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R Spanagel

Publications and source records attributed to R Spanagel.

72 records · Page 4Linked to original sources
PubMed1995

Modulation of drug-induced sensitization processes by endogenous opioid systems.

Behavioural sensitization involves progressive increases in behavioural responses to repeated intermittent administration of drugs of abuse. Behavioural sensitization is observed to the locomotor stimulant, rewarding and discriminative effects of a drug. These are effects which seem to be essential in the initiation, expression and maintenance of a drug-seeking behaviour. Therefore the phenomenon of behavioural sensitization may have important implications for the understanding of addictive processes. Findings given in this review demonstrate the involvement of endogenous opioid systems in the initiation of sensitized responses on the neurochemical level, i.e., within the mesolimbic dopaminergic system, as well as on the behavioural level. Specifically, it is shown that behavioural sensitization to morphine and cocaine is modulated by endogenous kappa-opioid systems.

Animals↗
PubMed1995

Microdialysis studies with amantadine and memantine on pharmacokinetics and effects on dopamine turnover.

Amantadine and memantine are in clinical use for the treatment of neurodegenerative diseases such as M. Parkinson and dementia syndrome. In order to contribute to the understanding of the interaction of these uncompetitive NMDA-antagonists with the dopaminergic system in the striatum, the pharmacokinetics and the effects of amantadine and memantine on the dopaminergic system were examined in a microdialysis study in anaesthetized rats. Both substances achieved extracellular fluid concentrations in the striatum known to block NMDA receptors, supporting the assumption that NMDA receptor antagonism is their primary mechanism of action. Both, memantine, and to a lesser degree, amantadine induce a modest dopamine overflow not paralleled by HVA or DOPAC. The small increase in dopamine overflow cannot add substantially to the drugs' action and may be generated indirectly via their NMDA-antagonistic properties.

3,4-Dihydroxyphenylacetic Acid↗
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

Memantine-induced dopamine release in the prefrontal cortex and striatum of the rat--a pharmacokinetic microdialysis study.

Memantine (1-amino-3,5-dimethyl-adamantane) has therapeutic potential in Parkinson's disease and dementia. However, its effect on dopaminergic activity in the central nervous system is still unclear. Therefore, we studied the effect of memantine on dopamine release in prefrontal cortex and striatum, using in vivo microdialysis. Memantine (5, 10 and 20 mg/kg i.p.) caused a dose-dependent increase in dopamine release up to nearly 50% over basal levels. The output of the metabolites was of later onset and longer duration in prefrontal cortex and in striatum. After administration of 10 and 20 mg/kg, in both brain areas memantine levels could be detected over the investigated period of 160 min. The maximal concentrations (Cmax) differed dose dependently, whereas the time to reach this maximum (tmax) was almost identical (68.5 +/- 3.4 min). From the flat elimination profile a half-life of 2.8 +/- 0.5 h (range 2-3.4 h) was calculated. These data demonstrate enhanced dopamine release and metabolism after memantine treatment and support the assumption of an interaction between noncompetitive NMDA-receptor antagonists and dopaminergic systems.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Ventral tegmental area (VTA) injections of tyrosine hydroxylase phosphorothioate antisense oligonucleotide suppress operant behavior in rats.

Dopaminergic A 10 neurons are known to be the essential part of the brain reinforcement system. An antisense oligonucleotide corresponding to the start coding region of rat tyrosine hydroxylase (TH) mRNA, the transcriptional message of the rate limiting enzyme in the metabolic pathway leading to catecholamine synthesis, was constructed and injected into the ventral tegmental area (VTA). 36 h after injection operant behavior was markedly reduced, and this suppression was fully reversed within 5 days following the antisense injection. Accordingly, TH immunoreactivity in the VTA was reduced in comparison to control experiments using mixed bases oligonucleotides. Our results demonstrate that highly specific inhibition of TH expression can be accomplished in the intact mesolimbic system by antisense treatment, thus providing a novel tool for studies on motivational processes in vivo.

Animals↗
PubMed1994

Mesolimbic sites mediate the discriminative stimulus effects of morphine.

The neuroanatomical basis of opiate addiction has been studied using a variety of behavioural techniques. Mesolimbic structures such as the ventral tegmental area and nucleus accumbens appear to be critical in mediating the expression of rewarding effects of opiates. However, the role of these brain structures in mediating the discriminative stimulus effects have not been fully examined. The aim of the present study was to investigate the role of the ventral tegmental area and the nucleus accumbens in a two-lever operant drug discrimination paradigm. Male Wistar rats were trained to discriminate morphine (3.0 mg/kg s.c.) from saline with a fixed ratio schedule of food reinforcement (FR10). Once rats had acquired the discrimination, a randomised sequence of morphine microinjections (1-10 micrograms) were evaluated. Subsequently, tests with morphine (1.0-10.0 mg/kg s.c.) administered systemically were performed to confirm the integrity of the discrimination. Small doses of morphine (1-3 micrograms) administered into the ventral tegmental area proved sufficient to produce generalisation to the systemic cue, whereas similar injections into the nucleus accumbens produced only partial generalisation. Furthermore, these intra-nucleus accumbens injections (3-10 micrograms) produced significant increases in the latency to complete the first ratio. Similar doses of morphine administered into the striatum failed to show generalisation. These results demonstrate that activation of opioid receptors located within mesolimbic structures mediate, in part, the discriminative stimulus effects of morphine. Furthermore, the finding that the discriminative stimulus effects and rewarding effects share common neural pathways suggest a possible linkage between the two stimulus properties.

Animals↗
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↗
PubMed1994

Involvement of mesolimbic kappa-opioid systems in the discriminative stimulus effects of morphine.

The neuroanatomical basis of opiate addiction has been studied using a variety of behavioural techniques. The aim of the present study was to investigate the role of mesolimbic opioid systems, in particular kappa-opioid systems, in the expression of the discriminative stimulus effects of abused drugs. Rats were trained to discriminate morphine (3.0 mg/kg s.c.) from saline under a fixed ratio schedule of food reinforcement. Once rats had acquired the discrimination, a randomized sequence of different doses of the highly selective kappa-opioid receptor agonist U69593 (0.02-0.16 mg/kg s.c.) was given 20 min prior to a systemic morphine injection. U69593 dose-dependently blocked the morphine discrimination. It is important to note that U69593 at these doses failed to generalize to the systemic morphine cue. The site of action by U69593 (0.02-0.16 microgram) was examined by microinjecting discrete amounts into target brain regions. Intra-nucleus accumbens injections of U69593 dose-dependently blocked the systemic morphine cue, whereas, U69593 failed to generalize to the discriminative stimulus. The same doses did not affect morphine discrimination after intra-ventral tegmental area or striatum injections. Besides the rewarding effects of drugs of abuse, the discriminative stimulus properties of these agents are seen as a major factor in drug seeking behaviours. The present study shows that the discriminative effects of morphine, a measure of the subjective effects of this drug can be blocked by the activation of kappa-opioid receptors located in the nucleus accumbens. In view of these findings which show that the activity of endogenous potassium-opioid systems (dynorphin) may serve as physiological antagonists to counteract the effects of morphine, potassium-agonists therefore may be useful in the treatment of opioid addictions.

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↗
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↗
PubMed1991

Modulation of the mesolimbic dopaminergic system by beta-endorphin-(1-27) as assessed by microdialysis.

In the present study we used in vivo microdialysis to examine the influence of beta-endorphin-(1-27) (beta-EP-(1-27) upon beta-endorphin (beta-EP)-induced dopamine (DA) release in the nucleus accumbens of anesthetized rats. Microdialysis probes were inserted into the nucleus accumbens and perfusates were analyzed for DA and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using a reversed-phase HPLC system with electrochemical detection. Intracerebroventricular (i.c.v.) administration of beta-EP-(1-27) (5-20 micrograms) resulted in a dose-dependent increase in DA release which was smaller than the beta-EP-induced DA release, whereas metabolite levels were not altered. Pretreatment with beta-EP-(1-27) (5-20 micrograms) significantly altered the beta-EP (5 micrograms)-induced increase in DA release. These results indicate that beta-EP-(1-27) antagonizes the beta-EP-induced release of DA in the nucleus accumbens. In addition to its antagonistic properties at the beta-endorphin binding site, beta-EP-(1-27) appears to be a partial agonist, inducing increased DA release. These findings suggest a regulatory function for this naturally occurring beta-EP fragment within the mesolimbic system.

Animals↗
PubMed1991

Beta-endorphin-induced locomotor stimulation and reinforcement are associated with an increase in dopamine release in the nucleus accumbens.

In vivo microdialysis was used to compare the effects of beta-endorphin upon dopamine (DA) release in the nucleus accumbens (NAC) of anesthetized versus freely moving rats, and to examine the role of the mesolimbic DA system in mediating both the motoric and secondary reinforcing effects of this peptide. Microdialysis probes were inserted into the NAC and perfusates were analyzed for DA and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using a reversed phase HPLC system with electrochemical detection for separation and quantification. Intracerebroventricular (ICV) administration of beta-endorphin (2.5 and 5.0 micrograms) increased DA release and metabolites in both freely moving and anesthetized rats. This effect was of greater magnitude and duration in freely moving rats and was accompanied by stimulation of locomotor activity. The 5 micrograms dose also functioned as a secondary reinforcer in a conditioned place preference paradigm. A higher dose of beta-endorphin (7.5 micrograms) stimulated DA release and metabolites in anesthetized rats but failed to affect these parameters in freely moving rats. At this dose, catalepsy and a loss of the reinforcing effects of this peptide were observed. These data demonstrate marked differences in the effects of beta-endorphin upon DA release in the awake versus anesthetized rat. Further, the finding that the reinforcing and locomotor stimulating effects of beta-endorphin only occur at those doses which stimulate DA release suggest that this action is critical for the expression of both behavioral effects.

Anesthesia↗
PubMed1990

Identification of the opioid receptor types mediating beta-endorphin-induced alterations in dopamine release in the nucleus accumbens.

In the present study we used in vivo microdialysis to examine the influence of beta-endorphin on dopamine (DA) release in the nucleus accumbens of anesthetized rats and to identify the opioid receptor types mediating its effects. Microdialysis probes were inserted into the nucleus accumbens and perfusates were analysed for DA and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using a reversed phase HPLC system with electrochemical detection for separation and quantification. Intracerebroventricular (i.c.v.) administration of beta-endorphin resulted in a dose-dependent increase in DA and its metabolites. Pretreatment with the selective delta-antagonist ICI 174,864 significantly attenuated the beta-endorphin-induced increase in DA release and metabolism whereas pretreatment with the selective mu-antagonist CTOP resulted abolition of the beta-endorphin effect. These data demonstrate that the blockade of either mu- or delta-opioid receptors is sufficient to antagonize the stimulatory effects of beta-endorphin on DA release and metabolism. As such, these findings suggest that the concomitant activation of both mu- and delta-receptors underlies the effects of beta-endorphin on DA release in the nucleus accumbens.

Analgesics↗
PubMed1990

The effects of opioid peptides on dopamine release in the nucleus accumbens: an in vivo microdialysis study.

An involvement of the mesolimbic dopamine (DA) system in mediating the motivational effects of opioids has been suggested. Accordingly, the present study employed the technique of in vivo microdialysis to examine the effects of selective mu-, delta-, and kappa- opioids on DA release in the nucleus accumbens (NAC) of anesthetized rats. Microdialysis probes were inserted into the NAC and perfusates were analyzed for DA and its metabolites, dihydroxyphenylacetic acid (DO-PAC) and homovanillic acid (HVA), using a reverse-phase HPLC system with electrochemical detection for separation and quantification. Intracerebroventricular (i.c.v.) administration of selective mu-opioid [D-Ala2, N-methyl-Phe4, Gly5-ol]-enkephalin (DAMGO) or delta-opioid [D-Pen2, D-Pen5]-enkephalin (DPDPE) agonists, at doses that function as positive reinforcers in rats, resulted in an immediate and significant increase in extracellular DA. DOPAC and HVA levels were also significantly increased. The effects of DAMGO were blocked by the selective mu-antagonist D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) whereas those of DPDPE were blocked by the delta-antagonist allyl2-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864). In contrast to mu- and delta-agonists, the kappa-agonist N-CH3-Tyr-Gly-Gly-Phe-Leu-Arg-N-CH3-Arg-D-Leu-NHC2H5 (E-2078), a dynorphin analog that produces aversive states, decreased DA release in a biphasic manner. Norbinaltorphimine, a selective kappa-antagonist, could block this effect. These results demonstrate that mu-, delta-, and kappa-opioid agonists differentially affect DA release in the NAC and this action is centrally mediated.

Analgesics↗
PubMedDate not supplied

Long-term alcohol self-administration with repeated alcohol deprivation phases: an animal model of alcoholism?

In order to study the neurobiological and molecular mechanisms of alcohol dependence and addiction, appropriate animal models are warranted. Although animal models cannot incorporate all aspects and criteria of an addictive behaviour to alcohol seen in human alcoholics, they can at least reflect some of the criteria given in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association (1994). Novel aspects of addictive behaviour to alcohol, craving and relapse might be uncovered by animal models of long-term, free-choice, alcohol self-administration followed by alcohol deprivation phases. After several months of voluntary alcohol consumption, the drug-taking behaviour following a deprivation (withdrawal) phase is characterized by increased alcohol intake and preference (alcohol deprivation effect) and changes in alcohol intake patterns where animals consume large amounts of highly concentrated alcohol solutions even at inappropriate times (e.g. during the inactive light phase when drinking activity is minimal). Altogether, alcohol drinking following alcohol deprivation seems to become uncontrolled and inelastic, reflecting an incentive demand for the drug in such a model. Furthermore, the alcohol deprivation effect outlasts very long abstinence phases, which indicates the persistence of a drug memory for alcohol.

Alcohol Drinking↗