10 results on '"Korpi, Esa R."'
Search Results
2. GABA B receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self‐administration of alcohol and cocaine
- Author
-
Miguel, Elena, primary, Vekovischeva, Olga, additional, Kuokkanen, Katja, additional, Vesajoki, Marja, additional, Paasikoski, Nelli, additional, Kaskinoro, Janne, additional, Myllymäki, Mikko, additional, Lainiola, Mira, additional, Janhunen, Sanna K., additional, Hyytiä, Petri, additional, Linden, Anni‐Maija, additional, and Korpi, Esa R., additional
- Published
- 2018
- Full Text
- View/download PDF
3. GABAB receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self-administration of alcohol and cocaine.
- Author
-
Miguel, Elena, Vekovischeva, Olga, Kuokkanen, Katja, Vesajoki, Marja, Paasikoski, Nelli, Kaskinoro, Janne, Myllymäki, Mikko, Lainiola, Mira, Janhunen, Sanna K., Hyytiä, Petri, Linden, Anni‐Maija, Korpi, Esa R., de Miguel, Elena, and Linden, Anni-Maija
- Subjects
TREATMENT of drug addiction ,COCAINE ,ALCOHOL ,COMPULSIVE behavior ,BINDING site assay ,BIOCHEMISTRY ,RODENTS ,GABA agonists ,QUINONE ,ANIMAL behavior ,RESEARCH ,NEURONS ,ANIMAL experimentation ,HETEROCYCLIC compounds ,RESEARCH methodology ,NEUROPLASTICITY ,CELL receptors ,EVALUATION research ,MEDICAL cooperation ,GABA modulators ,PHENOMENOLOGY ,SELF medication ,RATS ,COMPARATIVE studies ,REWARD (Psychology) ,BACLOFEN ,IMPACT of Event Scale ,RESEARCH funding ,ETHANOL ,DOPAMINE uptake inhibitors ,CENTRAL nervous system depressants ,BRAIN stem ,MICE ,PHARMACODYNAMICS - Abstract
Drugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug-induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug-seeking behavior. To evaluate the impact of GABAB receptors on addiction-related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABAB receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward-related behaviors induced by ethanol and cocaine. A novel compound (S)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-4-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (ORM-27669) was found to be a GABAB PAM of low efficacy as agonist, whereas the reference compound (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) had a different allosteric profile being a more potent PAM in the calcium-based assay and an agonist, coupled with potent PAM activity, in the [35 S] GTPγS binding assay in rat and human recombinant receptors. Using autoradiography, the high-efficacy rac-BHFF and the low-efficacy ORM-27669 potentiated the effects of baclofen on [35 S] GTPγS binding with identical brain regional distribution. Treatment of mice with baclofen, rac-BHFF, or ORM-27669 failed to induce glutamate receptor neuroplasticity in the VTA DA neurons. Pretreatment with rac-BHFF at non-sedative doses effectively reversed both ethanol- and cocaine-induced plasticity and attenuated cocaine i.v. self-administration and ethanol drinking. Pretreatment with ORM-27669 only reversed ethanol-induced neuroplasticity and attenuated ethanol drinking but had no effects on cocaine-induced neuroplasticity or self-administration. These findings encourage further investigation of GABAB receptor PAMs with different efficacies in addiction models to develop novel treatment strategies for drug addiction. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
4. Addiction-related interactions of pregabalin with morphine in mice and humans: reinforcing and inhibiting effects
- Author
-
Vashchinkina, Elena, primary, Piippo, Ossi, additional, Vekovischeva, Olga, additional, Krupitsky, Evgeny, additional, Ilyuk, Ruslan, additional, Neznanov, Nikholay, additional, Kazankov, Kirill, additional, Zaplatkin, Igor, additional, and Korpi, Esa R., additional
- Published
- 2017
- Full Text
- View/download PDF
5. Addiction-related interactions of pregabalin with morphine in mice and humans: reinforcing and inhibiting effects.
- Author
-
Vashchinkina, Elena, Piippo, Ossi, Vekovischeva, Olga, Krupitsky, Evgeny, Ilyuk, Ruslan, Neznanov, Nikholay, Kazankov, Kirill, Zaplatkin, Igor, and Korpi, Esa R.
- Subjects
MORPHINE abuse ,PREGABALIN ,REINFORCEMENT (Psychology) ,RESPONSE inhibition ,TRANQUILIZING drugs ,LABORATORY mice - Abstract
The gabapentinoid pregabalin is a rapid-acting anxiolytic and analgesic, possibly suitable in supervised opioid detoxification. However, clinicians have been cautious in using it because of its unknown addictive risk and rising number of mortalities after pregabalin self-medication in opioid abusers. Here, we studied interactions of pregabalin and morphine on reward functions of the dopamine system in mice and the efficacy of pregabalin on withdrawal in opioid addicts. After the treatment of mice with pregabalin and morphine, we used electrophysiology to study neuroplasticity in midbrain slices, self-administration and conditioned place preference tests to investigate the rewarding potential of pregabalin and naloxone-precipitated morphine withdrawal to evaluate opioid withdrawal symptoms. Further, we ran a pilot single-blind, randomized, controlled trial (34 heroin addicts) to evaluate the efficacy and safety of pregabalin in the treatment of opioid withdrawal syndrome. Pregabalin alone did not induce glutamate receptor neuroplasticity of dopamine neurons in the ventral tegmental area, but pre-treatment with pregabalin suppressed morphine-induced neuroplasticity, hyperlocomotion and morphine self-administration. Pregabalin administration after chronic morphine exposure failed to induce any rewarding effects. Instead, pregabalin suppressed withdrawal symptoms in both morphine-treated mice and opioid addicts and was well tolerated. Intriguingly, pregabalin administration after a low dose of morphine strongly facilitated ventral tegmental area neuroplasticity and led to increased conditioned place preference. Pregabalin appears to have the efficacy to counteract both reinforcing and withdrawal effects of opioids, but it also has a potentiating effect when given to mice with existing opioid levels. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
6. Continuous delivery of naltrexone and nalmefene leads to tolerance in reducing alcohol drinking and to supersensitivity of brain opioid receptors.
- Author
-
Korpi, Esa R., Linden, Anni‐Maija, Hytönen, Heidi R., Paasikoski, Nelli, Vashchinkina, Elena, Dudek, Mateusz, Herr, Deron R., and Hyytiä, Petri
- Subjects
- *
NALTREXONE , *OPIOID receptors , *G protein coupled receptors , *PEOPLE with alcoholism , *HEALTH , *THERAPEUTICS , *ALCOHOLISM , *ANIMAL experimentation , *BIOLOGICAL models , *BRAIN , *CELL receptors , *ETHANOL , *NARCOTIC antagonists , *RATS , *PHARMACODYNAMICS ,ALCOHOL drinking prevention - Abstract
Opioid antagonist treatments reduce alcohol drinking in rodent models and in alcohol-dependent patients, with variable efficacy across different studies. These treatments may suffer from the development of tolerance and opioid receptor supersensitivity, as suggested by preclinical models showing activation of these processes during and after subchronic high-dose administration of the short-acting opioid antagonist naloxone. In the present study, we compared equipotent low and moderate daily doses of naltrexone and nalmefene, two opioid antagonists in the clinical practice for treatment of alcoholism. The antagonists were given here subcutaneously for 7 days either as daily injections or continuous osmotic minipump-driven infusions to alcohol-preferring AA rats having trained to drink 10% alcohol in a limited access protocol. One day after stopping the antagonist treatment, [35 S]GTPγS autoradiography on brain cryostat sections was carried out to examine the coupling of receptors to G protein activation. The results prove the efficacy of repeated injections over infused opioid antagonists in reducing alcohol drinking. Tolerance to the reducing effect on alcohol drinking and to the enhancement of G protein coupling to μ-opioid receptors in various brain regions were consistently detected only after infused antagonists. Supersensitivity of κ-opioid receptors was seen in the ventral and dorsal striatal regions especially by infused nalmefene. Nalmefene showed no clear agonistic activity in rat brain sections or at human recombinant κ-opioid receptors. The findings support the as-needed dosing practice, rather than the standard continual dosing, in the treatment of alcoholism with opioid receptor antagonists. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
7. Chronic ethanol treatment and GABA A receptor a6 subunit gene expression: a study using a6 subunit-deficient mice
- Author
-
Vekovischeva, Olga Y., primary, Uusi-Oukari, Mikko, additional, and Korpi, Esa R., additional
- Published
- 2000
- Full Text
- View/download PDF
8. Chronic ethanol treatment and GABAAreceptor α6 subunit gene expression: a study using α6 subunit-deficient mice.
- Author
-
Vekovischeva, Olga Y., Uusi-Oukari, Mikko, and Korpi, Esa R.
- Subjects
PHYSIOLOGICAL effects of alcohol ,GABA ,RAT physiology ,ALCOHOLISM ,BIOCHEMICAL mechanism of action ,GENETICS - Abstract
Chronic alcohol administration increases the expression of cerebellum-specific GABA[sub A] receptor alpha 6 subunit mRNA, protein and selective autoradiographical finger print on rat and mouse brain sections. We have tested whether the alpha 6 gene is activated by chronic alcohol administration (daily p.o. injection of 2 g/kg during the first 3 days and 2.5 g/kg during the next 17 days) that produced tolerance in the rotarod test to motor impairment by acute challenge of ethanol (2 g/kg, i.p.). We utilized a mouse line engineered to express E. coli beta-galactosidase enzyme and an unfunctional truncated alpha 6 subunit under the control of the alpha 6 gene promoter. Chronic ethanol treatment failed to alter the cerebellar beta-galactosidase activity when compared with no treatment and isocaloric sucrose treatment in groups of alpha 6 subunit-deficient mice. The results suggest that tolerance to motor-impairing effects of ethanol can be achieved in the absence of alpha 6 subunit-containing GABA[sub A] receptors, but that the reported upregulation of alpha 6 gene transcription by ethanol treatment requires functional alpha 6 subunits. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
9. GABA B receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self-administration of alcohol and cocaine.
- Author
-
de Miguel E, Vekovischeva O, Kuokkanen K, Vesajoki M, Paasikoski N, Kaskinoro J, Myllymäki M, Lainiola M, Janhunen SK, Hyytiä P, Linden AM, and Korpi ER
- Subjects
- Allosteric Regulation, Animals, Baclofen pharmacology, Behavior, Animal drug effects, Benzofurans pharmacology, CHO Cells, Cricetulus, GABA-B Receptor Agonists pharmacology, Humans, Mice, Quinazolinones pharmacology, Rats, Receptors, Glutamate drug effects, Receptors, Glutamate metabolism, Reward, Self Administration, Ventral Tegmental Area cytology, Ventral Tegmental Area drug effects, Central Nervous System Depressants pharmacology, Cocaine pharmacology, Dopamine Uptake Inhibitors pharmacology, Dopaminergic Neurons drug effects, Ethanol pharmacology, GABA Modulators pharmacology, Neuronal Plasticity drug effects, Receptors, GABA-B drug effects
- Abstract
Drugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug-induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug-seeking behavior. To evaluate the impact of GABA
B receptors on addiction-related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABAB receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward-related behaviors induced by ethanol and cocaine. A novel compound (S)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-4-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (ORM-27669) was found to be a GABAB PAM of low efficacy as agonist, whereas the reference compound (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) had a different allosteric profile being a more potent PAM in the calcium-based assay and an agonist, coupled with potent PAM activity, in the [35 S] GTPγS binding assay in rat and human recombinant receptors. Using autoradiography, the high-efficacy rac-BHFF and the low-efficacy ORM-27669 potentiated the effects of baclofen on [35 S] GTPγS binding with identical brain regional distribution. Treatment of mice with baclofen, rac-BHFF, or ORM-27669 failed to induce glutamate receptor neuroplasticity in the VTA DA neurons. Pretreatment with rac-BHFF at non-sedative doses effectively reversed both ethanol- and cocaine-induced plasticity and attenuated cocaine i.v. self-administration and ethanol drinking. Pretreatment with ORM-27669 only reversed ethanol-induced neuroplasticity and attenuated ethanol drinking but had no effects on cocaine-induced neuroplasticity or self-administration. These findings encourage further investigation of GABAB receptor PAMs with different efficacies in addiction models to develop novel treatment strategies for drug addiction., (© 2018 Society for the Study of Addiction.)- Published
- 2019
- Full Text
- View/download PDF
10. Selective delta-opioid receptor antagonist N,N(CH3)2-Dmt-Tic-OH does not reduce ethanol intake in alcohol-preferring AA rats.
- Author
-
Ingman K, Salvadori S, Lazarus L, Korpi ER, and Honkanen A
- Subjects
- Animals, Behavior, Animal physiology, Brain drug effects, Brain metabolism, Dipeptides administration & dosage, Drug Administration Schedule, Enkephalin, D-Penicillamine (2,5)- metabolism, Enkephalin, D-Penicillamine (2,5)- therapeutic use, Ethanol administration & dosage, Locomotion drug effects, Male, Naltrexone therapeutic use, Narcotic Antagonists administration & dosage, Rats, Alcoholism rehabilitation, Choice Behavior, Dipeptides pharmacology, Dipeptides therapeutic use, Ethanol adverse effects, Narcotic Antagonists pharmacology, Narcotic Antagonists therapeutic use, Receptors, Opioid, delta antagonists & inhibitors, Tetrahydroisoquinolines
- Abstract
We studied the effect of a novel delta-opioid receptor antagonist N,N(CH(3))(2)Dmt-Tic-OH (Me(2)-Dmt-Tic-OH) on voluntary ethanol intake in an alcohol-preferring AA (Alko, Alcohol) rat line using a 4-hour limited access paradigm. Acute injections of Me(2)-Dmt-Tic-OH (10 and 30 mg/kg, i.p.) did not reduce 1-hour or 4-hour ethanol intake. Subtype non-selective opioid receptor antagonist naltrexone [0.1 and 0.3 mg/kg, subcutaneously (s.c.)] significantly reduced 1-hour ethanol drinking but had no effect on 4-hour ethanol consumption. Locomotor stimulation induced by the delta-opioid receptor agonist Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE; 15 microg, intracerebroventricularly) was significantly attenuated by Me(2)-Dmt-Tic-OH (10 and 30 mg/kg, i.p.), which confirmed its efficacy as a delta-opioid receptor antagonist in rat brain. Our results support the idea that delta-opioid receptors do not mediate alcohol reward in AA rats.
- Published
- 2003
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.