Sara Lindholm

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (13)42.42 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Amphetamine, and other stimulants, readily induces behavioral sensitization, an effect hypothesized to reflect neurobiological changes that may underlie certain aspects of drug addiction. Apart from the effects on the dopamine system, previous studies have also shown that amphetamine interacts with other neurotransmitters, including the endogenous opioid system. The unselective opioid receptor antagonist naltrexone (NTX) modulates amphetamine-induced effects in both laboratory animals and humans. To further examine this interaction, the aim of the present study was to investigate the effect of NTX on the expression of locomotor sensitization and conditioned locomotor response in animals previously conditioned with amphetamine. Sensitization was induced by repeated administration of amphetamine (2 mg/kg) for 10 consecutive days. After a 10-day drug-free period, the rats were administered NTX (3 mg/kg) 30 minutes prior to the administration of a challenge dose of either amphetamine (0.5 mg/kg) (test for drug-induced sensitization) or saline (test for conditioned locomotor response). NTX had no effect on acute amphetamine-induced locomotor activity or on general locomotor activity in animals without a history of amphetamine conditioning. However, animals previously conditioned with amphetamine showed a sensitized locomotor response to the amphetamine challenge following the 10-day drug-free period. This sensitized response was significantly inhibited by NTX pre-treatment. In addition, NTX pre-treatment blocked the conditioned locomotor response when the amphetamine-conditioned animals were placed in the previously amphetamine-paired context. This study showed that NTX attenuates drug- and cue-induced locomotor behavior in amphetamine-conditioned animals, supporting recent clinical findings that indicated a potential role of NTX as a treatment for amphetamine dependence.
    Addiction Biology 02/2010; 16(1):20-9. · 5.91 Impact Factor
  • Jenny Häggkvist, Sara Lindholm, Johan Franck
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    ABSTRACT: Whereas amphetamine and other psychostimulants primarily act on the dopamine system, there is also evidence that other neurotransmitter systems, such as the endogenous opioid system, modulate psychostimulant-induced effects. Several studies have investigated the role of opioid antagonists on cocaine-induced conditioned place preference (CPP), but there is limited information about the interaction with amphetamines. The aim of the present study was to investigate the effect of the opioid receptor antagonist, naltrexone (NTX) on the conditioning, expression and reinstatement of amphetamine-induced place preference. In addition, the effect of NTX on locomotor behaviour was measured during all sessions. During training, animals were conditioned with amphetamine (2 mg/kg) to induce place preference. In order to extinguish the conditioned behaviour, animals received saline for 12 days. Reinstatement of CPP was induced by a priming dose of amphetamine (0.5 mg/kg). The interaction of NTX and amphetamine was evaluated using three paradigms of CPP: with NTX (vehicle, 0.3, 1.0 and 3.0 mg/kg) administered either 30 minutes prior to amphetamine conditioning, or 30 minutes before the expression, or 30 minutes before the amphetamine priming to induce reinstatement. Naltrexone had no effect on the conditioning, the expression or the reinstatement induced by a priming dose of amphetamine. Further, NTX by itself did not induce place preference or place aversion. In contrast, NTX significantly attenuated the locomotor response to a priming dose of amphetamine without affecting general locomotor behaviour. The results suggest differences in opioid modulation of amphetamine-induced behaviours in the rat.
    Addiction Biology 04/2009; 14(3):260-9. · 5.91 Impact Factor
  • Jenny Häggkvist, Sara Lindholm, Johan Franck
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    ABSTRACT: Amphetamine produces its rewarding effects by enhancing dopamine transmission in the mesocorticolimbic pathway. Several studies have also suggested the involvement of the endogenous opioid system in mediating the neurochemical and behavioural effects of amphetamine. The aim of this study was to investigate the effect of the unselective opioid receptor antagonist naltrexone (NTX) on reinstatement of amphetamine self-administration in the rat. Animals were trained to self-administer amphetamine under a fixed ratio 1 (FR1) schedule (0.1mg/kg/infusion). After receiving a stable drug intake the amphetamine was replaced with saline and the animals went through an extinction period. After reaching the extinction criteria, animals were pre-treated with NTX (0, 0.3, 1.0 and 3.0mg/kg, s.c.) 30min before giving a priming dose of amphetamine (0.5mg/kg s.c). To study the effects of NTX on operant behaviour, animals were trained to lever press for food pellets under a FR1 schedule of reinforcement. Results from the present study shows that a single injection of amphetamine reinstated self-administration behaviour. NTX (0.3 and 1.0mg/kg) significantly attenuated the amphetamine-induced reinstatement but NTX had no effect at any dose studied on food taking behaviour. These results show that NTX attenuates reinstatement of amphetamine self-administration in rats without suppressing general behaviour, implicating a functional role for opioid receptors in modulating amphetamine seeking behaviour.
    Behavioural brain research 09/2008; 197(1):219-24. · 3.22 Impact Factor
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    ABSTRACT: Repeated exposure to ethanol has previously been shown to induce alterations in both midbrain dopamine and dynorphin systems. The aim of this study was to investigate functional changes in the sensitivity of dynorphin/kappa-receptor systems following repeated ethanol administration, using dopamine as an indirect marker. The effects of kappa-opioid receptor ligands on dopamine release in the rat nucleus accumbens were investigated following repeated ethanol administration (2 g/kg body weight, twice daily for 7 days). The selective kappa-receptor agonist U50, 488H reduced dopamine levels in both ethanol- and saline-treated animals, although the decline had a later onset and lasted shorter in the ethanol-treated group. Nor-binaltorphimine, a kappa-antagonist, produced a significant increase of dopamine in ethanol-treated rats, but lacked effect in the saline-treated group. This change in responsiveness of dopamine neurons following repeated ethanol administration could be related to changes in the sensitivity of kappa-receptor systems and/or an increase in dynorphin tone in the nucleus accumbens.
    Physiology & Behavior 10/2007; 92(1-2):167-71. · 3.16 Impact Factor
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    ABSTRACT: Wheel running performed by rats is reinforcing, rewarding and possibly addictive. In this study we analyzed if wheel running could affect ethanol preference. Lewis rats, known to be both addiction-prone and to develop an excessive wheel running behavior, were given access to ethanol in a two-bottle free-choice paradigm. The animals reached a high and stable ethanol intake after 5 weeks. In the next phase, rats were subjected to ethanol withdrawal for 1, 2 or 4 weeks with or without access to running wheels. Finally animals were again given access to ethanol in the same two-bottle free-choice paradigm, combined with access to running wheels. The rats that ran in running wheels during 1 or 2, but not 4, weeks of ethanol withdrawal increased both ethanol intake and preference as compared with the control group that did not have access to the wheels. Previous studies have demonstrated that low doses of morphine increases ethanol preference. Here we show that also running potentiates ethanol intake and preference. Thus, running which shares many of the reinforcing properties with addictive drugs appears to potentiate rats to an increased preference for ethanol. Our results describe a behavioral interaction where running increases ethanol consumption.
    Behavioural Brain Research 08/2002; 133(2):301-8. · 3.33 Impact Factor
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    ABSTRACT: The aim of this study was to study short- and long-term effects of repeated ethanol administration on nociceptin/orphanin FQ (N/OFQ) tissue concentrations in rat brain with radioimmunoassay. Animals were given either ethanol (intraperitoneal) or saline for 13 consecutive days. N/OFQ levels were examined at 30 min, 5 days and 21 days after the last dose on day 13. Ethanol-treated rats had significantly decreased N/OFQ tissue concentration in the hippocampus at 30 min after the last dose. N/OFQ levels were decreased in the cingulate cortex at 5 days after cessation of ethanol administration whereas no significant changes were found at 21 days. There were no significant changes in N/OFQ tissue concentrations at any time point studied in the mesolimbic dopamine (DA) system, a brain area associated with ethanol-induced activation. However, the results indicate that repeated ethanol administration may induce short- and long-term changes in N/OFQ tissue concentrations in other brain regions innervated with dopaminergic neurons.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2002; 26(2):303-6. · 3.55 Impact Factor
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    ABSTRACT: Ethanol and cocaine are frequently co-abused, and the drug combination has been reported to produce an increased and prolonged subjective euphoria as compared to when either drug is administered alone. Acute administration of ethanol or cocaine increases the extracellular dopamine (DA) concentration in the nucleus accumbens (NAcc), a terminal region of the mesolimbic dopaminergic pathway. In the present study, the effects of separate and concurrent administration of cocaine and ethanol on DA concentrations in the NAcc were studied in rats pretreated with ethanol. Four groups of rats received either ethanol (2 g/kg, i.p.) or saline twice daily for 6 consecutive days. Thereafter, rats were given injections of saline or cocaine for another 2 days (i.e. treatment days 7 and 8) using a 'binge' administration pattern (three i.p. injections of 15 mg/kg each with 1-h interval starting 40 min after the first of the two daily doses of ethanol/saline). Stereotypic behavior was scored after each 'binge' of cocaine or saline on days 7 and 8. The DA and DA metabolite concentrations were measured using microdialysis on day 8. Ethanol enhanced the effect of cocaine on DA concentration in the NAcc as compared to a single administration of cocaine. The DA levels increased and reached their maximum values within 20-40 min after the cocaine administration, then gradually declined until the next injection 1-h later. Cocaine-induced stereotypic behavior was significantly increased in both saline and ethanol pretreated groups, though there was no significant difference between the two groups. The results of this study suggest that the enhanced DA transmission may be related to the experience produced by concurrent abuse of ethanol and cocaine in humans.
    Brain Research 11/2001; 915(2):176-84. · 2.88 Impact Factor
  • S Lindholm, M Werme, S Brené, J Franck
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    ABSTRACT: Non-selective opioid receptor antagonists are increasingly used in the treatment of alcohol dependence. The clinical effects are significant but the effect size is rather small and unpleasant side effects may limit the benefits of the compounds. Ligands acting at mu- and/or delta- receptors can alter the voluntary intake of ethanol in various animal models. Therefore, the attenuating effects of selective opioid receptor ligands on ethanol intake may be of clinical interest in the treatment of alcoholism. The objective of this study was to examine the effects of a selective kappa-receptor agonist, U50,488H on voluntary ethanol intake in the rat. We used a restricted access model with a free choice between an ethanol solution (10% v/v) and water. During the 3-days baseline period, the rats received a daily saline injection (1 ml/kg, i.p.) 15 min before the 2 h access to ethanol. The animals had free access to water at all times. The control group received a daily saline injection during the 4-days treatment-period, whereas the treatment groups received a daily dose of U50,488H (2.5, 5.0 or 10 mg/kg per day). Animals treated with U50,488H dose-dependently decreased their ethanol intake. The effect of the highest dose of U50,488H was reduced by pre-treatment with the selective kappa-antagonist nor-binaltorphimine (nor-BNI). These results demonstrate that activation of kappa-opioid receptors can attenuate voluntary ethanol intake in the rat, and the data suggest that the brain dynorphin/kappa-receptor systems may represent a novel target for pharmacotherapy in the treatment of alcohol dependence.
    Behavioural Brain Research 06/2001; 120(2):137-46. · 3.33 Impact Factor
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    ABSTRACT: Non-selective opioid receptor antagonists are increasingly used in the treatment of alcohol dependence. The clinical effects are significant but the effect size is rather small and unpleasant side effects may limit the benefits of the compounds. Ligands acting at μ- and/or δ- receptors can alter the voluntary intake of ethanol in various animal models. Therefore, the attenuating effects of selective opioid receptor ligands on ethanol intake may be of clinical interest in the treatment of alcoholism. The objective of this study was to examine the effects of a selective κ-receptor agonist, U50,488H on voluntary ethanol intake in the rat. We used a restricted access model with a free choice between an ethanol solution (10% v/v) and water. During the 3-days baseline period, the rats received a daily saline injection (1 ml/kg, i.p.) 15 min before the 2 h access to ethanol. The animals had free access to water at all times. The control group received a daily saline injection during the 4-days treatment-period, whereas the treatment groups received a daily dose of U50,488H (2.5, 5.0 or 10 mg/kg per day). Animals treated with U50,488H dose-dependently decreased their ethanol intake. The effect of the highest dose of U50,488H was reduced by pre-treatment with the selective κ-antagonist nor-binaltorphimine (nor-BNI). These results demonstrate that activation of κ-opioid receptors can attenuate voluntary ethanol intake in the rat, and the data suggest that the brain dynorphin/κ-receptor systems may represent a novel target for pharmacotherapy in the treatment of alcohol dependence.
    Behavioural Brain Research. 01/2001;
  • S Lindholm, K Ploj, J Franck, I Nylander
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    ABSTRACT: Recently, we have shown that rats repeatedly treated with ethanol and/or cocaine have decreased kappa-opioid receptor mRNA levels in the mesolimbic system. The aim of the present study was to investigate the short- and long-term effects of repeated ethanol administration on opioid peptide concentrations in brain tissue of male Sprague-Dawley rats. Dynorphin B (1-13) (Dyn B) and Met-enkephalinArg(6)Phe(7) (MEAP), endogenous ligands to kappa- and delta-opioid receptors, respectively, were measured using radioimmunoassays. The rats were given either ethanol [intraperitoneal (ip), twice daily, 2 g/kg bw/dose] or saline for 13 consecutive days. Thirty minutes after the last ethanol dose on Day 13, the Dyn B tissue concentration was significantly decreased in the cingulate cortex. The MEAP tissue concentration was decreased in the hippocampus 5 days after the last ethanol injection as compared to saline-treated controls. Furthermore, the Dyn B and the MEAP concentrations were increased in the periaqueductal grey area (PAG) at this time point. Of particular interest were the significant increases in Dyn B tissue concentrations found in the nucleus accumbens (NAcc) at 30 min and at 21 days after the last ethanol dose. The results suggest that repeated ethanol administration induces both short- and long-term changes in the tissue concentrations of opioids in certain brain regions associated with motivation and reward.
    Alcohol 12/2000; 22(3):165-71. · 2.26 Impact Factor
  • A Rosin, S Lindholm, J Franck, J Georgieva
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    ABSTRACT: The combination of ethanol and cocaine is commonly abused by human addicts which has serious clinical consequences. Here, the effects of separately and concurrently administered ethanol and 'binge' cocaine on kappa opioid receptor (KOR) mRNA in the ventral tegmental area (VTA) and nucleus accumbens (NAc) of rats were studied. KOR mRNA was down-regulated in both brain regions during concurrent as well as separate treatment with these drugs. In the VTA, the most pronounced decrease was obtained following combined treatment with ethanol and 'binge' cocaine. In the NAc, the strongest decrease was observed in the 'binge' cocaine group. This profound decrease of KOR mRNA in regions important for brain reward suggests a potential role of the KOR system in the abuse of cocaine and ethanol.
    Neuroscience Letters 12/1999; 275(1):1-4. · 2.03 Impact Factor
  • J Franck, S Lindholm, P Raaschou
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    ABSTRACT: The acute effect of opioid antagonists on volitional ethanol intake was studied in unselected Sprague-Dawley rats using a two-bottle, free-choice model. The total daily intake of ethanol during saline treatment was 1.79 +/- 0.4 g/kg/day (n = 136). The rats were deprived of fluids for the last 4 hr of the light period. Saline or drug was given intraperitoneally 20 to 30 min before the onset of dark, and the ethanol and water intakes were measured during the following hour. The ethanol intake during this hour was 0.75 +/- 0.06 g/kg (n = 136). Naltrexone significantly reduced ethanol intake. There was also a significant reduction in ethanol intake following administration of ICI-174,864. Naloxonazine and naloxone methiodide lacked effect. None of the treatments had any effect on the water or food intake. The results suggest that central delta-opioid receptors modulate volitional ethanol intake in the rat.
    Alcoholism Clinical and Experimental Research 10/1998; 22(6):1185-9. · 3.42 Impact Factor
  • Johan Franck, Sara Lindholm, Pauline Raaschou
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    ABSTRACT: The acute effect of opioid antagonists on volitional ethanol intake was studied in unselected Sprague-Dawley rats using a two-bottle, free-choice model. The total daily intake of ethanol during saline treatment was 1.79 ± 0.4 g/kg/day (n= 136). The rats were deprived of fluids for the last 4 hr of the light period. Saline or drug was given intraperitoneally 20 to 30 min before the onset of dark, and the ethanol and water intakes were measured during the following hour. The ethanol intake during this hour was 0.75 ± 0.06 g/kg (n= 136). Naltrexone significantly reduced ethanol intake. There was also a signiflcant reduction in ethanol Intake following administration of ICI-174,864. Naloxonazine and naloxone methiodide lacked effect. None of the treatments had any effect on the water or food intake. The resutts suggest that central bopioid receptors modulate volitional ethanol intake in the rat.
    Alcoholism Clinical and Experimental Research 08/1998; 22(6):1185 - 1189. · 3.42 Impact Factor