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ABSTRACT: Cocaine blocks uptake of the monoamines dopamine, serotonin and norepinephrine, and monoamine uptake inhibitors constitute one class of drugs under consideration as candidate "agonist" medications for the treatment of cocaine abuse and dependence. The pharmacological selectivity of monoamine uptake inhibitors to block uptake of dopamine, serotonin and norepinephrine is one factor that may influence the efficacy and/or safety of these compounds as drug abuse treatment medications. To address this issue, the present study compared the effects of 7-day treatment with a non-selective monoamine uptake inhibitor (RTI-112) and a dopamine-selective uptake inhibitor (RTI-113) on cocaine- and food-maintained responding in rhesus monkeys. Monkeys (N=3) were trained to respond for cocaine injections (0.01 mg/kg/inj) and food pellets under a second-order schedule [FR2(VR16:S)] during alternating daily components of cocaine and food availability. Both RTI-112 (0.0032-0.01 mg/kg/hr) and RTI-113 (0.01-0.056 mg/kg/h) produced dose-dependent, sustained and nearly complete elimination of cocaine self-administration. However, for both drugs, the potency to reduce cocaine self-administration was similar to the potency to reduce food-maintained responding. These findings do not support the hypothesis that pharmacological selectivity to block dopamine uptake is associated with behavioral selectivity to decrease cocaine- vs. food-maintained responding in rhesus monkeys.
Pharmacology Biochemistry and Behavior 09/2008; 91(3):333-8. · 2.53 Impact Factor
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ABSTRACT: Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin-selective [m-fluoroamphetamine (PAL-353), methamphetamine, m-methylamphetamine (PAL-314), 1-napthyl-2-aminopropane (PAL-287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine (0.4 mg/kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food (1-g pellets) under a second-order fixed-ratio 2 (variable-ratio 16:S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/norepinephrine-selective releasers decreased cocaine self-administration with minimal effects on food-maintained responding, whereas the more serotonin-selective releasers produced nonselective reductions in both cocaine- and food-maintained responding. These results are consistent with the conclusion that dopamine/norepinephrine-selective releasers retain cocaine-like abuse-related effects but may also be capable of producing relatively selective reductions in the reinforcing effects of cocaine.
Journal of Pharmacology and Experimental Therapeutics 03/2007; 320(2):627-36. · 3.83 Impact Factor
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N K Mello
NIDA research monograph 06/2005; 185:82-104.
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ABSTRACT: Buprenorphine is an opioid with high affinity for delta, mu and kappa opioid receptors. The delta receptor-mediated effects of buprenorphine have not been studied. Thus, the present study examined the delta receptor-mediated effects of buprenorphine in rhesus monkeys. assays of receptor binding and agonist-stimulated GTP S binding confirmed that buprenorphine had high affinity for, and low efficacy at, delta receptors. In an assay of schedule-controlled responding for food presentation in four monkeys, buprenorphine produced little effect alone, but it antagonized the effects of the delta agonist SNC80, the mu agonist morphine and the kappa agonist U50,488. Buprenorphine was approximately 30-fold less potent as a delta antagonist than as a mu or kappa antagonist. In three monkeys trained to discriminate SNC80 from saline, buprenorphine alone produced only saline-appropriate responding, and buprenorphine pretreatment antagonized the discriminative stimulus effects of SNC80. In a fourth monkey, buprenorphine produced a partial substitution for SNC80 that could be blocked by the delta-selective antagonist naltrindole but not by the mu-selective antagonist quadazocine. These results indicate that, in rhesus monkeys, buprenorphine has very low efficacy at delta receptors, and that buprenorphine produces delta receptor-mediated effects with lower potency than it produces mu or kappa receptor-mediated effects.
Behavioural Pharmacology 12/2002; 13(7):557-70. · 2.72 Impact Factor
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ABSTRACT: A series of new N-substituted derivatives of morphinan was synthesized and their binding affinity for the three opioid receptors (mu, delta, and kappa) was determined. A paradoxical effect of N-propargyl (MCL-117) and N-(3-iodoprop-(2E)-enyl) (MCL-118) substituents on the binding affinities for the mu and kappa opioid receptors was observed. All of these novel derivatives showed a preference for the mu and kappa versus delta binding.
Bioorganic & Medicinal Chemistry Letters 11/2001; 11(20):2735-40. · 2.55 Impact Factor
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ABSTRACT: The simultaneous intravenous (i.v.) administration of heroin and cocaine, called a "speedball," is often reported clinically, and identification of effective pharmacotherapies is a continuing challenge. We hypothesized that treatment with combinations of a dopamine reuptake inhibitor, indatraline, and a mu partial agonist, buprenorphine, might reduce speedball self-administration by rhesus monkeys more effectively than either drug alone. Speedballs (0.01 mg/kg/inj cocaine + 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 [fixed ratio (FR)4; variable ratio (VR)16:S]. Monkeys were treated for 10 days with saline or ascending dose combinations of indatraline (0.001-0.032 mg/kg/day) and buprenorphine (0.00032-0.01 mg/kg/day). Two combinations of indatraline (0.32 and 0.56 mg/kg/day) + buprenorphine (0.10 and 0.18 mg/kg/day) significantly reduced speedball self-administration in comparison to the saline treatment baseline (p <.01-.001), whereas the same doses of each compound alone had no significant effect on speedball-maintained responding. Daily treatment with 0.56 mg/kg/day indatraline + 0.18 mg/kg/day buprenorphine produced a significant downward shift in the speedball dose-effect curve (p <.01) and transient changes in food-maintained responding. 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.
Neuropsychopharmacology 07/2001; 25(1):104-17. · 7.99 Impact Factor
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ABSTRACT: The effects of SNC80 and other structurally related delta-opioid receptor agonists were assessed under conditions of chemically induced hypersensitivity to thermal stimuli in four rhesus monkeys. The shaved tail of each monkey was exposed to warm water (38, 42, 46, and 50 degrees C), and the tail-withdrawal latency from each temperature was recorded. The effects of drugs on the temperature that produced a 10-s tail-withdrawal latency (the T(10) value) were examined. Capsaicin (0.01-0.32 mg) injected into the tail of monkeys dose dependently decreased the T(10), indicating that capsaicin increased sensitivity to thermal stimuli. A dose of 0.1 mg of capsaicin decreased the T(10) from 48.0 to 42.1 degrees C (a -5.9 degrees C change) 15 min after injection. SNC80 (1.0-10.0 mg/kg s.c.) dose dependently blocked the capsaicin-induced decrease in the T(10), and 10.0 mg/kg SNC80 fully blocked the effects of capsaicin. The delta-selective antagonist naltrindole (0.1-1.0 mg/kg) dose dependently antagonized the effects of SNC80, whereas a mu-selective dose of the opioid antagonist quadazocine (0.1 mg/kg) did not. Two other delta-selective agonists, SNC162 (1.0-10.0 mg/kg) and SNC243A (1.0-10.0 mg/kg), also dose dependently blocked capsaicin-induced thermal hypersensitivity. In contrast, neither SNC67 (10.0 mg/kg), which is the (-)-enantiomer of SNC80, nor the nonsteroidal anti-inflammatory drug (NSAID) ketorolac (1.0-10.0 mg/kg) modified the effects of capsaicin. SNC80 was also effective in reversing thermal hypersensitivity induced by prostaglandin E(2) (0.0158 mg) and Freund's complete adjuvant (10% concentration). These findings suggest that delta-agonists have antinociceptive effects in primates under conditions of chemically induced thermal hypersensitivity and might be effective under a broader range of conditions than clinically available NSAIDs.
Journal of Pharmacology and Experimental Therapeutics 04/2001; 296(3):939-46. · 3.83 Impact Factor
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ABSTRACT: Cocaine stimulates luteinizing hormone (LH) release in rhesus monkeys and in men, but its effects on LH in women are unknown. Cocaine (0.2 and 0.4 mg/kg i.v.) was administered to groups of follicular and luteal phase women (N = 22) and to men (N = 12) to examine the influence of gender and menstrual cycle phase on cocaine and LH interactions. All subjects met American Psychiatric Association Diagnostic and Statistical Manual IV criteria for cocaine abuse, and menstrual cycle phase was verified by estradiol and progesterone measures. Baseline LH levels were equivalent between groups. Peak cocaine levels did not differ significantly between men and women and averaged between 87 +/- 21 and 124 +/- 18 ng/ml after 0.2 mg/kg cocaine and between 227 +/- 22 and 287 +/- 21 ng/ml after 0.4 mg/kg cocaine. The lower dose of cocaine (0.2 mg/kg) significantly increased LH levels in men (P < 0.001) but not in women at either phase of the menstrual cycle. The higher dose of cocaine (0.4 mg/kg) stimulated significant increases in LH in men (P < 0.001) and in women at both phases of the menstrual cycle (P < 0.004-0.001). Although cocaine's effects on LH in women were dose-dependent, there were no significant differences as a function of menstrual cycle phase. LH remained significantly elevated longer in men (32 min) than in women (8 and 12 min). This gender difference in cocaine's potency in stimulating LH was unexpected.
Journal of Pharmacology and Experimental Therapeutics 04/2001; 296(3):972-9. · 3.83 Impact Factor
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ABSTRACT: Dopaminergic systems thought to mediate the abuse-related effects of cocaine are under inhibitory control by GABAergic systems. These findings suggest that GABA agonists may attenuate some abuse-related effects of cocaine.
To assess the effects of GABA receptor agonists and GABA-A receptor modulators on cocaine discrimination in rhesus monkeys.
Rhesus monkeys were trained to discriminate 0.4 mg/kg cocaine from saline in a two-key, food-reinforced drug discrimination task. The effects of the GABA-A agonist muscimol, the GABA-B agonist baclofen, the barbiturate GABA-A receptor modulator pentobarbital, and the benzodiazepine GABA-A modulators triazolam and imidazenil were examined alone and as pretreatments to cocaine. For comparison, the effects of pentobarbital pretreatment on the cocaine-like discriminative stimulus effects of amphetamine were also examined.
When administered alone, the GABA agonists and GABA-A receptor modulators produced primarily saline-appropriate responding. When administered as pretreatments to cocaine, pentobarbital attenuated the discriminative stimulus effects of cocaine in all monkeys tested, and the high efficacy benzodiazepine agonist triazolam attenuated cocaine's effects in three of five monkeys. Muscimol, baclofen and the low efficacy benzodiazepine agonist imidazenil did not alter cocaine's discriminative stimulus effects. Although pentobarbital blocked the effects of the monoamine reuptake blocker cocaine, it did not alter the cocaine-like effects of the monoamine releaser amphetamine.
These results are consistent with the hypothesis that GABA-A receptor modulators attenuate the discriminative stimulus effects of cocaine in rhesus monkeys by decreasing the activity of dopaminergic systems. Direct GABA receptor agonists may be less effective in blocking the abuse-related effects of cocaine in rhesus monkeys.
Psychopharmacologia 12/2000; 152(4):398-407. · 4.08 Impact Factor
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ABSTRACT: Effects of D1-like and D2-like agonists were compared in rats (Rattus norvegicus) with differing levels of experience (24 or 9 mo) in a cocaine discrimination procedure (5.6 mg/kg cocaine; fixed-ratio 20 schedule of food presentation). Cocaine, d-amphetamine, and D2-like agonists (quinelorane, 7-OH-DPAT) dose-dependently substituted for cocaine in both groups of rats. In contrast, D1-like agonists (SKF 82958, SKF 77434) substituted for cocaine only in rats with less discrimination experience. Pretreatment with D2-like agonists increased the stimulus effects of low cocaine-doses in both groups, whereas D1-like agonists produced these effects only in rats with less discrimination experience. The data suggest that the stimulus effects of cocaine overlap with those of D2-like agonists across a broader range of conditions than with those of D1-like agonists. Thus, D2-like receptors may play an especially important role in cocaine's behavioral effects.
Experimental and Clinical Psychopharmacology 09/2000; 8(3):404-14. · 2.58 Impact Factor
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ABSTRACT: Cocaine stimulates gonadotropin (luteinizing hormone) release from the anterior pituitary in humans and in rhesus monkeys, but its acute effects on ovarian steroid hormones are unknown. The acute effects of cocaine and placebo on estradiol and progesterone were studied in 13 drug-naive female rhesus monkeys during the mid-follicular (days 8-10) and the mid-luteal (days 21-23) phases of the menstrual cycle. Each monkey was her own control under cocaine and placebo conditions. Samples for ovarian steroid hormone analysis were collected before and at 15-min intervals for 300 min after cocaine or placebo administration. In follicular phase females, estradiol levels increased significantly within 15 min after cocaine (0.8 mg/kg i.v.) administration (P <.008) but did not change after placebo administration. Estradiol remained significantly above baseline for 45 min (P <.002-0.02). In contrast, in mid-luteal phase females, estradiol did not change after cocaine or placebo administration. Basal progesterone levels did not change after cocaine or placebo administration in either mid-follicular or mid-luteal phase females. After hCG (500 I.U. i.m.) was administered to mid-luteal phase females, cocaine (0.4 and 0.8 mg/kg i.v.) and placebo administration did not increase or decrease estradiol or progesterone. One implication of these findings is that cocaine-induced increases in follicular phase estradiol levels could disrupt folliculogenesis and contribute to the menstrual cycle abnormalities observed during chronic cocaine self-administration.
Journal of Pharmacology and Experimental Therapeutics 09/2000; 294(3):1137-45. · 3.83 Impact Factor
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ABSTRACT: This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of kappa agonists related to the morphinan (-)-cyclorphan (3a) and the benzomorphan (-)-cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N-cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)-mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for mu, delta, and kappa opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the kappa receptor than for the mu receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the kappa receptor in comparison to the delta receptor, while cyclorphan (3a) had only 4-fold greater affinity for the kappa receptor in comparison to the delta receptor. These findings were confirmed in the antinociceptive tests (tail-flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the delta receptor while 3b did not produce agonist or antagonist effects at the delta receptor. Both 3a,b had comparable kappa agonist properties. 3a,b had opposing effects at the mu receptor: 3b was a mu agonist whereas 3a was a mu antagonist.
Journal of Medicinal Chemistry 02/2000; 43(1):114-22. · 5.25 Impact Factor
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ABSTRACT: The reinforcing effects of cocaine have been most compellingly related to its action as an indirect dopamine agonist. Although it is generally believed that both D(1-like )and D(2-like )receptor mechanisms may be involved, recent studies suggest that D(1-like )and D(2-like )agonists have differing profiles of cocaine-related actions.
To develop a procedure for rapid assessment of complete dose-effect functions for cocaine self-administration in rhesus monkeys and to compare the effects of D(1-like )and D(2-like )agonists on cocaine self-administration using this procedure.
Responding was maintained by various doses of cocaine or by food under a multiple-component schedule [fixed ratio (FR) 30; time out period (TO) 10 s] in 2-h sessions. After responding stabilized, the effects of pretreatment with D(1-like )and D(2-like )agonists (administered i.m., 10 min or 30 min prior to the session) were assessed.
Complete inverted U-shaped dose-effect functions for cocaine self-administration were obtained in all five rhesus monkeys trained with the rapid assessment procedure. Both the position and shape of the cocaine dose- effect function remained stable in repeated assessments, and levels of responding were controlled by the unit dose of cocaine rather than by other variables (e.g., infusion duration and volume) that were used to vary the cocaine dose. Pretreatment with the D(1-like) agonists SKF 82958 (0.32-1.8 mg/kg) and R-6-Br-APB (0.1-1. 0 mg/kg) produced downward shifts in the cocaine dose-effect function at doses that also markedly decreased food-maintained responding. In contrast, pretreatment with the D(2-like) agonists quinelorane (0.001-0.01 mg/kg) and 7-OH-DPAT (0.01-0.10 mg/kg) shifted the cocaine dose-effect function to the left. D(2-like) agonists also increased responding maintained by the cocaine-associated cue lights alone, and moderately decreased food-maintained responding.
The results suggest that D(1-like) and D(2-like) agonists produce qualitatively different effects on cocaine self-administration that may influence their usefulness for the treatment of cocaine abuse and dependence.
Psychopharmacologia 02/2000; 148(1):41-51. · 4.08 Impact Factor
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ABSTRACT: Kappa opioid agonists inhibit dopamine release from mesolimbic dopaminergic neurons and attenuate some behavioral effects of cocaine in rodents. Evidence that kappa opioid agonists may act as functional antagonists of cocaine led us to examine their interactions with cocaine's abuse-related effects in rhesus monkeys. In cocaine self-administration studies, four arylacetamides (U50,488, enadoline, (-) spiradoline and PD117302) and four benzomorphans (ethylketocyclazocine [EKC], bremazocine, Mr2033 and cyclazozine) each were administered as continuous infusions over 10 days. EKC, Mr2033, bremazocine, U50,488 and enadoline produced significant dose-dependent and sustained decreases in cocaine self-administration and also decreased food-maintained responding at some doses. Emesis and sedation were occasionally observed during the first two days of kappa agonist treatment, but tolerance developed rapidly to these effects. Cyclazocine, PD117302 and spiradoline did not significantly alter cocaine self-administration. The behavioral effects of EKC and U50,488 were antagonized by both the kappa opioid antagonist nor-binaltorphimine and the non-selective opioid antagonist naloxone. In general, compounds with mixed activity at both kappa and mu opioid receptors (e.g. EKC, Mr2033) decreased cocaine self-administration more consistently and with fewer or less severe undesirable side effects than more selective kappa agonists (e.g. U50,488, spiradoline). Although several kappa agonists decreased cocaine self-administration, EKC and U50,488 did not consistently block the discriminative stimulus effects of cocaine in monkeys trained to discriminate cocaine from saline. The extent to which kappa agonist-induced decreases in cocaine self-administration reflect an antagonism of cocaine's abuse-related effect remains to be determined.
Annals of the New York Academy of Sciences 02/2000; 909:104-32. · 3.15 Impact Factor
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ABSTRACT: 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.
Journal of Pharmacology and Experimental Therapeutics 11/1999; 291(1):60-9. · 3.83 Impact Factor
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ABSTRACT: 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.
Journal of Pharmacology and Experimental Therapeutics 11/1999; 291(1):353-60. · 3.83 Impact Factor
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ABSTRACT: 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.
Experimental and Clinical Psychopharmacology 11/1999; 7(4):307-17. · 2.58 Impact Factor
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ABSTRACT: 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.
Neuropsychopharmacology 10/1999; 21(4):575-88. · 7.99 Impact Factor
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ABSTRACT: 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.
Journal of Pharmacology and Experimental Therapeutics 10/1999; 290(3):1132-40. · 3.83 Impact Factor
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ABSTRACT: 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.
Journal of Pharmacology and Experimental Therapeutics 10/1999; 290(3):1157-64. · 3.83 Impact Factor
