Modulation of cocaine-induced sensitization by kappa-opioid receptor agonists. Role of the nucleus accumbens and medial prefrontal cortex.
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Animals↗
Biomedical subjects
T S Shippenberg
Publications and source records attributed to T S Shippenberg.
U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking.
RATIONALE: Previous research has shown that kappa-opioid receptor agonists decrease intravenous cocaine self-administration. These agents also block the development of sensitization that occurs following repeated exposure to cocaine, which is thought to be important in the maintenance and reinstatement of compulsive drug-seeking behavior. OBJECTIVES: This study was designed to determine the effects of the kappa-opioid receptor agonist, U69593, on the maintenance of cocaine self-administration and on the ability of a priming injection of cocaine to reinitiate drug-seeking. METHODS: During daily test sessions, the dose-effect curve (0.015-1.0 mg/kg per infusion) was obtained by either repeatedly reducing the cocaine dose from a starting dose of 1.0 mg/kg per infusion or by repeatedly doubling the cocaine dose from a starting dose of 0.015 mg/kg per infusion. The effect of U69593 (0.0 or 0.32 mg/kg) on responding reinforced by different cocaine doses was determined. The effect of U69593 on the reinstatement of extinguished cocaine-taking behavior was measured in other groups. RESULTS: U69593 decreased responding maintained by low doses of cocaine, regardless of whether cocaine doses were presented in an ascending or descending order. Responding maintained by high doses was unaffected. In animals which received pretreatment with U69593, the priming effects of cocaine were significantly attenuated. The effects of U69593 were specific, since amphetamine-induced cocaine-seeking was not altered by prior administration of U69593. CONCLUSIONS: These findings demonstrate that U69593 attenuates cocaine self-administration and the reinstatement of drug-taking behavior which occurs in response to experimenter-administered cocaine. It is suggested that U69593 may decrease low dose cocaine self-administration by decreasing the priming effects of cocaine.
Amphetamine↗
The use of microdialysis in the mouse: conventional versus quantitative techniques.
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Animals↗
Stress- and corticosteroid-induced modulation of the locomotor response to morphine in rats.
Stress alters the sensitivity to drugs of abuse and is, therefore, considered to be an important contributory factor to drug-seeking behaviour. There is only a limited amount of information available on stress-induced alterations in the behavioural response to opioids. We thus evaluated the influences of different stressors (restraint, handling, social defeat) on the locomotor effects induced by morphine. Further the importance of additional factors such as the number of stress events or the delay between stress and locomotor testing on stress-induced alterations were evaluated. Since these modulatory effects of stress on the locomotor effects of morphine might be mediated via the release of endogenous corticosteroids we also tested the influence of repeated intermittent and chronic administration of corticosterone (CORT) and the synthetic corticosteroid dexamethasone (DEX) on the locomotor response to morphine. Enhanced morphine-induced locomotor activity was observed in response to the repeated application (three times) of all stressors: restraint, handling and social defeat. An augmentation of the locomotor effects of a low (1 and 5 mg/kg) but not of a high dose (10 mg/kg) of morphine was seen after three, but not after one stress event. In addition, the repeated application of restraint stress (three times) resulted in an augmentation of morphine-induced locomotor stimulation 3 days, but not 1 or 10 days , after the last stress event. Similarly the repeated intermittent and chronic administration of corticosteroids, in particular of DEX, increased morphine's efficacy in stimulating locomotor activity. Our results show that stress is able to alter the locomotor stimulant effects of morphine in rats--a phenomenon called stress-induced behavioural sensitization. Moreover, these stress-induced alterations depend upon temporal factors such as number of stress events and the interval between stress and locomotor testing. Further, stress-induced CORT-release seems to be involved in stress-induced behavioural sensitization to morphine.
Adrenal Cortex Hormones↗
The kappa-opioid agonist, U-69593, decreases acute amphetamine-evoked behaviors and calcium-dependent dialysate levels of dopamine and glutamate in the ventral striatum.
The effects of a kappa-opioid receptor agonist on acute amphetamine-induced behavioral activation and dialysate levels of dopamine and glutamate in the ventral striatum were investigated. Amphetamine (2.5 mg/kg i.p.) evoked a substantial increase in rearing, sniffing, and hole-poking behavior as well as dopamine and glutamate levels in the ventral striatum of awake rats. U-69593 (0.32 mg/kg s.c.) significantly decreased the amphetamine-evoked increase in behavior and dopamine and glutamate levels in the ventral striatum. Reverse dialysis of the selective kappa-opioid receptor antagonist, nor-binaltorphimine, into the ventral striatum antagonized the effects of U-69593 on amphetamine-induced behavior and dopamine and glutamate levels. Reverse dialysis of low calcium (0.1 mM) into the ventral striatum decreased basal dopamine, but not glutamate, dialysate levels by 91% 45 min after initiation of perfusion. Strikingly, 0.1 mM calcium perfusion significantly reduced the 2.5 mg/kg amphetamine-evoked increase in dopamine and glutamate levels in the ventral striatum, distinguishing a calcium-dependent and a calcium-independent component of release. U-69593 did not alter the calcium-independent component of amphetamine-evoked dopamine and glutamate levels. These data are consistent with the view that a transsynaptic mechanism augments the increase in dopamine and glutamate levels in the ventral striatum evoked by a moderately high dose of amphetamine and that stimulation of kappa-opioid receptors suppresses the calcium-dependent component of amphetamine's effects.
Amphetamine↗
Infusion of a D-1 receptor agonist into the nucleus accumbens enhances cocaine-induced behavioural sensitization.
The present study was designed to evaluate the effect of dopamine (DA) D-1 receptor activation in the nucleus accumbens (NAC) on the locomotor sensitizing effects of repeated intra-accumbens (intra-NAC) infusions of cocaine. Repeated infusion of cocaine (10 microg/0.5 microl daily for 2 days) resulted in an enhanced locomotor response to a subsequent intra-NAC and systemic (i.p.) challenging dose of the psychostimulant. Pretreatment with the selective D-1 agonist SK&F82958 (1.0 microg) markedly enhanced the sensitizing effects of both intra-NAC and systemic cocaine. The effect of SK&F82958 was completely blocked by systemic administration of the D-1 antagonist SCH23390 (0.1 mg/kg, i.p.). These data give further support to the idea that activation of D-1 receptors plays an important role in the induction of locomotor sensitization and show that the NAC may, in fact, be an anatomical locus of initiation of behavioural sensitization.
Analysis of Variance↗
Phentermine and fenfluramine. Preclinical studies in animal models of cocaine addiction.
Combined dopamine (DA) and 5-hydroxytryptamine (5-HT) releases such as phentermine (PHEN) and fenfluramine (FEN) are reported, in open label studies, to reduce craving for alcohol and cocaine and to prevent relapse. The objective of the studies reported here was to assess the actions of these agents alone and in combination in various animal models of drug addiction. Study 1. In vivo microdialysis experiments demonstrate that these agents preferentially release mesolimbic DA (PHEN) and 5-HT (FEN). Patients who relapse and use cocaine while taking these medications report diminished cocaine-like subjective effects. Microdialysis experiments were performed in awake rats, and dialysate samples were analyzed for DA and 5-HT. PHEN (1 mg/kg, intravenously (i.v.)) elevated DA (2-3-fold) for over 1.5 hr. Administration of cocaine (3 mg/kg, i.v.) increased DA 6-fold in saline-treated rats, but only 3-fold in PHEN-treated rats. PHEN did not reduce cocaine-induced increases in 5-HT. Study 2. These agents were assessed in a mouse model of cocaine-conditioned motoric activity (CCMA). Pretreatment with non-activating doses of PHEN (4.6 mg/kg, intraperitoneally (i.p.)) enhanced CCMA, whereas non-depressing doses of FEN (0.1 mg/kg, i.p.) did not alter CCMA or the PHEN-induced increase in CCMA. In contrast, sub-effective doses of FEN reduced CCMA stereotypy-like locomotion, whereas sub-effective doses of PHEN were without effect. PHEN reversed the FEN-induced increase in CCMA stereotypy-like locomotion. Study 3. PHEN and FEN were assessed in the conditional place preference model. FEN produced marked aversions for an environment previously associated with its administration and the minimum dose producing this effect was 3.0 mg/kg. In contrast, administration of PHEN, amphetamine (1.0-3.0 mg/kg) or morphine (3.0-5.0 mg/kg) produced dose-related preferences for the drug-paired place. However, the magnitude of the response to PHEN was less than that produced by the other prototypic drugs of abuse. In rats that received FEN (0.3 or 3.0 mg/kg) in combination with PHEN (3.0 mg/kg), the conditioned rewarding effects of PHEN were abolished. These data demonstrate that the rewarding effects of PHEN can be conditioned to stimuli previously associated with its administration. However, the conditioned response to this agent is less than that produced by prototypic drugs of abuse. The finding that PHEN-induced place preferences were attenuated by doses of FEN demonstrates that the combination of FEN/PHEN is devoid of motivational effects. The preclinical data obtained with PHEN/FEN in various models of drug provide a strong rationale for pursuing controlled clinical trials in humans with agents that act via a similar mechanism of action.
Animals↗
Sensitization to the conditioned rewarding effects of morphine and cocaine: differential effects of the kappa-opioid receptor agonist U69593.
The ability of the kappa-opioid receptor agonist U69593 to attenuate the sensitization and cross-sensitization which develops to the conditioned rewarding effects of morphine and cocaine was examined using an unbiased place-preference conditioning procedure. The influence of U69593 treatment upon sensitization and cross-sensitization to cocaine was also assessed. Doses of morphine (1.0-5.0 mg kg(-1)) which failed to produce a conditioned response in drug-naive rats produced marked preferences for the drug-paired place in animals which had previously received once daily injections of morphine (5.0 mg kg(-1); s.c.) or cocaine (10.0 mg kg(-1); i.p.) for 5 days. Morphine-induced place preferences also occurred in animals which had received morphine in combination with U69593 (0.04-0.32 mg kg(-1); s.c.) on either days 3-5 or 1-5 of the morphine treatment regimen. In contrast, morphine failed to produce significant conditioning in animals which had received U69593 with cocaine for 5 days. Doses of cocaine (1.0-5.0 mg kg(-1)) which did not produce a conditioned response in naive rats produced preferences for the drug-paired place in animals which had received once daily injections of cocaine (10.0 mg kg(-1) day(-1) x 5 days; i.p.) or morphine (5.0 mg kg(-1) day(-1) x 5 days; s.c.). No enhancement of cocaine-induced conditioning occurred in animals which had received U69593 on days 3-5 or on days 1-5 of the five-day cocaine treatment. In animals, however, which had received U69593 with morphine for 5 days, an enhanced response to cocaine was still seen. These findings confirm that sensitization and cross-sensitization develop to the conditioned rewarding effects of cocaine and morphine. They also indicate that the ability of a kappa-opioid receptor agonist to prevent the development of these sensitized responses depends on the sensitizing agent employed. U69593 prevents sensitization and cross-sensitization induced by cocaine, but does not modify morphine-induced sensitization or the cross-sensitization which develops to cocaine after morphine administration.
Analgesics↗
Evaluation of the conditioned reinforcing effects of phentermine and fenfluramine in the rat: concordance with clinical studies.
An unbiased place-preference conditioning procedure was used to characterize the conditioned reinforcing effects of phentermine (PHEN), fenfluramine (FEN), and their combination (PHEN/FEN) in previously drug-naive rats. Animals exhibited marked preferences for an environment previously associated with the administration of phentermine. The minimum dose producing a significant effect was 3.0 mg/kg. In contrast, FEN produced dose-related place aversions. In animals which received a subthreshold dose of FEN in combination with a dose of PHEN that produced a conditioned place preference, no preference or aversion for the drug-paired place was seen. Similarly, no significant conditioning in response to administration of PHEN (3.0 mg/kg) and FEN (3.0 mg/kg) was seen. The failure of PHEN/FEN to produce conditioned reinforcing effects is in line with recent clinical studies, and suggests that PHEN/FEN and drug combinations sharing the same neurochemical mechanisms of action will have low potential for abuse.
Animals↗
Increased responsiveness of mesolimbic and mesostriatal dopamine neurons to cocaine following repeated administration of a selective kappa-opioid receptor agonist.
Previous data have shown that the repeated administration of kappa-opioid receptor agonists attenuates the acute behavioral effects of cocaine. The site and mechanism by which kappa-agonists interact with this psychostimulant, however, are unknown. Accordingly, the present microdialysis study characterized the effects of prior, repeated administration of the selective kappa-opioid receptor agonist U69593 on basal and cocaine-evoked DA levels within the nucleus accumbens (NAC) and caudate putamen (CPU). The influence of U69593 treatment on the locomotor-activating effects of an acute cocaine challenge was also assessed. Rats received once daily injections of U69593 (0.16-0.32 mg/kg/day) or vehicle (1.0 ml/kg/day) for 3 days. The behavioral and neurochemical effects produced by an acute cocaine challenge (20 mg/kg i.p.) were assessed 2 days following treatment cessation. Administration of cocaine to control animals increased locomotor activity. This effect was attenuated in animals which had previously received U69593 (0.32 mg/kg/day x 3 days). Prior administration of U69593 failed to modify basal DA levels in either the NAC or CPU. Thus, 2 days following the cessation of U69593 treatment, dialysate DA levels did not differ from that of controls. Administration of cocaine to vehicle-treated animals increased dialysate levels of DA in both brain regions. However, in animals previously exposed to U69593 (0.32 mg/kg/day x 3 days), a significant enhancement in the response of DA neurons to cocaine was seen. These data demonstrate that prior, repeated administration of a selective kappa-opioid receptor agonist attenuates the locomotor-activating effects of cocaine and increases cocaine-evoked DA overflow in terminal projection areas of mesostriatal and mesolimbic DA neurons. These findings indicate that the behavioral interactions of kappa-agonists with cocaine observed in this and previous studies cannot be attributed to a presynaptic inhibition of DA release. Rather, they suggest that postsynaptic or non-DA mechanisms mediate the interaction of these agents with cocaine.
Analgesics↗
The neurobiology of opiate reinforcement.
This article provides a basic introduction into two commonly used behavioral paradigms used for the assessment of the reinforcing and rewarding effects of drugs in experimental animals. Behavioral as well as neurochemical data regarding the neural basis of opiate reward are then critically reviewed in order to evaluate the neuroanatomical and neurochemical substrates mediating the primary and conditioned reinforcing effects of opiates as well as current hypotheses of drug-induced reward and aversion.
Animals↗
Sensitization to the behavioral effects of cocaine: modulation by dynorphin and kappa-opioid receptor agonists.
Several lines of evidence suggest an involvement of the mesolimbic dopamine (DA) system in the mediation of psychostimulant-induced sensitization. It is also apparent that endogenous opioid peptide systems can modulate the activity of this same DA system. Psychostimulant-induced alterations in opioid peptide gene expression have also been reported. In this review, evidence will be presented that demonstrates that the administration of kappa-opioid agonists can prevent the initiation of behavioral sensitization to cocaine and that such treatment is also effective in preventing alterations in mesolimbic DA neurotransmission that occur as a consequence of repeated cocaine administration. The putative role of opioid-DA interactions in the modulation of psychostimulant-induced sensitization will also be discussed.
Animals↗
Role of delta-opioid receptors in mediating the aversive stimulus effects of morphine withdrawal in the rat.
An unbiased place preference conditioning procedure was used to examine the role of delta-opioid receptors in mediating the aversive effects of opioid withdrawal. Rats were implanted s.c. with two pellets each containing placebo or 75 mg morphine. Single-trial conditioning sessions with saline and the opioid receptor antagonists naloxone (0.001-1.0 mg/kg, s.c.), naltrindole (0.01-3.0 mg/kg, s.c.) or naltriben (0.01-3.0 mg/kg, s.c.) commenced 4 days later. During these conditioning sessions, physical signs of withdrawal were also quantified. Tests of conditioning were conducted on day 5. Naloxone in doses of 0.01-1.0 mg/kg produced significant conditioned place aversions in morphine-implanted animals. A dose of 0.01 mg/kg produced few physical withdrawal signs whereas higher doses resulted in marked wet dog shakes, body weight loss ptosis and diarrhea. No such effects were observed in control (placebo-implanted) animals. Administration of the selective delta-opioid receptor antagonists naltrindole and naltriben produced dose-related place aversions in morphine-implanted animals. The magnitude of these effects did not differ from that observed with naloxone. The minimum effective doses of naltrindole and naltriben were 0.1 mg/kg. Doses of 0.1-1.0 mg/kg produced few, if any, somatic signs of withdrawal whereas higher doses of these antagonists only produced diarrhea and wet-dog shakes. Other withdrawal signs were absent. In contrast to the opioid receptor antagonists tested, the dopamine D1 receptor antagonist SCH23390 failed to produced conditioned place aversions or physical signs of withdrawal in morphine-pelleted animals. These data demonstrate that the selective blockade of either delta- or mu-opioid receptors is sufficient to induce conditioned aversive effects in morphine-dependent animals. They also indicate that physical symptoms associated with precipitated morphine withdrawal differ depending upon the opioid receptor antagonist employed.
Animals↗
Sensitization to the conditioned rewarding effects of morphine: pharmacology and temporal characteristics.
An unbiased place preference conditioning procedure was used to determine whether the repeated administration of morphine results in sensitization to its conditioned rewarding effects. Rats received once daily injections of saline or morphine (5.0 mg/kg; i.p.) for 5 days in a room distinct from that where conditioning would occur. Place preference conditioning commenced 72 h later. A minimum of three drug conditioning sessions was necessary for the establishment of morphine-induced conditioned place preferences in saline-pretreated rats. The minimum dose producing this effect was 5.0 mg/kg. In animals pre-exposed to morphine, significant place preferences occurred after only two drug conditioning sessions and in response to doses of 3.0 mg/kg and greater. The augmented response to morphine was apparent when conditioning commenced 3, 10 or 21 days after the cessation of morphine pretreatment. It was not apparent when conditioning commenced 1 day after treatment cessation. An enhanced response to morphine was also observed in rats which had previously received either fentanyl (0.016 mg/kg/day) or nicotine (0.4 mg/kg/day) for 5 days. Animals which received morphine or fentanyl in combination with naloxone (0.5 mg/kg; s.c.) for 5 days failed to exhibit a conditioned response to morphine. When, however, naloxone was administered in combination with nicotine, significant morphine-induced place preferences were still seen. These data demonstrate that both sensitization and cross-sensitization develop to the conditioned rewarding effects of morphine. Furthermore, they indicate that the sensitization induced by morphine and fentanyl, but not nicotine, is opioid-receptor mediated.
Animals↗
Differential role of delta-opioid receptors in the development and expression of behavioral sensitization to cocaine.
The present study was designed to determine whether the selective delta-opioid receptor antagonist naltrindole hydrochloride can prevent the expression and development of sensitization to the locomotor-activating effects of cocaine. Rats were sensitized to the motor stimulant effects of cocaine (20 mg/kg i.p. x 3 days). 48 h after withdrawal of pretreatment, rats were pretreated with naltrindole (0.1-1.0 mg/kg s.c.) or its vehicle and 15 min later challenged with either saline or the sensitizing dose of cocaine. In a second set of experiments, naltrindole (0.1-1.0 mg/kg s.c.) or its vehicle were given in combination with either saline or cocaine (20 mg/kg i.p.) for 3 days. Activity in response to saline and to cocaine (20 mg/kg i.p.) was assessed on days 4 and 5, respectively. Additional experiments determined whether naltrindole prevents the development of sensitization to the locomotor-activating effects of nicotine: naltrindole (0.3, 1.0 mg/kg s.c.) or its vehicle were given in combination with nicotine (0.6 mg/kg s.c.) for 3 days. Naltrindole blocked the development but not expression of sensitization to the locomotor-activating effects of cocaine. In contrast, naltrindole failed to modify nicotine-induced sensitization in nicotine-treated animals. These data suggest that delta-opioid receptors are involved in the development but not expression of behavioral sensitization to cocaine.
Animals↗
Evidence for an involvement of muscarinic cholinergic systems in the induction but not expression of behavioral sensitization to cocaine.
The present study was designed to determine whether the muscarinic cholinergic antagonist scopolamine can prevent the expression and induction of sensitization to the locomotor-activating effects of cocaine. Rats received one daily injection of cocaine (20 mg/kg i.p.) for 5 days. Two days after withdrawal of pretreatment, rats were pretreated with scopolamine (3.0 mg/kg s.c) or its vehicle and challenged 15 min later with either saline or cocaine (20-30 mg/kg i.p.). In second set of experiments, scopolamine (3.0 mg/kg s.c) or its vehicle was given in combination with either saline or cocaine (20 mg/kg i.p.) for 5 days. Activity in response to saline and to cocaine (20 mg/kg i.p.) was assessed on day 7. The effects of acute administration of scopolamine (3.0 mg/kg s.c.) on cocaine-induced locomotor activity were also assessed. Acute administration of scopolamine increased both distance traveled and time spent in stereotypy. When scopolamine was administered 15 min prior to an acute injection of cocaine, a significant increase in the behavioral response to cocaine was seen. Daily injections of cocaine for 5 days produced sensitized behavioral responses to a subsequent cocaine challenge. Acute administration of scopolamine to animals preexposed and sensitized to cocaine did not disrupt the expression of sensitization to the locomotor and stereotypic effects of cocaine. In contrast, when scopolamine was given in combination with cocaine for 5 days, sensitization to the locomotor-activating effects of cocaine was prevented. These results suggest an important role of cholinergic muscarinic systems in mediating sensitization to the locomotor-activating effects of cocaine, which occurred after the repeated context-independent administration of this agent. In contrast, the enhanced stereotypic effects in response to the repeated administration of cocaine seem to be independent of alterations in muscarine cholinergic transmission.
Animals↗
Adrenalectomy attenuates nicotine-induced dopamine release and locomotor activity in rats.
Adrenalectomy (ADX) in mice can potentiate several physiological and behavioural responses to nicotine. The present experiments sought to examine this issue in this rat by characterising the influence of ADX upon the locomotor depressant, activating and dopamine-releasing properties of nicotine. Nicotine (0.8-1.2 mg/kg s.c.) dose-dependently depressed locomotor activity, an effect that was potentiated by ADX, while the locomotor activating effects of a smaller dose (0.4 mg/kg) were attenuated by ADX. In both SHAM and ADX rats chronically treated with nicotine for 5 days (daily injections of 0.4 mg/kg s.c.), the locomotor depressant effects of nicotine did not differ from saline-treated controls. Nicotine (0.4 mg/kg s.c.) increased extracellular levels of dopamine in the nucleus accumbens. This response was unaffected in rats pretreated with nicotine for 5 days (daily injections of 0.4 mg/kg s.c.). However, both ADX groups of rats showed smaller increases in dopamine following administration of nicotine. The results suggest that depletion of circulating corticosteroids can modulate sensitivity to nicotine in rats. The suppressant effects of ADX on nicotine-induced locomotor activity may be due to its effects on dopamine release in the nucleus accumbens.
Adrenalectomy↗
kappa-Opioid receptor agonists prevent sensitization to the conditioned rewarding effects of cocaine.
A place preference conditioning procedure was used to examine the influence of kappa-opioid receptor ligands upon the development of sensitization to the conditioned rewarding effects of cocaine. Previous exposure to cocaine (10-20 mg/kg; i.p.; days 1-5) resulted in an enhancement of the conditioned rewarding effects of this agent, e.g., sensitization. Thus, doses of cocaine (5.0-10.0 mg/kg; i.p.) that failed to produce place preferences in control rats produced significant place preferences in cocaine-experienced animals. In animals that had received the kappa-agonist U50,488H (5.0 mg/kg; s.c.) in combination with the repeated cocaine treatment regimen, no enhancement of cocaine-induced place conditioning was seen. Similarly, the kappa-agonist U69593 administered on days 1 to 5 or only on days 3 to 5 of the cocaine treatment regimen prevented the enhanced response to cocaine. This effect occurred after either systemic (0.04-0.16 mg/kg; s.c.) or intracerebroventricular (1.0 mg) treatment and was abolished by the kappa-opioid receptor antagonist, nor-binaltorphimine. In contrast to its effects when administered in combination with cocaine, prior administration of U69593, alone, failed to modify the conditioned response to cocaine. Microdialysis studies revealed a marked elevation of extracellular dopamine levels within the ventral striatum after repeated cocaine administration. In animals that had received U69593 in combination with cocaine, no elevation of dopamine was seen. These data demonstrate that sensitization develops to the conditioned rewarding effects of cocaine and that the activation of central nervous system kappa-opioid receptors prevents the development of this phenomenon. An involvement of the mesolimbic dopamine system in mediating the interaction of kappa-agonists with cocaine is suggested.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗