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L J Vanderschuren

Publications and source records attributed to L J Vanderschuren.

At least 37 records · Page 2Linked to original sources
PubMed1998

Drug-induced reinstatement of heroin- and cocaine-seeking behaviour following long-term extinction is associated with expression of behavioural sensitization.

The present study was designed to evaluate the relationship between reinstatement of drug-seeking behaviour following long-term extinction of intravenous (i.v.) drug self-administration (an animal model for craving) and long-term behavioural sensitization. Rats were allowed to self-administer heroin (50 microg/kg per inj., 14 daily sessions), cocaine (500 microg/kg per inj., 10 daily sessions) or saline. Following a 3-week extinction period, reinstatement tests were performed to evaluate priming effects of amphetamine, cocaine and heroin on nonreinforced drug-seeking behaviour. In addition, the occurrence of long-term behavioural sensitization in rats with a history of heroin or cocaine self-administration was determined. Heroin-seeking behaviour was reinstated by heroin (0.25 mg/kg), amphetamine (1.0 mg/kg) and cocaine (10 mg/kg). In addition, animals with a history of heroin self-administration displayed locomotor sensitization to both heroin and amphetamine. Cocaine-seeking behaviour was reinstated by cocaine and amphetamine, but not by heroin. Interestingly, locomotor sensitization to amphetamine, but not heroin, was observed in animals with a history of cocaine self-administration. In other words, the induction of drug-seeking behaviour following a prolonged drug-free period was found to be associated with the expression of long-term behavioural sensitization. These data provide experimental evidence for a role of behavioural sensitization in the incentive motivation underlying drug-seeking behaviour. If drug hyperresponsiveness would indeed be a crucial factor in drug-induced craving in human addicts, pharmacological readjustment of the neuroadaptations underlying drug sensitization may prevent relapse to drug use long after detoxification.

Animals↗
PubMed1997

Intermittent morphine administration induces a long-lasting synergistic effect of corticosterone on dopamine D1 receptor functioning in rat striatal GABA neurons.

Glucocorticoid receptor (GR)-mediated facilitation of striatal dopaminergic (DA) neurotransmission has been proposed to play a role in behavioral sensitization induced by intermittent exposure to drugs of abuse or stressors. Searching for possible common neuronal substrates acted upon by drugs of abuse and corticosterone, we addressed the question as to whether such a facilitatory effect is apparent (i.e., persists) in primary cultures of rat striatum subsequent to intermittent (prenatal) morphine administration. As previously observed in striatal slices of morphine-treated rats, intermittent morphine exposure in vivo caused a long-lasting increase in DA D1 receptor-stimulated adenylyl cyclase activity, that appeared to persist in primary cultures of rat striatal gamma-aminobutyric acid (GABA) neurons. Subsequent in vitro exposure of these striatal neurons to corticosterone or dexamethasone, simultaneously activating GR and mineralocorticoid receptors (MR), about doubled this adaptive effect of previous in vivo morphine administration. The selective MR agonist aldosterone was ineffective in this respect. Prior in vivo morphine treatment also enhanced the stimulatory in vitro effect of corticotropin releasing hormone (CRH) on adenylyl cyclase in cultured GABA neurons. However, the enhanced CRH receptor functioning was not potentiated by in vitro corticosterone exposure. Activation of GR by corticosterone did not facilitate the increase in D1 receptor efficacy induced by sustained activation of muscarinic receptors in cultured striatal neurons. These data indicate that previous intermittent morphine administration induces a long-lasting synergistic effect of corticosterone on enhanced striatal DA neurotransmission at the level of postsynaptic D1 receptors. Moreover, the induction of this neuroadaptation seems to display opioid receptor selectivity and its long-term expression may be confined to D1 receptors. Since exposure to drugs of abuse or stressors not only increase striatal DA release but also plasma corticosterone levels, we hypothesize that this adaptive phenomenon in DA-sensitive GABA neurons is involved in the expression of morphine-induced long-term behavioral sensitization to drugs of abuse and stressors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

Morphine-induced long-term sensitization to the locomotor effects of morphine and amphetamine depends on the temporal pattern of the pretreatment regimen.

The development of behavioural sensitization is thought to depend on the dose and temporal pattern of drug treatment. Previous studies have shown that two distinct morphine pretreatment regimens cause different long-term neuroadaptations in rat striatum. Therefore, in the present study the ability of these pretreatment regimens to induce long-term behavioural sensitization was investigated. One pretreatment regimen, termed "chronic", consisted of three daily injections, for 5 days, with escalating doses (10-50 mg/kg) of morphine, and the other, termed "intermittent", of 14 daily injections with morphine (10 mg/kg). Both intermittent and chronic morphine pretreatment caused sensitization to the locomotor effects of morphine, 3 weeks post-treatment, although the former induced a far greater level of sensitization. Moreover, 3 weeks post-treatment, intermittent, but not chronic, morphine pretreatment induced cross-sensitization to the locomotor stimulant effects of amphetamine. Behavioural sensitization following intermittent morphine pretreatment was clear-cut both 1 day and 3 weeks post-treatment, while after 9 weeks, the locomotor effects of morphine were still slightly augmented. It is concluded that intermittent morphine pretreatment is far more effective in inducing long-term behavioural sensitization than chronic morphine pretreatment.

Amphetamine↗
PubMed1997

Ethanol, like psychostimulants and morphine, causes long-lasting hyperreactivity of dopamine and acetylcholine neurons of rat nucleus accumbens: possible role in behavioural sensitization.

Repeated treatment of rats with ethanol (1 g/kg, once daily for 15 days) enhanced the locomotor effect of morphine, 3 weeks post-treatment. This ethanol-induced long-term behavioural sensitization to morphine was associated with an increase in the electrically evoked release of [3H]dopamine (DA) and [14C]acetylcholine (ACh) from nucleus accumbens slices. A similar enhanced responsiveness of accumbal dopaminergic and cholinergic neurons to depolarization was apparent 3 weeks after repeated morphine, amphetamine or cocaine administration. Prior ethanol exposure also caused a long-term enhancement of electrically evoked release of [3H]DA and [14C]ACh from slices of the caudate-putamen. Unlike the locomotor effect of morphine, that of amphetamine was not enhanced in ethanol-pretreated rats. These data indicate that ethanol administration may cause long-term behavioural sensitization associated with adaptive changes in dopaminergic and cholinergic neurons of rat nucleus accumbens and caudate-putamen. Furthermore, an enhanced reactivity of nucleus accumbens dopaminergic nerve terminals and dopamine-sensitive cholinergic neurons appears to be a common long-term neuroadaptive effect of distinct types of addictive drugs. However, since repeated ethanol exposure did not cause a long-term increase in the locomotor effect of amphetamine, these neuroadaptations may not always be sufficient to cause long-lasting behavioural (cross-)sensitization.

Acetylcholine↗
PubMed1997

Does dizocilpine (MK-801) inhibit the development of morphine-induced behavioural sensitization in rats?

Intermittent morphine pretreatment (10 mg/kg/day for 14 days) induced long-lasting (one month post-treatment) sensitization to the locomotor effects of morphine and amphetamine in rats. Co-administration of the non-competitive NMDA-receptor antagonist dizocilpine (MK-801) (0.1 mg/kg) with morphine did not prevent the development of long-term behavioural sensitization. However, this dose of MK-801 did cause long-term sensitization to its own locomotor effects. Co-administration of 0.25 mg/kg MK-801 with morphine caused death in 60% of the animals. In the animals that survived MK-801 plus morphine pretreatment, neither short-term (3 days) nor long-term morphine-induced sensitization was observed. MK-801 alone (0.25 mg/kg/day for 14 days) induced short-term cross-sensitization to morphine. Thus, the development of long-term morphine-induced locomotor sensitization could only be prevented by a dose of MK-801 that yields a lethal combination with morphine. In addition, MK-801 induced sensitization to its own locomotor effects and cross-sensitization to morphine. These findings seriously question whether MK-801 can be used to study the development of morphine-induced behavioural sensitization.

Amphetamine↗
PubMed1997

The neurobiology of social play behavior in rats.

Social play behavior is one of the earliest forms of non-mother-directed social behavior appearing in ontogeny in mammalian species. During the last century, there has been a lot of debate on the significance of social play behavior, but behavioral studies have indicated that social play behavior is a separate and relevant category of behavior. The present review provides a comprehensive survey of studies on the neurobiology of social play behavior. Evidence is presented that opioid and dopamine systems play a role in the reward aspect of social play behavior. The role of cholinergic, noradrenergic and opioid systems in attentional processes underlying the generation of social play behavior and the involvement of androgens in the sexual differentiation of social play behavior in rats is summarized. It is concluded that there is not only behavioral, but also neurobiological evidence to suggest that social play behavior represents a separate category of behavior, instead of a precursor for adult social, sexual or aggressive behavior.

Animals↗
PubMed1997

Delayed occurrence of enhanced striatal preprodynorphin gene expression in behaviorally sensitized rats: differential long-term effects of intermittent and chronic morphine administration.

Protracted changes in basal "steady-state" opioid peptide gene expression in the brain may represent adaptations underlying the behavioral effects of drugs of abuse, observed long after drug exposure. Here, we have studied the long-term effects of two distinct regimens of morphine administration ("intermittent" vs "chronic" morphine treatment) on behavioral sensitization and "steady-state" striatal preprodynorphin and preproenkephalin gene expression in rats. Opioid peptide gene expression was investigated using in situ hybridization at three rostrocaudal levels (rostral, intermediate and caudal) of the caudate-putamen and the nucleus accumbens. Behavioral studies showed that the intermittent morphine treatment resulted in a significantly greater enhancement of morphine-induced locomotion than the chronic morphine treatment three weeks after cessation of opiate exposure. The intermittent morphine treatment resulted in an initial decrease of preprodynorphin gene expression of about 5-10% in the caudate-putamen and the nucleus accumbens at the rostral and intermediate levels one day after the last morphine administration. In contrast, a protracted increase of preprodynorphin gene expression of about 20% throughout the caudate-putamen and of about 6% in intermediate sections of the nucleus accumbens was observed 21 days after cessation of intermittent morphine treatment. Although the chronic morphine treatment induced a decrease of preprodynorphin messenger RNA levels one day after the last administration, no significant changes were observed three weeks after cessation of chronic morphine treatment. No long-term changes were observed in preproenkephalin gene expression after either morphine treatment. Since the intermittent morphine administration induced long-term behavioral sensitization much more effectively than the chronic morphine treatment, we tentatively suggest that the protracted increase of preprodynorphin gene expression may play a facilitative role in the long-term character of opiate-induced behavioral sensitization.

Animals↗
PubMed1996

Mifepristone prevents the expression of long-term behavioural sensitization to amphetamine.

Three weeks following intermittent amphetamine exposure (2.5 mg/kg/day for 5 days), rats showed an enhanced locomotor response to an amphetamine challenge. Mifepristone (20 mg/kg) given 45 min prior to the challenge completely prevented the expression of amphetamine hyperresponsiveness. The glucocorticoid antagonist did not affect the locomotor response to amphetamine in drug-naive rats. These data demonstrate for the first time that glucocorticoid receptor antagonist treatment may prevent long-term hyperreactivity to drugs of abuse in individuals with a drug history.

Amphetamine↗
PubMed1996

Morphine-induced increase in D-1 receptor regulated signal transduction in rat striatal neurons and its facilitation by glucocorticoid receptor activation: possible role in behavioral sensitization.

One month (but not 1-3 days) after intermittent morphine administration, the hyperresponsiveness of rats toward the locomotor effects of morphine and amphetamine was associated with an increase in dopamine (DA) D-1 receptor-stimulated adenylyl cyclase activity and enhanced steady state levels of preprodynorphin gene expression in slices of the caudate/putamen and nucleus accumbens. Such an enduring increase in postsynaptic D-1 receptor efficacy also occurred in cultured gamma-aminobutyric acid (GABA) neurons of the striatum obtained from rats prenatally treated with morphine. Interestingly, in vitro glucocorticoid receptor activation in these cultured striatal neurons by corticosterone potentiated this neuroadaptive effect of prior in vivo morphine exposure. Since activation of glucocorticoid receptors by corticosterone did not affect D-1 receptor functioning in cultured neurons of saline-pretreated rats, prior intermittent exposure to morphine (somehow) appears to induce a long-lasting state of corticosterone hyperresponsiveness in striatal neurons. Therefore, DA-sensitive striatal GABA neurons may represent common neuronal substrates acted upon by morphine and corticosterone. We hypothesize that the delayed occurrence of these long-lasting morphine-induced neuroadaptive effects in GABA/dynorphin neurons of the striatum is involved in the enduring nature of behavioral sensitization to drugs of abuse and cross-sensitization to stressors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1995

Sequential analysis of social play behavior in juvenile rats: effects of morphine.

The effects of morphine on social play behavior in juvenile rats were investigated using sequential analysis. Social play behavior of 21-day-old rats treated with 1.0 mg/kg of morphine or saline was analyzed for 15 min. Frequencies and durations of measures of social play behavior, such as pinning, boxing/wrestling and following/chasing were significantly increased after treatment with morphine. Social behaviors not related to play, such as social exploration and crawling over/under were slightly decreased, while social grooming and non-social behavior were not affected by morphine treatment. Using sequential analysis, the dissociation between social behaviors related and unrelated to play was confirmed. Pinning and boxing/wrestling were highly significantly associated. In addition, crawling over/under significantly often preceded social grooming, and an association between social exploration and non-social behavior was found as well. Pinning and boxing/wrestling appeared to be negatively associated with non-social behaviors, social exploration and crawling over/under. A negative association between social grooming and social exploration was also found. Upon treatment with morphine, no major effects on the sequential structure of social behavior were observed: pinning and boxing/wrestling appeared more associated with following/chasing, and the negative association between pinning and boxing/wrestling on the one hand and social exploration on the other was enhanced. Thus, morphine slightly increased the coherence of social play behavior. It is concluded that morphine exerts its effects on social play behavior by increasing social play behavior as a whole rather than by changing its structure, suggesting a key role for opioid systems in the regulation of social play behavior.

Aggression↗
PubMed1995

Intermittent morphine treatment causes a protracted increase in cholinergic striatal neurotransmission measured ex vivo.

Considering the long-lasting neuroadaptations that occur in the brain after exposure to drugs of abuse, we found that the facilitatory effect of an EC50 concentration (0.1 microM) of the acetylcholinesterase inhibitor physostigmine, unlike that of the muscarinic receptor agonist oxotremorine, on K(+)-induced [3H]dopamine release from rat striatal slices was enhanced about 2-fold 1 month after cessation of intermittent morphine treatment. Similarly, the inhibitory effect of physostigmine on K(+)-induced [14C]acetylcholine release from the slices was enhanced subsequent to morphine treatment, whereas that of oxotremorine appeared to be unchanged. Therefore, intermittent morphine administration may cause a very long-lasting increase of muscarinic receptor activation by released endogenous acetylcholine in rat striatum, which may play a pivotal role in the enduring character of stimulus hyperresponsiveness after exposure to drugs of abuse.

Acetylcholine↗
PubMed1995

Social play alters regional brain opioid receptor binding in juvenile rats.

An in vivo autoradiographic procedure was employed to visualize local changes in brain opioid receptor occupancy in juvenile rats. This procedure is based on the assumption that released endogenous ligand will exclude exogenously applied tracer, in this case [3H]diprenorphine, from opioid receptors. Increases in availability of opioid peptides will then result in decreased opioid receptor binding. From behavioral studies there is ample evidence that opioid systems are involved in the regulation of social play behavior in juvenile rats. In the present study, changes in regional brain opioid activity as a result of social isolation-induced social play behavior were monitored. Twenty-one-day-old rats were socially isolated for 0, 3.5 or 24 h prior to testing, and tested alone or in a dyadic encounter. After behavioral testing, [3H]diprenorphine was administered and the brain was prepared for autoradiography. Social isolation caused increases in social behavior (dyadic encounters) but not in non-social behavior (singly tested animals). Modest differences in brain opioid receptor binding due to social isolation, social play behavior, or an interaction of the two, were found in claustrum, nucleus accumbens, globus pallidus, paraventricular and arcuate nuclei of the hypothalamus, and the dorsolateral and paratenial thalamic nuclei. These results support the notion that opioid systems are involved in the regulation of social play behavior. In addition, the observation of changes in opioid binding in areas involved in reward processes, adds evidence to the hypothesis that opioid systems are involved in the regulation of the rewarding aspects of social play in juvenile rats.

Animals↗
PubMed1995

Mu- and kappa-opioid receptor-mediated opioid effects on social play in juvenile rats.

Previously, morphine has been shown to influence social play behavior in rats on two levels. An increasing effect on social play was interpreted as an effect on the rewarding aspects of social play. A lower dose of morphine abolished the effects of an unfamiliar environment on social play, supposedly by affecting the integration of environmental stimuli. In the present study the effects of receptor-specific opioid drugs on social play and measures of social behavior unrelated to play were investigated. Fentanyl, a mu-opioid receptor agonist, seemingly mimicked both effects of morphine. The mu-opioid receptor antagonist, beta-funaltrexamine, decreased social play, although a low dose of this drug increased it. BUBUC (Tyr-D-Cys(StBu)-Gly-Phe-Leu-Thr(OtBu)) and naltrindole, a delta-opioid receptor agonist and delta-opioid receptor antagonist, respectively, had no effects on social behavior. The kappa-opioid receptor agonist, U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide), dose dependently suppressed all measures of social behavior. The kappa-opioid receptor antagonist, nor-binaltorphimine, abolished the effect of an unfamiliar environment on social play. These studies suggest that the opioidergic effect on social play is mediated through mu- and kappa-opioid receptor systems.

Amino Acid Sequence↗
PubMed1995

Effects of morphine on different aspects of social play in juvenile rats.

To clarify the influence of opioids on social play, the effects of morphine on playful and non-playful social behavior in juvenile rats was investigated under different conditions. Environmental variables employed were different (dim and intense) levels of illumination during testing, familiarity to the test cage, and different periods of social isolation prior to testing. Under dim light conditions, morphine markedly increased playful social behavior, such as pinning, boxing/wrestling and following/chasing, whereas non-playful social behavior such as social exploration and contact behavior was hardly affected. This effect of morphine was independent of duration of previous isolation and dose-dependent, with a maximal effect at 1.0 mg/kg. The mechanism of this effect is interpreted as an action on the rewarding aspects of play. A dose of 0.1 mg/kg of morphine abolished the initial suppression of play induced by unfamiliarity to the test cage, without influencing total levels of play. This may be an effect of morphine on the integration of sensory stimuli. Under intense light conditions, whereas playful behavior was completely suppressed, morphine itself hardly affected such behavior, but decreased some aspects of non-playful social behavior. These results suggest that in juvenile rats playful and non-playful forms of social behavior are differentially regulated. In addition, opioid systems may be involved at different levels in the regulation of social play.

Animals↗
PubMed1995

Influence of environmental factors on social play behavior of juvenile rats.

The effects of light level and familiarity to the testing environment on social behaviors related and unrelated to play were investigated in juvenile rats accustomed to dim light conditions. Pinning, a measure characteristic for social play in rats, was completely suppressed under intense light conditions. Following/chasing and boxing/wrestling, social behaviors related to play, were also decreased under intense light. Of the measures of social behavior not related to play, contact behavior was decreased under intense light whereas social exploration was hardly affected. Levels of social exploration and following/chasing gradually declined during the 15-min test period. Frequency of contact behavior decreased, whereas duration increased with time. Under dim light conditions, unfamiliarity to the test cage suppressed pinning and boxing/wrestling but not the other social behaviors in the first part of the test period. These findings show that social behavior in juvenile rats, as in adult rats, can be influenced by light level and familiarity to the test cage. Social behaviors related and unrelated to play seem to be differentially influenced by environmental stimuli.

Animals↗
PubMed1995

Social isolation and social interaction alter regional brain opioid receptor binding in rats.

Endogenous opioid systems have been implicated in the consequences of social isolation and in the regulation of social behavior, although their precise role is not clear. There is not much information on a possible locus in the brain at which opioids exert their effects on social behavior. In an effort to address this issue we analyzed regional opioidergic activity upon social isolation-induced social interaction using in vivo autoradiography. Animals were either socially isolated for 7 days or group housed, and tested singly or in a dyadic encounter. Subsequently, a tracer dose of [3H]diprenorphine was administered and in vivo autoradiographic analysis was performed. Seven days of social isolation caused changes in both social behavior (dyadic encounters) and non-social behavior (singly tested animals). Opioid receptor binding was increased in the medial prefrontal cortex and the parafascicular area in isolates, suggesting that social isolation may evoke an upregulation of opioid receptors in these areas. Social interaction increased opioid binding in the parafascicular area of non-isolated rats. In substantia nigra para compacta and ventral tegmental area binding was increased upon social isolation, and social interaction decreased opioid binding in isolates, but these changes failed to reach significance. These observed local changes in opioid receptor binding suggest a role for opioid systems in discrete areas in the consequences of social isolation and the regulation of social behavior in rats.

Animals↗
PubMed1995

Glucocorticoid receptor activation potentiates the morphine-induced adaptive increase in dopamine D-1 receptor efficacy in gamma-aminobutyric acid neurons of rat striatum/nucleus accumbens.

The present study was designed to evaluate the hypothesis that enhanced corticosterone levels may facilitate the enduring neuroadaptive effects in the brain caused by drugs of abuse. Treatment of primary neuronal cultures of the rat striatal complex (striatum/nucleus accumbens, consisting for more than 90% of gamma-aminobutyric acid neurons) with 10 microM morphine for 2 hr to 3 days, enhanced the maximal stimulatory effect of the dopamine D-1 receptor agonist SKF38393 on adenylyl cyclase activity. This adaptive increase in D-1 receptor efficacy upon long-term mu-opioid receptor activation was about doubled after simultaneous or previous exposure of the neurons to the glucocorticoid receptor agonist dexamethasone (EC50 about 2 nM). A similar facilitation of the effect of morphine was observed upon exposure of the neurons to relatively high (nanomolar) concentrations of corticosterone, whereas the mineralocorticoid receptor agonist aldosterone appeared to be ineffective in this respect, indicating the involvement of glucocorticoid receptors. Interestingly, whereas morphine exposure also enhanced isoprenaline-stimulated adenylyl cyclase activity, this increase of beta adrenoceptor efficacy was not at all affected by dexamethasone. In both morphine-treated and untreated neurons, low concentrations (< .3 nM) of corticosterone or aldosterone, but not dexamethasone, caused a slight (about 20%) reduction of dopamine D-1 receptor-stimulated adenylyl cyclase activity, indicating the involvement of mineralocorticoid receptors. These data show that the morphine-induced adaptive increase of postsynaptic dopamine D-1 receptor efficacy (also observed in striatal slices of rats weeks after repeated treatment with morphine or cocaine) is strongly enhanced after previous or simultaneous glucocorticoid receptor activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗