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T S Shippenberg

Publications and source records attributed to T S Shippenberg.

At least 55 records · Page 3Linked to original sources
PubMed1996

Role of extracellular dopamine in the initiation and long-term expression of behavioral sensitization to cocaine.

Repeated intermittent administration of cocaine has been shown to sensitize animals to the locomotor-activating effects of this agent. The neurobiochemical basis of this phenomenon, however, remains only partially understood. The present study sought to characterize basal dialysate dopamine (DA) concentrations within the nucleus accumbens (NAc), 2, 12 or 22 days after the cessation of either repeated cocaine (20 mg/kg/day x 5 days) or saline (1.0 ml/kg/day x 5 days) treatment. Locomotor activity and dialysate DA levels in response to a subsequent cocaine administration (20 mg/kg i.p.) were assessed at the same time intervals. Cocaine-pretreated animals exhibited an enhanced motor response to a cocaine injection 2 days after cessation of cocaine treatment. The magnitude of this effect increased progressively over time. Basal DA overflow was elevated 2 days after termination of cocaine treatment; at this time, however, a blunted response of DA neurons to the cocaine administration was observed. As the duration of withdrawal increased, basal dialysate DA concentrations gradually declined, whereas the response of DA neurons to cocaine progressively increased. By day 22 of withdrawal, a significant enhancement of cocaine-induced DA overflow was seen. These findings demonstrate that increased DA overflow in response to cocaine cannot account for the short-term expression of behavioral sensitization to cocaine. Rather, an enhanced DA response develops during later stages of the sensitization process and, therefore, may be one of the mechanisms responsible for the long-term expression of cocaine sensitization.

Animals↗
PubMed1995

The delta-opioid receptor antagonist naltrindole prevents sensitization to the conditioned rewarding effects of cocaine.

A conditioned place preference paradigm was used to determine whether: (i) prior exposure to cocaine results in an enhancement of its rewarding effects, and (ii) the delta-opioid receptor antagonist naltrindole can prevent the development of this response. Rats received daily injections of saline or cocaine (10.0 mg/kg i.p.) for 5 days in the colony room. Additional animals received naltrindole (0.03-0.3 mg/kg s.c.), lithium chloride (20 mg/kg s.c.) or vehicle prior to i.p. injections. Conditioning sessions (2 drug; 2 vehicle) commenced 3 days later. Cocaine (1.0-10.0 mg/kg) was ineffective as a conditioning stimulus in saline pre-exposed rats. In cocaine pre-exposed animals, however, doses of 5.0 and 10.0 mg/kg cocaine resulted in significant drug-induced place preferences. Significant cocaine-induced place preferences were also observed in animals which had received lithium chloride with the cocaine treatment regimen. In animals which had received naltrindole together with the chronic cocaine treatment regimen, cocaine failed to produce a conditioned response. These data demonstrate that the repeated administration of cocaine results in an enhancement of its rewarding effects (e.g. sensitization) and that this phenomenon is prevented by a delta-opioid receptor antagonist. Furthermore, the finding that naltrindole does not modify the acute rewarding effects of cocaine suggests a specific role of delta-opioid receptors in the sensitization process.

Animals↗
PubMed1995

Strain differences in the rewarding and dopamine-releasing effects of morphine in rats.

Studies examining differential sensitivity to psychoactive drugs in mice suggest that genotype may play a critical role. Furthermore, an involvement of genotype in mediating individual differences in sensitivity to the rewarding effects of several drugs of abuse has also been postulated. The aim of this study was to examine the conditioned rewarding and dopamine-releasing effects of morphine in two outbred rat strains commonly used in addiction research. Additionally, the behavioural and neuroendocrine responses of these strains to the stress of novelty were also examined. Basal locomotor activity was higher in Wistar rats than Sprague-Dawley following exposure to a novel environment. In contrast, elevations in plasma corticosteroid levels following novelty exposure did not differ between the two strains. In a counterbalanced place preference conditioning procedure, increasing doses of morphine (1.0-10.0 mg/kg SC) produced significant conditioned place preferences (CPP) in both Wistar and Sprague-Dawley strains. However, Wistar rats required a significantly larger dose of morphine (5.0 mg/kg) to produce a significant CPP than the Sprague-Dawley rats. In the latter strain, CPP occurred with doses of 3.0 mg/kg and greater. In parallel microdialysis experiments, both strains showed significant dose-related increases in dopamine release in the nucleus accumbens following acute morphine challenge (1.0-10.0 mg/kg SC). Again in Wistar rats, a larger dose of morphine was necessary to produce a significant increase in comparison to Sprague-Dawley rats. These results show that genetically distinct rat strains can show differential sensitivity to opioids, more specifically to drug-seeking responses.

Animals↗
PubMed1995

Lack of involvement of delta-opioid receptors in mediating the rewarding effects of cocaine.

The non-selective opioid antagonist naltrexone and the partial agonist buprenorphine have been reported to reduce cocaine self-administration (SA) and relapse in both humans and rhesus monkeys. Data suggesting an involvement of delta-opioid receptors in modulating the conditioned rewarding effects of cocaine were also recently presented. In view of such findings, the present SA and place conditioning studies were conducted to examine the influence of the selective delta-opioid receptor antagonist naltrindole upon the rewarding effects of cocaine. Sprague-Dawley rats were trained to self-administer cocaine (1.0 mg/kg per infusion) on an FR2 schedule of reinforcement. Dose-response and antagonist testing commenced once stable rates of cocaine SA were achieved. For antagonist testing, rats received naltrindole (0.03-10.0 mg/kg, IP) 30 min prior to the start of 2-h SA sessions. SA behavior in response to cocaine delivery (0.25 and 1.0 mg/kg per infusion) was then determined. Naltrindole in doses of 0.03-3.0 mg/kg did not alter the number of cocaine infusions taken by the rats. A higher dose of naltrindole (10.0 mg/kg), which markedly depressed locomotor activity, resulted in a 16% reduction of cocaine (0.25 mg/kg per infusion) SA behavior. When SA sessions were terminated and naltrindole (1.0 mg/kg) was administered repeatedly for 3 days, no alterations in the re-acquisition of cocaine SA were seen. Place conditioning studies also failed to find an effect of naltrindole (0.1-3.0 mg/kg) on cocaine (10 mg/kg)-induced conditioned place preferences. Naltrindole, by itself, did not induce significant place conditioning.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Development of behavioral sensitization to cocaine: influence of kappa opioid receptor agonists.

The effects of acute or repeated administrations of the selective kappa opioid receptor agonists U-69593 and U-50488H on cocaine-induced locomotor stimulation were examined in the rat. Acute administration of cocaine (10-30 mg/kg i.p.) produced a dose-dependent increase in locomotor activity. A single injection of U-69593 (0.04-0.32 mg/kg s.c.) or U-50488H (2.5-7.5 mg/kg s.c.) administered 15 min before cocaine did not modify the effects of an acute cocaine challenge. In contrast, repeated administration of U-69593 or U-50488H in combination with saline for 3 days prevented the acute locomotor-activating effects of cocaine. Repeated administration of cocaine (10-30 mg/kg i.p.) for 3 days resulted in an enhancement of its locomotor-activating effects, i.e., sensitization. No such sensitized responses were observed in animals that had received U-69593 or U-50488H in combination with the cocaine treatment regimen. Repeated administration of U-69593 (0.16 mg/kg s.c.) for 3 days failed to block the acute locomotor-activating effects of nicotine (0.6 mg/kg s.c.). Furthermore, when U-69593 was given in combination with nicotine, sensitized motor responses to a subsequent nicotine challenge were still observed. These data demonstrate that the repeated activation of kappa opioid receptors prevents the locomotor activation that occurs in response to an acute cocaine challenge as well as the sensitized motor responses that develop after the repeated administration of cocaine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

Sensitization to the conditioned rewarding effects of cocaine: pharmacological and temporal characteristics.

An unbiased place preference conditioning procedure was used to determine whether the repeated administration of cocaine results in sensitization to its conditioned rewarding effects. Rats received noncontingent injections of saline or cocaine (10 mg/kg i.p.) for 5 days. Place preference conditioning commenced 72 hr later. A minimum of three drug conditioning sessions was necessary for the establishment of cocaine-induced conditioned place preferences (CPP) in saline-pretreated rats. The minimum dose producing this effect was 10.0 mg/kg. In contrast, pre-exposure to cocaine resulted in significant place preferences occurring after only two drug conditioning sessions. Furthermore, CPP was observed in response to doses as low as 5.0 mg/kg. This shift in the cocaine dose-response curve was apparent when conditioning commenced either 3 or 7, but not 14, days after the cessation of cocaine pretreatment. An increased sensitivity to cocaine was also observed in rats which received only two cocaine (25.0 mg/kg) injections before conditioning and in those which had received either d-amphetamine (0.5 mg/kg) or morphine (5.0 mg/kg) for 5 days. Repeated administration of the D1 dopamine (DA) receptor antagonist, SCH-23390 (0.01-0.05 mg/kg), or the D2 antagonist, raclopride (0.1-1.0 mg/kg), for 5 days did not modify cocaine-induced place conditioning. Administration of SCH-23390 (0.05 mg/kg) in combination with cocaine, however, prevented the sensitized response to cocaine. In contrast, raclopride did not influence the sensitized response to cocaine. These data demonstrate that sensitization occurs to the conditioned rewarding effects of cocaine and suggest an involvement of D1 DA receptors in the development of this phenomenon.

Amphetamine↗
PubMed1994

Evidence that nor-binaltorphimine can function as an antagonist at multiple opioid receptor subtypes.

This study examined the influence of acute and repeated administration of the kappa-opioid receptor antagonist, nor-binaltorphimine, upon opioid-induced antinociception as measured by the tail-pressure test. A single intracerebroventricular (i.c.v.) injection of nor-binaltorphimine (30 micrograms) administered 1, 10 or 30 days prior to algesiometric testing prevented the analgesic effect of the kappa-opioid receptor agonist, (5 alpha, 7 alpha, 8 beta)-(-)-N- methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)benzenacet amide (U69593). The analgesic effect of the mu-opioid receptor agonist, [D-Ala2,N-methyl-Phe4,Gly5-ol]enkephalin (DAMGO), and the delta-opioid receptor agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE), was not modified. In contrast, when nor-binaltorphimine was administered repeatedly (twice daily i.c.v. administration of 30 micrograms nor-binaltorphimine for 10 days), the analgesic effect of DAMGO, DPDPE as well as U69593 was abolished. In the case of mu- and delta-opioid receptor agonists, this abolition was apparent when testing occurred 1 or 2, but not 5 days after termination of nor-binaltorphimine treatment. This treatment regimen also resulted in a long-lasting antagonism (e.g. 20 days) of U69593-induced analgesia. These data show that, depending on the treatment regimen employed, nor-binaltorphimine can function as a selective kappa-opioid receptor antagonist, or as an antagonist at multiple opioid receptor subtypes. Further, they demonstrate that nor-binaltorphimine functions as a long-lasting kappa-opioid receptor antagonist in vivo.

Amino Acid Sequence↗
PubMed1994

U-69593 prevents cocaine sensitization by normalizing basal accumbens dopamine.

Repeated intermittent administration of cocaine (20 mg kg-1, i.p.) for 3 days dramatically increased basal dopamine (DA) overflow in the nucleus accumbens (ACB) 48 h after the final daily injection. This cocaine pretreatment also produced a significant increase in stereotypy in response to a subsequent cocaine challenge. However, when the selective kappa-opioid receptor agonist U-69593 was administered in combination with cocaine for 3 days, these cocaine-induced biochemical and behavioral effects were abolished. It is suggested that the responsiveness of mesolimbic DA neurons to cocaine is intimately related to basal DA concentrations within the ACB and that U-69593, by normalizing cocaine-induced increases in basal DA overflow, may prevent the development of behavioral sensitization to cocaine.

Analgesics↗
PubMed1994

Endogenous kappa-opioid systems in opiate withdrawal: role in aversion and accompanying changes in mesolimbic dopamine release.

The kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) was recently shown to potentiate certain overt withdrawal signs in morphine-dependent rats. The present study sought to further assess this phenomenon by examining the influence of nor-BNI treatment upon the conditioned place aversion associated with the naloxone-precipitated withdrawal syndrome. In addition, in vivo microdialysis studies were conducted in morphine-dependent rats to determine whether nor-BNI treatment can modify withdrawal-induced changes in basal dopamine (DA) release within the mesolimbic system. Rats were pretreated with either saline or a single dose of nor-BNI and then received ascending doses of morphine for 10 days. A withdrawal syndrome was then precipitated by the administration of naloxone (1 mg/kg SC). In rats which received chronic morphine injections, administration of naloxone produced a characteristic withdrawal syndrome and a marked aversion for an environment previously associated with naloxone-precipitated withdrawal. Nor-BNI treatment potentiated most overt signs of physical dependence. This treatment also resulted in a greater withdrawal-induced place aversion. Morphine-dependent rats exhibited a marked reduction in basal mesolimbic DA release. An even greater decrease in basal DA release was observed in nor-BNI treated rats. These results suggest that endogenous kappa-systems are important in the modulation of mesolimbic DA release and the accompanying place aversion which occurs during opiate withdrawal.

Animals↗
PubMed1993

Inhibition of cocaine-induced sensitization by the delta-opioid receptor antagonist naltrindole.

The influence of the delta-opioid receptor antagonist naltrindole upon sensitization to the locomotor activating effects of cocaine was assessed. Activity in response to a challenge dose of cocaine (20 mg/kg, i.p.) was significantly increased in rats which had received cocaine (20 mg/kg, i.p.) once daily for 3 days as compared to those which had previously received saline. The repeated administration of naltrindole (0.3-3.0 mg/kg, s.c.) alone did not affect activity. However, in animals which had received both naltrindole and cocaine for 3 days, no sensitization to the locomotor activating effects of cocaine was observed. These data demonstrate that the selective blockade of delta-opioid receptors modifies the development of cocaine-induced sensitization and suggest an important role of delta-opioid receptor systems in modulating the development of drug-induced sensitization.

Animals↗
PubMed1993

The kappa-opioid receptor agonist U-69593 attenuates cocaine-induced behavioral sensitization in the rat.

The effects of treatment with the selective kappa-opioid receptor agonist U-69593 upon cocaine-induced changes in locomotor activity and stereotypy were examined in rats. U-69593 (0.16 mg/kg s.c.) administered either acutely or chronically attenuated both the motor stimulant effect and stereotypy produced by an acute injection of cocaine (20 mg/kg i.p.). Daily cocaine treatment resulted in sensitization to both effects of cocaine. In contrast, no such sensitized responses were seen in animals which had received U-69593 either prior to or in conjunction with daily cocaine treatment. These data demonstrate that activation of kappa-opioid receptors attenuates the acute and chronic effects of cocaine on locomotor activity and stereotypy. Given the inhibitory effects ascribed to both exogenous and endogenous kappa-opioid agonists upon dopamine release in the mesolimbic dopaminergic system, it is suggested that this action may underlie the observed effects of U-69593 on cocaine-induced changes in locomotor activity and stereotypy.

Analgesics↗
PubMed1993

Modulation of morphine-induced sensitization by endogenous kappa opioid systems in the rat.

Sensitization to both the motor stimulant and mesolimbic dopamine-releasing effects of morphine were studied in animals chronically treated with morphine and those that had received the kappa opioid receptor antagonist, nor-binaltorphimine (nor-BNI) prior to the commencement of morphine treatment. Rats were pretreated with either nor-BNI (30 micrograms; i.c.v.) or its vehicle and then received injections of morphine for 10 days. Locomotor activity and microdialysis studies were then conducted 3 and 30 days after termination of the chronic morphine treatment. In chronic morphine-treated rats, sensitization developed to both the motor stimulatory effects of morphine and the mesolimbic dopamine-releasing effects of this drug. Sensitization was observed 3 and 30 days after termination of morphine treatment. In animals pretreated with nor-BNI, sensitization to both the motoric and dopamine-releasing effects of morphine was significantly greater than that of chronic morphine-treated rats. These results suggest that endogenous kappa opioid systems play an important role in morphine-induced sensitization and that manipulations of these systems can markedly influence both its behavioral and neurochemical expression.

Animals↗
PubMed1993

Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats.

An unbiased conditioned place preference paradigm was used to examine the neuroanatomical substrates mediating the reinforcing and aversive effects of mu and kappa opioid agonists. Unilateral microinjection of the selective mu agonist DAMGO into the ventral tegmental area (VTA), the origin of the mesolimbic and mesocortical dopamine (DA) systems, resulted in dose-dependent preferences for the drug-associated place. Intracranial injections of DAMGO into terminal projection sites of VTA DA neurons, the nucleus accumbens and the medial prefrontal cortex, however, as well as into the lateral hypothalamus, were without effect. In contrast, microinjections of the kappa agonist U50,488H and the dynorphin derivative E-2078 into the VTA produced place aversions. Place aversions were also observed after microinjections of U50,488H and E-2078 into the nucleus accumbens, medial prefrontal cortex and lateral hypothalamus. However, microinjections of mu and kappa agonists into either the origin of the mesostriatal DA system, the substantia nigra or into its major terminal field, the nucleus caudatus-putamen, was without effect. Autoradiographic studies revealed that the substances remained within a restricted area around the injection site, confirming that the effects observed were mediated therein. Thus, these data suggest an important role for the A10 neurons in the VTA in the regulation of both mu and kappa opioid-induced motivational states. The rewarding effects are associated with the activation of mu receptors in the VTA, whereas aversive effects are associated with the activation of kappa receptors in the VTA and its limbic-cortical terminal regions.

Amino Acid Sequence↗
PubMed1993

Examination of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D-1 vs. D-2 dopamine receptors.

Both the reinforcing and aversive effects of exogenous opioids have been attributed to the activation of opioid receptors within the mesolimbic dopamine (DA) system. At present, however, it is unclear whether the activity of DA neurons projecting to the nucleus accumbens (NAC) is necessary for the expression of these effects. The present study sought to address this issue in rats by examining the influence of 6-hydroxydopamine (6-OHDA) lesions of the NAC and microinjections of selective DA receptor antagonists into this brain area upon the place conditioning produced by systemically administered opioids. The mu-opioid receptor agonist morphine produced dose-related preferences for the drug-paired place in control animals, whereas the kappa-opioid agonist U-69593 produced place aversions. Bilateral 6-OHDA lesions of the NAC abolished the place conditioning produced by both opioids. Lesions of the caudate/putamen or medial prefrontal cortex were, however, without effect. Microinjection of the D-1 DA antagonist SCH-23390 into the NAC, at a dose which was as ineffective as a conditioning stimulus, attenuated the place conditioning produced by low doses of morphine and U-69593. Over the dose range tested, the D-2 DA antagonist (-)-sulpiride was without effect. Neither SCH-23390 nor 6-OHDA lesions of the NAC modified the place conditioning produced by lithium chloride, a drug of a different pharmacological class. These data demonstrate that the rewarding and aversive effects of opioids are dependent on DA neural transmission within the mesolimbic system and suggest a role for NAC D-1 DA receptors in the mediation of both motivational effects.

Animals↗
PubMed1992

Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway.

The mesolimbic dopaminergic system has been implicated in mediating the motivational effects of opioids and other drugs of abuse. The site of action of opioids within this system and the role of endogenous opioid peptides in modulating dopamine activity therein remain unknown. Employing the technique of in vivo microdialysis and the administration of highly selective opioid ligands, the present study demonstrates the existence of tonically active and functionally opposing mu and kappa opioid systems that regulate dopamine release in the nucleus accumbens, the major terminal area of A10 dopaminergic neurons. Thus, stimulation of mu-type receptors in the ventral tegmental area, the site of origin of A10 dopaminergic neurons, increases dopamine release whereas the selective blockade of this opioid receptor type results in a significant decrease in basal dopamine release. In contrast, stimulation of kappa-type receptors within the nucleus accumbens decreases dopamine release whereas their selective blockade markedly increases basal dopamine release. These data show that tonic activation of mu and kappa receptors is required for the maintenance of basal dopamine release in the nucleus accumbens. In view of the postulated role of the mesolimbic system in the mediation of drug-induced alterations in mood and affect, such findings may have implications for the treatment of opiate dependence and affective disorders.

Analgesics↗
PubMed1992

[Opiate addiction. Pharmacologic and biochemical aspects].

The detailed information now available regarding the neurobiology of opiates (opioids) has contributed greatly to our understanding of opioid addiction. This in turn has permitted a more complete understanding of the processes underlying drug addiction. Opioid agonists with a high affinity for mu- or delta-receptors produce conditioned preferences for an environment previously associated with their administration, whereas kappa-agonists induce place aversions. Studies in which opioids were microinjected into discrete brain areas suggest that these opposing motivational effects are mediated via an interaction with the mesolimbic dopamine (DA) system originating in the midbrain. Microdialysis studies have clearly shown that mu-agonists preferentially increase DA release and metabolism in the Nucleus accumbens, whereas kappa-receptor agonists decrease release. Opposite effects on DA are observed in response to microinjections of selective antagonists for these receptor types, suggesting the existence of tonically active endogenous opioid systems which maintain DA release in the mesolimbic system: a continuous "reward" tone, probably mediated by beta-endorphin in the ventral tegmentum of the midbrain and an "aversive" tone, mediated by dynorphin in the Nucleus accumbens. Aspects of such a bidirectional regulation of the mesolimbic system by endogenous opioids are discussed.

Animals↗