeys.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Effects of luteinizing hormone-releasing hormone on plasma cocaine levels in rhesus monkeys.

No effective pharmacotherapy for the treatment of cocaine abuse is currently available. In addition to pharmacological approaches, immunologic methods that use specific antibodies to bind cocaine in blood and prevent it from reaching the central nervous system are also being evaluated. There is considerable evidence that cocaine binds to the dopamine transporter, and there are structural similarities between the dopamine transporter and an anterior pituitary hormone, luteinizing hormone (LH). These structural similarities led us to hypothesize that LH may bind cocaine and decrease plasma levels of free cocaine. Synthetic LH-releasing hormone (LHRH) was used to stimulate LH release from pituitary gonadotropes before i.v. cocaine administration to male and female rhesus monkeys. The effects of placebo-LHRH and 15 and 30 micrograms/kg LHRH on levels of free cocaine in plasma after i.v. administration of 0.8 mg/kg cocaine were studied. LHRH (15 and 30 micrograms/kg) significantly increased LH secretion in both males (P <.01-.001) and females (P <.01-.05). Peak plasma cocaine levels were significantly lower after both doses of LHRH than after placebo-LHRH in males and in females (P <.05). There was an inverse relationship between peak plasma cocaine levels and LHRH-stimulated LH levels in males (P <. 01) but not in females. Pharmacokinetic analyses showed that the time to reach peak plasma cocaine levels, the elimination half-life, and the area under the plasma cocaine curve did not differ as a function of the LHRH dose compared with placebo LHRH. Moreover, there were no gender differences in any cocaine-related, pharmacokinetic parameter after placebo-LHRH administration. These data suggest the feasibility of reducing peak levels of free cocaine in plasma by stimulating secretion of LH. The functional consequences and underlying mechanisms of LHRH-induced decreases in peak plasma cocaine levels remain to be determined.

Animals↗

PubMed1999

Opioid antinociception in ovariectomized monkeys: comparison with antinociception in males and effects of estradiol replacement.

Baseline nociception and opioid antinociception were compared in male and ovariectomized female rhesus monkeys. Females were studied without estradiol replacement or during treatment with estradiol benzoate at doses (0.002 and 0.01 mg/kg/day) designed to mimic 17beta-estradiol blood levels observed during different phases of the menstrual cycle and during pregnancy. Baseline sensitivity to thermal stimuli (42-54 degrees C) was similar in male and ovariectomized female monkeys. The antinociceptive effects of the mu-opioid agonists fentanyl, morphine, butorphanol, and nalbuphine were examined at 50 and 54 degrees C. There were no sex-related differences in the antinociceptive effects of the high-efficacy mu agonist fentanyl; however, the lower-efficacy mu agonists morphine, butorphanol, and nalbuphine produced greater antinociceptive effects in males than in untreated ovariectomized females. Because butorphanol and nalbuphine have low selectivity for mu versus kappa receptors and may produce kappa-agonist effects under some conditions, the high-efficacy, kappa-selective agonist U50,488 was also studied. U50,488 also produced greater antinociceptive effects in males. Treatment with estradiol benzoate tended to enhance opioid antinociception in the ovariectomized females; however, this effect was significant only for butorphanol and U50,488 during treatment with the highest dose of estradiol benzoate. These findings suggest that opioid agonists usually produce greater antinociception in male monkeys than in females, and the magnitude of these sex-related differences may be inversely related to efficacy at mu receptors or selectivity for mu versus kappa receptors. Estradiol appears to have little effect on mu-agonist antinociception in primates but may enhance the antinociceptive effects of kappa agonists.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1999

Discriminative stimulus effects of the nonpeptidic delta-opioid agonist SNC80 in rhesus monkeys.

Five rhesus monkeys were trained to discriminate the nonpeptidic, delta-opioid agonist SNC80 (0.32 mg/kg i.m.) from saline by using a food-reinforced drug-discrimination procedure. Cumulative doses of SNC80 produced a dose-dependent increase in SNC80-appropriate responding and a dose-dependent decrease in response rate. In time-course studies, peak effects of the training dose of SNC80 were observed after 15 min, and these effects diminished over 240 min. In substitution studies, other piperazinyl benzamide delta agonists (SNC86, SNC162, and SNC243A) substituted for SNC80 with relative potencies similar those of SNC80. However, SNC67, the (-)-enantiomer of SNC80, did not occasion SNC80-appropriate responding up to a dose (32.0 mg/kg) that produced convulsions in one monkey. The mu agonists morphine and fentanyl and the kappa agonists U-50,488 and enadoline failed to substitute for SNC80 up to doses that eliminated responding. Two nonopioids (the N-methyl-D-aspartate antagonist ketamine and the monoamine reuptake inhibitor cocaine) also produced primarily saline-appropriate responding. Both the discriminative stimulus and rate-decreasing effects of SNC80 were antagonized by the delta-selective antagonist naltrindole (0.01-1.0 mg/kg) but not by doses of the opioid antagonist quadazocine (0.1-1.0 mg/kg) that block the effects of mu and kappa agonists. These data suggest that the discriminative stimulus effects of SNC80 are mediated by delta-opioid receptors and that the discriminative stimulus effects of delta opioids in primates can be differentiated from the effects of other opioid and nonopioid compounds.

Analgesics, Opioid↗

PubMed1999

Effects of the long-acting monoamine reuptake inhibitor indatraline on cocaine self-administration in rhesus monkeys.

Cocaine is a nonselective monoamine reuptake inhibitor that is widely abused. Useful pharmacotherapies for cocaine dependence may include substitution medications that produce cocaine-like effects but have a slower onset and longer duration of action. Accordingly, the present study examined the effects of the long-acting, nonselective monoamine reuptake inhibitor indatraline in assays of cocaine discrimination and cocaine self-administration that have been used to evaluate other candidate treatment medications. In rhesus monkeys trained to discriminate cocaine (0.4 mg/kg) from saline, indatraline (0.1-1.0 mg/kg) produced a dose- and time-dependent substitution for cocaine. The effects of 1.0 mg/kg indatraline peaked after 30 min and lasted up to 24 h. In monkeys trained to self-administer 0.032 mg/kg/injection cocaine and food pellets during alternating daily sessions of cocaine and food availability, indatraline (0.0032-0.032 mg/kg/injection) maintained lower rates of responding than cocaine. Repeated treatments with indatraline (0.1-0.56 mg/kg/day) for 7 days produced dose-dependent and sustained decreases in cocaine self-administration across a broad range of cocaine doses (0.0032-0.1 mg/kg/injection), and the highest dose of indatraline (0.56 mg/kg/day) nearly eliminated cocaine-maintained responding. However, doses of indatraline that decreased cocaine self-administration also usually decreased rates of food-maintained responding and produced behavioral stereotypies and trends toward weight loss and mild anemia. These findings suggest that although indatraline may decrease cocaine-taking behavior in rhesus monkeys, it also produces undesirable side effects that may limit its clinical utility in the treatment of cocaine dependence.

Animals↗

PubMed1999

Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine.

The reinforcing effects of D(1-like) and D(2-like) agonists, and their capacity to modify cocaine self-administration, were compared in rats with extensive cocaine self-administration experience. Cocaine (0.01-1.0 mg i.v.) dose-dependently maintained responding under a fixed ratio (FR) 5 schedule of reinforcement, and an inverted U-shaped function characterized the relationship between unit dose and self-administration behavior. When substituted for cocaine, the D(1-like) agonists SKF 82958 (0.001-0.032 mg i.v.) and SKF 77434 (0.001-0.1 mg i.v.) did not maintain responding above levels observed during saline substitution. In contrast, the D(2-like) agonists quinelorane (0.001-0.1 mg i.v.) and 7-hydroxy-dipropylaminotetralin (7-OH-DPAT; 0.01-0.32 mg i.v.) reliably maintained i.v. self-administration behavior that was characterized by inverted U-shaped dose-effect functions. Pretreatment with the D(1-like) agonists SKF 82958 and SKF 77434 (0.1-1.0 mg/kg i.p.) shifted the dose-effect function for cocaine self-administration downward, whereas pretreatment with the D(2-like) agonists quinelorane (0.01 mg/kg i.p.) and 7-OH-DPAT (0.32-1.0 mg/kg i.p.) shifted the cocaine dose-effect function to the left. Effects of D(1-like) and D(2-like) agonists on patterns of responding maintained by cocaine (0.32 mg i.v.) also differed: D(1-like) agonists increased the latency to the first response but did not otherwise alter patterns of cocaine self-administration, whereas D(2-like) agonists increased the intervals between self-administered cocaine injections. The results suggest that D(2-like) agonists, but not D(1-like) agonists, have prominent reinforcing effects and enhance the effects of self-administered cocaine in rats with extensive cocaine self-administration experience. Consequently, D(2) receptor-related neuronal mechanisms may be especially important in mediating the abuse-related effects of cocaine.

Animals↗

PubMed1998

Reduction in BOLD fMRI response to primary visual stimulation following alcohol ingestion.

The physiology of alcohol's effects on brain function is poorly understood. Emission tomographic imaging has revealed both acute and chronic alterations in resting cerebral hemodynamics and metabolism following alcohol ingestion. However, cerebral functional integrity under these conditions has received less attention. Functional magnetic resonance imaging (fMRI) offers a non-invasive method for assessing brain functional activation. In order to assess its utility for studying the effect of alcohol on brain function, we performed fMRI with photic stimulation before and after administration of either 0.7 mg/kg alcohol (N = 12) or placebo (N = 5), resulting in peak breath alcohol levels averaging 0.069 g/dl. We found that the amplitude of visual cortical activation in response to photic stimulation was significantly reduced by approximately 33% following alcohol administration (4.0 +/- 1.7% vs. 2.7 +/- 1.3%, P = 0.02), but not following placebo (4.2 +/- 1.5% vs. 4.1 +/- 1.4%, P = 0.7). The results also suggest that the baseline right hemispheric predominance of activation in response to photic stimulation may be reduced following alcohol, suggesting a greater effect on the right hemisphere, consistent with previous studies and alcohol's known effects on visuospatial processing. In addition, through the course of each activation session, there was a progressive reduction in response following alcohol. These data demonstrate that the cerebral effects of alcohol intoxication can be studied with fMRI, and that the effects on brain function of even moderate alcohol intoxication may be widespread, may be lateralized, and may include the visual system.

Adult↗

PubMed1998

Antinociceptive effects of monoamine reuptake inhibitors administered alone or in combination with mu opioid agonists in rhesus monkeys.

Cocaine, which non-selectively blocks the reuptake of the monoamines serotonin, dopamine and norepinephrine, produces weak antinociceptive effects and increases the antinociceptive effects of low- to intermediate-efficacy mu opioid agonists in rhesus monkeys. In the present study, the antinociceptive effects of more selective monoamine reuptake inhibitors administered alone and in combination with mu opioid agonists were evaluated in rhesus monkeys using a warm-water tail-withdrawal assay of thermal nociception. Like cocaine, the selective serotonin reuptake inhibitors clomipramine (0.01-3.2 mg/kg) and fluoxetine (0.1-10 mg/kg) produced weak antinociceptive effects. Pretreatment with the serotonin receptor antagonist mianserin (0.032-0.32 mg/kg) produced rightward and downward shifts in the clomipramine dose-effect curve, suggesting that the effects of clomipramine were mediated by serotonin receptors. Combination of clomipramine with the low efficacy mu agonist nalbuphine or the intermediate efficacy mu agonist morphine produced more antinociception than did the mu agonists alone. Fluoxetine also produced a small leftward shift in the morphine dose-effect curve. The selective norepinephrine reuptake inhibitors nisoxetine (0.1-10 mg/kg) and tomoxetine (0.1-10 mg/kg) and the selective dopamine reuptake inhibitors bupropion (0.032-3.2 mg/kg) and GBR 12909 (0.1-10 mg/kg) did not produce antinociception or increase antinociception induced by nalbuphine or morphine. In fact, GBR 12909 produced dose-dependent allodynia and reduced the maximal antinociceptive effects of morphine. These results suggest that inhibition of serotonin reuptake is sufficient to produce weak antinociceptive effects and enhance the antinociceptive effects of low efficacy mu opioid agonists. These results also suggest that the effects of cocaine on serotonin reuptake may contribute to cocaine's antinociceptive effects in rhesus monkeys.

Analgesics, Opioid↗

PubMed1998

Effects of heroin/cocaine combinations in rats trained to discriminate heroin or cocaine from saline.

The effects of heroin and cocaine administered alone or in combination were examined in rats trained to discriminate either heroin (0.56 mg/kg i.p.; n = 6) or cocaine (5.6 mg/kg i.p.; n = 6) from saline. Heroin (0.032-1.8 mg/kg) substituted completely for the heroin training stimulus in all six heroin-trained rats, but failed to substitute for cocaine in any of the cocaine-trained rats. Cocaine (0.1-32 mg/kg) substituted completely for the cocaine training stimulus in all six cocaine-trained rats, and substituted for heroin in two of six heroin-trained rats. The opioid antagonist naltrexone (0.01-1.0 mg/kg) antagonized the discriminative stimulus effects of heroin, but naltrexone at doses up to 10 mg/kg had no effect on the discriminative stimulus effects of cocaine. The dopamine receptor antagonist flupenthixol (0.032-0.56 mg/kg) attenuated the discriminative stimulus effects of heroin and completely blocked the discriminative stimulus effects of cocaine. When heroin-cocaine combinations were administered to the heroin-trained rats, cocaine (1-5.6 mg/kg) did not significantly alter the mean heroin dose-effect curve. Similarly, in the cocaine-trained rats, heroin (0.1-0.56 mg/kg) did not significantly alter the mean cocaine dose-effect curve. These results suggest that combinations of heroin and cocaine usually produce discriminative stimulus effects similar to either heroin or cocaine alone.

Animals↗

PubMed1998

Cocaine tolerance: behavioral, cardiovascular, and neuroendocrine function in men.

Cocaine tolerance was assessed by comparing the acute effects of cocaine in drug-abstinent men who reported occasional cocaine use (n = 6) and in men who met DSM-III-R diagnostic criteria for dependence on both cocaine and opiates (n = 6). Peak plasma cocaine levels were equivalent in the two groups, and pharmacokinetic analyses revealed no significant differences in cocaine levels at any time. Cocaine induced a significantly greater increase in ACTH in the occasional cocaine users than in the cocaine dependent men (p < .01). Heart rate and systolic and diastolic blood pressure increases after cocaine were also significantly greater in the occasional cocaine users than in the cocaine-dependent men (p < .05). These neuroendocrine and physiologic differences were paralleled by significantly greater subjective reports of "high" and "euphoria" by the occasional cocaine users (p < .03 to .0001). These data are consistent with the conclusion that tolerance to cocaine's physiologic, neuroendocrine, and subjective effects may occur as a function of chronic use.

Adrenocorticotropic Hormone↗

PubMed1998

Effects of mu opioid agonists alone and in combination with cocaine and D-amphetamine in rhesus monkeys trained to discriminate cocaine.

Psychomotor stimulants and mu opioid agonists are often used together by polydrug abusers, and it has been suggested that this form of polydrug abuse may result from the ability of stimulants and mu agonists to enhance each other's abuse-related effects. To investigate this possibility, the present study examined stimulant-opioid interactions in rhesus monkeys trained to discriminate cocaine. Specifically, the effects of the mu opioid agonists heroin, alfentanil, fentanyl, and morphine administered alone or in combination with cocaine or d-amphetamine were examined in five monkeys trained to discriminate 0.4 mg/kg cocaine (IM) from saline in a two-lever, food-reinforced drug discrimination procedure. When administered alone, the rapid onset mu agonists heroin (0.032-0.32 mg/kg) and alfentanil (0.01-0.1 mg/kg) substituted completely for cocaine in three of five monkeys but produced primarily saline-appropriate responding in the other two monkeys. The slower onset mu agonists fentanyl (0.0056-0.056 mg/kg) and morphine (0.56-10 mg/kg) substituted for cocaine in only one of five monkeys. When administered as pretreatments to cocaine, morphine and fentanyl increased levels of cocaine-appropriate responding produced by low doses of cocaine in some monkeys. Morphine pretreatment also increased levels of cocaine-appropriate responding produced by low doses of amphetamine in some monkeys. However, in other monkeys, morphine and fentanyl pretreatment did not alter the discriminative stimulus effects of cocaine or amphetamine. These results indicate that there are substantial individual difference in the effects of mu agonists in cocaine-discriminating rhesus monkeys. In some monkeys, mu agonists mimic or enhance the discriminative stimulus of cocaine, whereas in other monkeys, mu agonists neither mimic nor enhance the effects of stimulants.

Analgesics, Opioid↗

PubMed1998

Sex differences in blood-oxygenation-level-dependent functional MRI with primary visual stimulation.

OBJECTIVE: The authors evaluated the effect of sex on data derived from activation studies using blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (MRI). METHOD: Gradient echo-echo planar imaging was used to measure BOLD signal response in the primary visual cortex in response to binocular photic stimulation in 16 healthy, young subjects (eight women and eight men). RESULTS: BOLD signal response was 38% lower in women than in men, and much of the difference was lateralized to the right hemisphere. CONCLUSIONS: Lower BOLD signal response in women may reflect a sex difference in the brain's response to a primary visual stimulation or in the physiology underlying BOLD functional MRI signal changes.

Adult↗

PubMed1998

Concurrent pharmacokinetic analysis of plasma cocaine and adrenocorticotropic hormone in men.

The purpose of this study was to determine the covariance between plasma cocaine and ACTH pharmacokinetics. Twelve healthy male occasional cocaine users participated in a double blind study. Intravenous cocaine (0.2 mg/kg) or placebo was infused over 1 min, and samples for cocaine, ACTH and cortisol analysis were collected at 2, 4, 8, 12, 16, 20, 30, 40, 60, 80, 120, 180, and 240 min. Peak cocaine plasma levels averaged 101.2 +/- 14.6 ng/mL. ACTH increases were significantly correlated (P < 0.0001) with increases in plasma cocaine levels (r = 0.67; r2 = 0.44). Pharmacokinetic analysis showed that the t(max) (observed time to maximum concentration) values for cocaine (6.0 +/- 1.4 min) and ACTH (7.3 +/- 1.2 min) were almost identical. The area under the curve was calculated using the trapezoidal rule. The area under the curve for plasma cocaine was 6463 +/- 1070 ng/min x mL, and the area under the curve for ACTH was 1873 +/- 188 pmol/min x L. The mean half-life for plasma cocaine was 46.7 +/- 4.0 min, and that for ACTH was 35.8 +/- 5.1 min. Cardiovascular and subjective effect measures were correlated with concurrent increases in plasma cocaine and ACTH levels.

Adrenocorticotropic Hormone↗

PubMed1998

The effects of buprenorphine on self-administration of cocaine and heroin "speedball" combinations and heroin alone by rhesus monkeys.

Concurrent abuse of cocaine and opioids is frequently observed clinically, and we have developed a model of "speedball" self-administration involving the simultaneous injection of cocaine and heroin combinations in rhesus monkeys (Mello et al. (1995) J Pharmacol Exp Ther 274:1325). In the present study, we evaluated the effects of buprenorphine (0.0075-0.75 mg/kg/day i.v.) and saline on speedball combinations of cocaine [0.001, 0.01 or 0.10 mg/kg/inj] and heroin [0.0001-0.032 mg/kg/inj]. We also examined the effects of buprenorphine (0.075 and 0.237 mg/kg/day i.v.) on self-administration of heroin alone (0.0001-0.01 mg/kg/inj). Drug and food (1-g banana pellets) self-administration were maintained on a second-order FR4 (VR16:S) schedule in four 1-hr sessions each day. Each buprenorphine or saline control treatment was evaluated for 10 consecutive days, and monkeys returned to base-line performance between each treatment condition. Buprenorphine (0.075-0.75 mg/kg/day) selectively reduced self-administration of speedball combinations of low-dose cocaine (0.001 mg/kg/inj) and heroin (0.001 or 0.0032 mg/kg/inj) (P < .05-.01), and buprenorphine (0.237 mg/kg/day) shifted dose-effect curves for speedball combinations of cocaine (0.001 mg/kg/inj) and heroin (0.0001-0.032 mg/kg/inj) downward (P < .05-.01) and approximately 1 log unit to the right. Buprenorphine treatment was less effective in decreasing responding maintained by speedball combinations of heroin and 0.01 and 0.10 mg/kg/inj cocaine. Buprenorphine treatment (0.075 and 0.237 mg/kg/day) also shifted the heroin dose-effect curve downward (P < .01-.001) and to the right. Both speedball and heroin self-administration were associated with dose-dependent decreases in food-maintained responding during saline control treatment. However, food-maintained responding was often higher than control levels during buprenorphine treatment (P < .05-.001), which suggests that buprenorphine antagonized the rate-decreasing effects of speedballs and of heroin. Buprenorphine's selective reduction of speedball and heroin self-administration is consistent with clinical treatment trials in opioid abusers and polydrug abusers. Thus, these primate models of speedball and heroin self-administration should be useful for preclinical evaluation of novel drug abuse treatment medications.

Animals↗

PubMed1998

Discriminative stimulus effects of a cocaine/heroin "speedball" combination in rhesus monkeys.

Cocaine and heroin often are abused together in a combination known as a "speedball," but relatively little is known about ways in which cocaine and heroin may interact to modify each other's abuse-related effects. The present study evaluated the discriminative stimulus effects of a speedball combination of cocaine and heroin. Three rhesus monkeys were trained to discriminate vehicle from a 10:1 ratio of cocaine (0.4 mg/kg) in combination with heroin (0.04 mg/kg). Both cocaine alone and heroin alone substituted completely for the cocaine/heroin combination, although cocaine and heroin were more potent when administered together than when administered alone. Combined pretreatment with the dopamine antagonist flupenthixol and the opioid antagonist quadazocine dose-dependently antagonized the discriminative stimulus effects of the cocaine/heroin combination, but pretreatment with either antagonist alone was less effective. These findings suggest that either cocaine or heroin alone was sufficient to substitute for the cocaine/heroin training combination. To characterize the discriminative stimulus properties of this speedball more fully, a series of cocaine-like and heroin-like agonists were studied in substitution tests. The indirect dopamine agonists CFT, amphetamine and bupropion and the mu opioid agonists alfentanil, fentanyl and morphine produced high levels of speedball-appropriate responding. However, the indirect dopamine agonist GBR12909, the D1 dopamine agonist SKF82958, the D2 dopamine agonist quinpirole and the partial mu opioid agonist nalbuphine did not substitute for the cocaine/heroin combination. Because these compounds produce discriminative stimulus effects similar to either cocaine or mu opioid agonists alone, these findings suggest that the discriminative stimulus effects of the cocaine/heroin combination do not overlap completely with the effects of cocaine and heroin alone. Finally, a series of compounds that produce partial or no substitution for cocaine or mu agonists alone also did not substitute for the cocaine/heroin combination, which indicates that the discriminative stimulus effects of the combination were pharmacologically selective. Taken together, these findings suggest that a combination of cocaine and heroin produces a pharmacologically selective discriminative stimulus complex that includes aspects of both component drugs.

Animals↗

PubMed1998

Behavioral effects of the delta-selective opioid agonist SNC80 and related compounds in rhesus monkeys.

The behavioral effects of the nonpeptidic delta opioid agonist SNC80 and a series of related piperazinyl benzamides derived from the parent compound BW373U86 were evaluated in rhesus monkeys. SNC80 (0.1-10 mg/kg) decreased response rates maintained by food-reinforcement in a dose- and time-dependent manner, with maximal effects occurring within 10 min of intramuscular injection. The potency of SNC80 and five other piperazinyl benzamides in this assay of schedule-controlled responding correlated with their affinity at cloned human delta opioid receptors but not with their affinity for cloned human mu receptors. Moreover, the effects of SNC80 were selectively antagonized by the delta-selective antagonist naltrindole (1.0 mg/kg), but not by the mu selective antagonist quadazocine (0.1 mg/kg) or the kappa-selective antagonist norbinaltorphimine (3.2 mg/kg). These findings indicate that SNC80 functions as a systemically active, delta-selective agonist with a rapid onset of action in rhesus monkeys. The antinociceptive effects of SNC80 were examined in a warm-water tail-withdrawal assay of thermal nociception. SNC80 (0.1-10 mg/kg) produced weak but replicable antinociceptive effects that were antagonized by naltrindole (1.0 mg/kg). SNC80 antinociception was also dose-dependently antagonized by BW373U86 (0.56-1.0 mg/kg), which was inactive in this procedure. These findings suggest that SNC80 may have higher efficacy than BW373U86 at delta opioid receptors. Moreover, SNC80 at doses up to 32 mg/kg did not produce convulsions, which suggests that SNC80 may also be safer than BW373U86. The effects of SNC80 were also examined in monkeys trained to discriminate cocaine (0.4 mg/kg i.m.) or self-administer cocaine (0.032 mg/kg/injection,i.v.). In drug discrimination studies, SNC80 (0.1-10 mg/kg) produced a dose-dependent and naltrindole-reversible increase in cocaine-appropriate responding, and complete substitution for cocaine was observed in five of seven monkeys tested. However, SNC80 (1.0-100 micrograms/kg/injection) did not maintain responding in monkeys trained to self-administer cocaine. Thus, despite its ability to produce cocaine-like discriminative stimulus effects, SNC80 may have relatively low abuse potential.

Analgesics, Opioid↗