15 results on '"Korpi, Esa R."'
Search Results
2. Mice Lacking GABAA Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs
- Author
-
Grotell, Milo, Abdurakhmanova, Shamsiiat, Elsilä, Lauri V., and Korpi, Esa R.
- Subjects
Pharmacology ,pharmaco-EEG ,extrasynaptic GABAA receptors ,stimulants ,opioids ,ethanol ,Therapeutics. Pharmacology ,RM1-950 ,psychedelics ,Original Research - Abstract
In the brain, extrasynaptically expressed ionotropic, δ subunit-containing γ-aminobutyric acid A-type receptors (δ-GABAARs) have been implicated in drug effects at both neuronal and behavioral levels. These alterations are supposed to be caused via drug-induced modulation of receptor ionophores affecting chloride ion-mediated inhibitory tonic currents. Often, a transgenic mouse model genetically lacking the δ-GABAARs (δ-KO) has been used to study the roles of δ-GABAARs in brain functions, because a specific antagonist of the δ-GABAARs is still lacking. We have previously observed with these δ-KO mice that activation of δ-GABAARs is needed for morphine-induced conditioning of place preference, and others have suggested that δ-GABAARs act as targets selectively for low doses of ethanol. Furthermore, activation of these receptors via drug-mediated agonism induces a robust increase in the slow-wave frequency bands of electroencephalography (EEG). Here, we tested δ-KO mice (compared to littermate wild-type controls) for the pharmaco-EEG responses of a broad spectrum of pharmacologically different drug classes, including alcohol, opioids, stimulants, and psychedelics. Gaboxadol (THIP), a known superagonist of δ-GABAARs, was included as the positive control, and as expected, δ-KO mice produced a blunted pharmaco-EEG response to 6 mg/kg THIP. Pharmaco-EEGs showed notable differences between treatments but also differences between δ-KO mice and their wild-type littermates. Interestingly mephedrone (4-MMC, 5 mg/kg), an amphetamine-like stimulant, had reduced effects in the δ-KO mice. The responses to ethanol (1 g/kg), LSD (0.2 mg/kg), and morphine (20 mg/kg) were similar in δ-KO and wild-type mice. Since stimulants are not known to act on δ-GABAARs, our findings on pharmaco-EEG effects of 4-MMC suggest that δ-GABAARs are involved in the secondary indirect regulation of the brain rhythms after 4-MMC.
- Published
- 2021
3. Alcohol Co-Administration Changes Mephedrone-Induced Alterations of Neuronal Activity
- Author
-
Grotell, Milo, primary, den Hollander, Bjørnar, additional, Jalkanen, Aaro, additional, Törrönen, Essi, additional, Ihalainen, Jouni, additional, de Miguel, Elena, additional, Dudek, Mateusz, additional, Kettunen, Mikko I., additional, Hyytiä, Petri, additional, Forsberg, Markus M., additional, Kankuri, Esko, additional, and Korpi, Esa R., additional
- Published
- 2021
- Full Text
- View/download PDF
4. Acute Lysergic Acid Diethylamide Does Not Influence Reward-Driven Decision Making of C57BL/6 Mice in the Iowa Gambling Task
- Author
-
Elsilä, Lauri V., primary, Korhonen, Nuppu, additional, Hyytiä, Petri, additional, and Korpi, Esa R., additional
- Published
- 2020
- Full Text
- View/download PDF
5. Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABAA Receptors to Histamine Receptor 3 Antagonists
- Author
-
Abdurakhmanova, Shamsiiat, primary, Grotell, Milo, additional, Kauhanen, Jenna, additional, Linden, Anni-Maija, additional, Korpi, Esa R., additional, and Panula, Pertti, additional
- Published
- 2020
- Full Text
- View/download PDF
6. Mice Lacking GABAA Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs.
- Author
-
Grotell, Milo, Abdurakhmanova, Shamsiiat, Elsilä, Lauri V., and Korpi, Esa R.
- Subjects
GABA receptors ,LABORATORY mice ,BRAIN waves ,CHLORIDE channels ,MICE ,TRANSGENIC mice ,PHARMACODYNAMICS ,OPIOID receptors - Abstract
In the brain, extrasynaptically expressed ionotropic, δ subunit-containing γ-aminobutyric acid A-type receptors (δ-GABA
A Rs) have been implicated in drug effects at both neuronal and behavioral levels. These alterations are supposed to be caused via drug-induced modulation of receptor ionophores affecting chloride ion-mediated inhibitory tonic currents. Often, a transgenic mouse model genetically lacking the δ-GABAA Rs (δ-KO) has been used to study the roles of δ-GABAA Rs in brain functions, because a specific antagonist of the δ-GABAA Rs is still lacking. We have previously observed with these δ-KO mice that activation of δ-GABAA Rs is needed for morphine-induced conditioning of place preference, and others have suggested that δ-GABAA Rs act as targets selectively for low doses of ethanol. Furthermore, activation of these receptors via drug-mediated agonism induces a robust increase in the slow-wave frequency bands of electroencephalography (EEG). Here, we tested δ-KO mice (compared to littermate wild-type controls) for the pharmaco-EEG responses of a broad spectrum of pharmacologically different drug classes, including alcohol, opioids, stimulants, and psychedelics. Gaboxadol (THIP), a known superagonist of δ-GABAA Rs, was included as the positive control, and as expected, δ-KO mice produced a blunted pharmaco-EEG response to 6 mg/kg THIP. Pharmaco-EEGs showed notable differences between treatments but also differences between δ-KO mice and their wild-type littermates. Interestingly mephedrone (4-MMC, 5 mg/kg), an amphetamine-like stimulant, had reduced effects in the δ-KO mice. The responses to ethanol (1 g/kg), LSD (0.2 mg/kg), and morphine (20 mg/kg) were similar in δ-KO and wild-type mice. Since stimulants are not known to act on δ-GABAA Rs, our findings on pharmaco-EEG effects of 4-MMC suggest that δ-GABAA Rs are involved in the secondary indirect regulation of the brain rhythms after 4-MMC. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
7. Attenuation of Novelty-Induced Hyperactivity of Gria1-/- Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics
- Author
-
Aitta-aho, Teemu, primary, Maksimovic, Milica, additional, Dahl, Kristiina, additional, Sprengel, Rolf, additional, and Korpi, Esa R., additional
- Published
- 2019
- Full Text
- View/download PDF
8. Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABAA Receptors to Histamine Receptor 3 Antagonists.
- Author
-
Abdurakhmanova, Shamsiiat, Grotell, Milo, Kauhanen, Jenna, Linden, Anni-Maija, Korpi, Esa R., and Panula, Pertti
- Subjects
ANTIHISTAMINES ,HISTAMINE receptors ,GABA transporters ,OPIOID receptors ,GABA ,MICE ,BIOGENIC amines - Abstract
Histamine/gamma-aminobutyric acid (GABA) neurons of posterior hypothalamus send wide projections to many brain areas and participate in stabilizing the wake state. Recent research has suggested that GABA released from the histamine/GABA neurons acts on extrasynaptic GABA
A receptors and balances the excitatory effect of histamine. In the current study, we show the presence of vesicular GABA transporter mRNA in a majority of quantified hypothalamic histaminergic neurons, which suggest vesicular release of GABA. As histamine/GABA neurons form conventional synapses infrequently, it is possible that GABA released from these neurons diffuses to target areas by volume transmission and acts on extrasynaptic GABA receptors. To investigate this hypothesis, mice lacking extrasynaptic GABAA receptor δ subunit (Gabrd KO) were used. A pharmacological approach was employed to activate histamine/GABA neurons and induce histamine and presumably, GABA, release. Control and Gabrd KO mice were treated with histamine receptor 3 (Hrh3) inverse agonists ciproxifan and pitolisant, which block Hrh3 autoreceptors on histamine/GABA neurons and histamine-dependently promote wakefulness. Low doses of ciproxifan (1 mg/kg) and pitolisant (5 mg/kg) reduced locomotion in Gabrd KO, but not in WT mice. EEG recording showed that Gabrd KO mice were also more sensitive to the wake-promoting effect of ciproxifan (3 mg/kg) than control mice. Low frequency delta waves, associated with NREM sleep, were significantly suppressed in Gabrd KO mice compared with the WT group. Ciproxifan-induced wakefulness was blocked by histamine synthesis inhibitor α-fluoromethylhistidine (αFMH). The findings indicate that both histamine and GABA, released from histamine/GABA neurons, are involved in regulation of brain arousal states and δ-containing subunit GABAA receptors are involved in mediating GABA response. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
9. Increased Motor-Impairing Effects of the Neuroactive Steroid Pregnanolone in Mice with Targeted Inactivation of the GABAA Receptor γ2 Subunit in the Cerebellum
- Author
-
Leppä, Elli, primary, Linden, Anni-Maija, additional, Aller, Maria I., additional, Wulff, Peer, additional, Vekovischeva, Olga, additional, Luscher, Bernhard, additional, Lüddens, Hartmut, additional, Wisden, William, additional, and Korpi, Esa R., additional
- Published
- 2016
- Full Text
- View/download PDF
10. GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area
- Author
-
Vashchinkina, Elena, primary, Panhelainen, Anne, additional, Aitta-aho, Teemu, additional, and Korpi, Esa R., additional
- Published
- 2014
- Full Text
- View/download PDF
11. Increased Motor-Impairing Effects of the Neuroactive Steroid Pregnanolone in Mice with Targeted Inactivation of the GABAA Receptor γ2 Subunit in the Cerebellum.
- Author
-
Leppä, Elli, Linden, Anni-Maija, Aller, Maria I., Wulff, Peer, Vekovischeva, Olga, Luscher, Bernhard, Lüddens, Hartmut, Wisden, William, and Korpi, Esa R.
- Subjects
GABA receptors ,INTRAPERITONEAL injections ,CEREBELLAR tumors - Abstract
Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABA
A receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABAA receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunitcontaining receptors and even on ab binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABAA receptormediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABAA receptor γ2 subunit gene selectively deleted either in parvalbumin-containing cells (including cerebellar Purkinje cells), cerebellar granule cells, or just in cerebellar Purkinje cells were trained on the accelerated rotating rod and then tested for motor impairment after cumulative intraperitoneal dosing of 5β-pregnan-3α-ol-20-one. Motorimpairing effects of 5β-pregnan-3α-ol-20-one were strongly increased in all three mouse models in which γ2 subunit-dependent synaptic GABAA responses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABAA receptors in Purkinje cells normalized the effect of the steroid. Anxiolytic/explorative effects of the steroid in elevated plus maze and light:dark exploration tests in mice with Purkinje cell γ2 subunit inactivation were similar to those in control mice. The results suggest that, when the deletion of γ2 subunit has removed synaptic GABAA receptors from the specific cerebellar neuronal populations, the effects of neuroactive steroids solely on extrasynaptic ab or abd receptors lead to enhanced changes in the cerebellum-generated behavior. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
12. GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area.
- Author
-
Vashchinkina, Elena, Panhelainen, Anne, Aitta-aho, Teemu, Korpi, Esa R., Sanna, Enrico, and Trantham-Davidson, Heather
- Subjects
GABA receptors ,NEUROPLASTICITY ,BENZODIAZEPINES ,DOPAMINE ,MESENCEPHALIC tegmentum - Abstract
GABA
A receptors are the main fast inhibitory neurotransmitter receptors in the mammalian brain, and targets for many clinically important drugs widely used in the treatment of anxiety disorders, insomnia and in anesthesia. Nonetheless, there are significant risks associated with the long-term use of these drugs particularly related to development of tolerance and addiction. Addictive mechanisms of GABAA receptor drugs are poorly known, but recent findings suggest that those drugs may induce aberrant neuroadaptations in the brain reward circuitry. Recently, benzodiazepines, acting on synaptic GABAA receptors, and modulators of extrasynaptic GABAA receptors (THIP and neurosteroids) have been found to induce plasticity in the ventral tegmental area (VTA) dopamine neurons and their main target projections. Furthermore, depending whether synaptic or extrasynaptic GABAA receptor populations are activated, the behavioral outcome of repeated administration seems to correlate with rewarding or aversive behavioral responses, respectively. The VTA dopamine neurons project to forebrain centers such as the nucleus accumbens and medial prefrontal cortex, and receive afferent projections from these brain regions and especially from the extended amygdala and lateral habenula, forming the major part of the reward and aversion circuitry. Both synaptic and extrasynaptic GABAA drugs inhibit the VTA GABAergic interneurons, thus activating the VTA DA neurons by disinhibition and this way inducing glutamatergic synaptic plasticity. However, the GABAA drugs failed to alter synaptic spine numbers as studied from Golgi-Cox-stained VTA dendrites. Since the GABAergic drugs are known to depress the brain metabolism and gene expression, their likely way of inducing neuroplasticity in mature neurons is by disinhibiting the principal neurons, which remains to be rigorously tested for a number of clinically important anxiolytics, sedatives and anesthetics in different parts of the circuitry. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
13. Mice Lacking GABA A Receptor δ Subunit Have Altered Pharmaco-EEG Responses to Multiple Drugs.
- Author
-
Grotell M, Abdurakhmanova S, Elsilä LV, and Korpi ER
- Abstract
In the brain, extrasynaptically expressed ionotropic, δ subunit-containing γ-aminobutyric acid A-type receptors (δ-GABA
A Rs) have been implicated in drug effects at both neuronal and behavioral levels. These alterations are supposed to be caused via drug-induced modulation of receptor ionophores affecting chloride ion-mediated inhibitory tonic currents. Often, a transgenic mouse model genetically lacking the δ-GABAA Rs (δ-KO) has been used to study the roles of δ-GABAA Rs in brain functions, because a specific antagonist of the δ-GABAA Rs is still lacking. We have previously observed with these δ-KO mice that activation of δ-GABAA Rs is needed for morphine-induced conditioning of place preference, and others have suggested that δ-GABAA Rs act as targets selectively for low doses of ethanol. Furthermore, activation of these receptors via drug-mediated agonism induces a robust increase in the slow-wave frequency bands of electroencephalography (EEG). Here, we tested δ-KO mice (compared to littermate wild-type controls) for the pharmaco-EEG responses of a broad spectrum of pharmacologically different drug classes, including alcohol, opioids, stimulants, and psychedelics. Gaboxadol (THIP), a known superagonist of δ-GABAA Rs, was included as the positive control, and as expected, δ-KO mice produced a blunted pharmaco-EEG response to 6 mg/kg THIP. Pharmaco-EEGs showed notable differences between treatments but also differences between δ-KO mice and their wild-type littermates. Interestingly mephedrone (4-MMC, 5 mg/kg), an amphetamine-like stimulant, had reduced effects in the δ-KO mice. The responses to ethanol (1 g/kg), LSD (0.2 mg/kg), and morphine (20 mg/kg) were similar in δ-KO and wild-type mice. Since stimulants are not known to act on δ-GABAA Rs, our findings on pharmaco-EEG effects of 4-MMC suggest that δ-GABAA Rs are involved in the secondary indirect regulation of the brain rhythms after 4-MMC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Grotell, Abdurakhmanova, Elsilä and Korpi.)- Published
- 2021
- Full Text
- View/download PDF
14. Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABA A Receptors to Histamine Receptor 3 Antagonists.
- Author
-
Abdurakhmanova S, Grotell M, Kauhanen J, Linden AM, Korpi ER, and Panula P
- Abstract
Histamine/gamma-aminobutyric acid (GABA) neurons of posterior hypothalamus send wide projections to many brain areas and participate in stabilizing the wake state. Recent research has suggested that GABA released from the histamine/GABA neurons acts on extrasynaptic GABA
A receptors and balances the excitatory effect of histamine. In the current study, we show the presence of vesicular GABA transporter mRNA in a majority of quantified hypothalamic histaminergic neurons, which suggest vesicular release of GABA. As histamine/GABA neurons form conventional synapses infrequently, it is possible that GABA released from these neurons diffuses to target areas by volume transmission and acts on extrasynaptic GABA receptors. To investigate this hypothesis, mice lacking extrasynaptic GABAA receptor δ subunit (Gabrd KO) were used. A pharmacological approach was employed to activate histamine/GABA neurons and induce histamine and presumably, GABA, release. Control and Gabrd KO mice were treated with histamine receptor 3 (Hrh3) inverse agonists ciproxifan and pitolisant, which block Hrh3 autoreceptors on histamine/GABA neurons and histamine-dependently promote wakefulness. Low doses of ciproxifan (1 mg/kg) and pitolisant (5 mg/kg) reduced locomotion in Gabrd KO, but not in WT mice. EEG recording showed that Gabrd KO mice were also more sensitive to the wake-promoting effect of ciproxifan (3 mg/kg) than control mice. Low frequency delta waves, associated with NREM sleep, were significantly suppressed in Gabrd KO mice compared with the WT group. Ciproxifan-induced wakefulness was blocked by histamine synthesis inhibitor α-fluoromethylhistidine (αFMH). The findings indicate that both histamine and GABA, released from histamine/GABA neurons, are involved in regulation of brain arousal states and δ-containing subunit GABAA receptors are involved in mediating GABA response., (Copyright © 2020 Abdurakhmanova, Grotell, Kauhanen, Linden, Korpi and Panula.)- Published
- 2020
- Full Text
- View/download PDF
15. Increased Motor-Impairing Effects of the Neuroactive Steroid Pregnanolone in Mice with Targeted Inactivation of the GABA A Receptor γ2 Subunit in the Cerebellum.
- Author
-
Leppä E, Linden AM, Aller MI, Wulff P, Vekovischeva O, Luscher B, Lüddens H, Wisden W, and Korpi ER
- Abstract
Endogenous neurosteroids and neuroactive steroids have potent and widespread actions on the brain via inhibitory GABA
A receptors. In recombinant receptors and genetic mouse models their actions depend on the α, β, and δ subunits of the receptor, especially on those that form extrasynaptic GABAA receptors responsible for non-synaptic (tonic) inhibition, but they also act on synaptically enriched γ2 subunit-containing receptors and even on αβ binary receptors. Here we tested whether behavioral sensitivity to the neuroactive steroid agonist 5β-pregnan-3α-ol-20-one is altered in genetically engineered mouse models that have deficient GABAA receptor-mediated synaptic inhibition in selected neuronal populations. Mouse lines with the GABAA receptor γ2 subunit gene selectively deleted either in parvalbumin-containing cells (including cerebellar Purkinje cells), cerebellar granule cells, or just in cerebellar Purkinje cells were trained on the accelerated rotating rod and then tested for motor impairment after cumulative intraperitoneal dosing of 5β-pregnan-3α-ol-20-one. Motor-impairing effects of 5β-pregnan-3α-ol-20-one were strongly increased in all three mouse models in which γ2 subunit-dependent synaptic GABAA responses in cerebellar neurons were genetically abolished. Furthermore, rescue of postsynaptic GABAA receptors in Purkinje cells normalized the effect of the steroid. Anxiolytic/explorative effects of the steroid in elevated plus maze and light:dark exploration tests in mice with Purkinje cell γ2 subunit inactivation were similar to those in control mice. The results suggest that, when the deletion of γ2 subunit has removed synaptic GABAA receptors from the specific cerebellar neuronal populations, the effects of neuroactive steroids solely on extrasynaptic αβ or αβδ receptors lead to enhanced changes in the cerebellum-generated behavior.- Published
- 2016
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.