Antipsychotic-Like Effect of Retigabine [<i>N</i>-(2-Amino-4-(fluorobenzylamino)-phenyl)carbamic Acid Ester], a KCNQ Potassium Channel Opener, via Modulation of Mesolimbic Dopaminergic Neurotransmission

Sotty, Florence; Damgaard, Trine; Montezinho, Liliana P.; Mørk, Arne; Olsen, Christina Kurre; Bundgaard, Christoffer; Husum, Henriette

doi:10.1124/jpet.108.146944

Cited by 58 publications

(54 citation statements)

References 39 publications

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“…Moreover, the effects described at the 4 mg·kg -1 dose in the anxiety, rotarod and ethanol interaction tests are consistent with the profile of retigabine (Blackburn-Munro et al, 2005;Korsgaard et al, 2005). Recently, Damgaard et al (2011) have shown that AA29504 reverses recognition memory deficits in an animal model of schizophrenia, albeit retigabine is also effective in schizophrenia models (Sotty et al, 2009). …”

Section: In Vivo Propertiessupporting

confidence: 71%

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors

Wafford

Brown

et al. 2013

British J Pharmacology

101

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BACKGROUND AND PURPOSEMost GABAA receptor subtypes comprise 2a, 2b and 1g subunit, although for some isoforms, a d replaces a g-subunit. Extrasynaptic d-GABAA receptors are important therapeutic targets, but there are few suitable pharmacological tools. We profiled DS2, the purported positive allosteric modulator (PAM) of d-GABAA receptors to better understand subtype selectivity, mechanism/site of action and activity at native d-GABAA receptors. EXPERIMENTAL APPROACHSubunit specificity of DS2 was determined using electrophysiological recordings of Xenopus laevis oocytes expressing human recombinant GABAA receptor isoforms. Effects of DS2 on GABA concentration-response curves were assessed to define mechanisms of action. Radioligand binding and electrophysiology utilising mutant receptors and pharmacology were used to define site of action. Using brain-slice electrophysiology, we assessed the influence of DS2 on thalamic inhibition in wild-type and d 0/0 mice. KEY RESULTSActions of DS2 were primarily determined by the d-subunit but were additionally influenced by the a, but not the b, subunit (a4/6bxd > a1bxd >> g2-GABAA receptors > a4b3). For d-GABAA receptors, DS2 enhanced maximum responses to GABA, with minimal influence on GABA potency. (iii) DS2 did not act via the orthosteric, or known modulatory sites on GABAA receptors. (iv) DS2 enhanced tonic currents of thalamocortical neurones from wild-type but not d 0/0 mice. CONCLUSIONS AND IMPLICATIONSDS2 is the first PAM selective for a4/6bxd receptors, providing a novel tool to investigate extrasynaptic d-GABAA receptors. The effects of DS2 are mediated by an unknown site leading to GABAA receptor isoform selectivity. AbbreviationsDS1, delta selective compound 1; DS2, delta selective compound 2; ECx, effective concentration giving the activation degree of X;

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Section: In Vivo Propertiessupporting

confidence: 71%

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors

Wafford

Brown

et al. 2013

British J Pharmacology

101

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“…85 Ketamine induces aberrant firing of dopamine neurons. 86 Perhaps that firing underpins the preserved sensitivity to devaluation in the NHVL rats.…”

Section: Imagining Rats?mentioning

confidence: 99%

Explaining Delusions: Reducing Uncertainty Through Basic and Computational Neuroscience

Feeney

Groman

Taylor

et al. 2017

Schizophrenia Bulletin

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Delusions, the fixed false beliefs characteristic of psychotic illness, have long defied understanding despite their response to pharmacological treatments (e.g., D 2 receptor antagonists). However, it can be challenging to discern what makes beliefs delusional compared with other unusual or erroneous beliefs. We suggest mapping the putative biology to clinical phenomenology with a cognitive psychology of belief, culminating in a teleological approach to beliefs and brain function supported by animal and computational models. We argue that organisms strive to minimize uncertainty about their future states by forming and maintaining a set of beliefs (about the organism and the world) that are robust, but flexible. If uncertainty is generated endogenously, beliefs begin to depart from consensual reality and can manifest into delusions. Central to this scheme is the notion that formal associative learning theory can provide an explanation for the development and persistence of delusions. Beliefs, in animals and humans, may be associations between representations (e.g., of cause and effect) that are formed by minimizing uncertainty via new learning and attentional allocation. Animal research has equipped us with a deep mechanistic basis of these processes, which is now being applied to delusions. This work offers the exciting possibility of completing revolutions of translation, from the bedside to the bench and back again. The more we learn about animal beliefs, the more we may be able to apply to human beliefs and their aberrations, enabling a deeper mechanistic understanding.Key words: delusions/behavioral neuroscience/cognitive neuroscience/computational psychiatry/associative learning The End of the World and the Beginning of a TheoryIn December 1954, the Chicago Tribune reported that Dorothy Martin was relaying a prophecy from extra-terrestrials that the world was about to end. A number of followers flocked to her but her prophecy did not manifest. She ultimately settled in Sedona, Arizona where she lived until she was 92, continuing to proselytize about aliens but evading interaction with psychiatric services. Did Martin have delusions? What about her acolytes? Defining, explaining, and ultimately understanding delusions has proven challenging (see Freeman and Bebbington, this issue). In this article, we describe how neuroscientists have tried to meet that challenge. The approach demands some simplifying assumptions. Basic neuroscience in preclinical models will not recapitulate all of the features of delusions. However, simple models can be useful.

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“…The concentration of dopamine in the dialysates was analysed by means of HPLC with electrochemical detection as previously described [26]. The monoamines were separated by reverse-phase liquid chromatography (ODS 150 9 3 mm).…”

Section: Methodsmentioning

confidence: 99%

Addiction‐Related Effects of DOV 216,303 and Cocaine: A Comparative Study in the Mouse

Sørensen

Husum

Brennum

et al. 2014

Basic Clin Pharma Tox

Self Cite

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DOV 216,303, an inhibitor of serotonin, noradrenaline and dopamine reuptake, belongs to a new line of drugs called 'triple reuptake inhibitors' that have been proposed for treatment of depression. The addictive drug cocaine has similar mechanism of action and exerts rewarding effects by blocking reuptake of dopamine, leading to increased extracellular concentrations of dopamine in the nucleus accumbens. Thus, DOV 216,303 and other triple reuptake inhibitors might be speculated to exhibit abuse potential, limiting their future therapeutic use. To further elucidate potential addictive properties of DOV 216,303, we conducted a comparative study of addiction-related effects of DOV 216,303 and cocaine in mice using acute self-administration, conditioned place preference (CPP) and drug-induced hyperlocomotion. Effects on accumbal extracellular dopamine levels were determined using microdialysis, and we measured monoamine receptor occupancy as well as brain and plasma exposure. DOV 216,303 was self-administered acutely in the same dose range as cocaine. However, in the CPP model, DOV 216,303 did not induce place preference at doses where cocaine caused place preference. Higher doses of DOV 216,303 than cocaine were needed to induce hyperlocomotion and increase extracellular accumbal dopamine with effective doses being higher than effective doses used in depression models. Moreover, DOV 216,303 displayed a pharmacokinetic profile with lower potential for addiction than cocaine. Thus, high levels of DAT occupancy were reached slower and decayed more slowly after DOV 216,303 than cocaine administration. The present study shows that acute administration of DOV 216,303 displays some addictive-like properties in mice, but these were less pronounced than cocaine, most likely due to different pharmacokinetic profiles.Triple reuptake inhibitors have been proposed as a novel type of antidepressant drugs that inhibit the reuptake of the three monoamines serotonin, noradrenaline and dopamine via inhibition of their respective transporters SERT, NAT and DAT [1,2]. DOV 216,303 is a prototype of the triple reuptake inhibitors that has shown antidepressant activity in animal models of depression [1,3,4] as well as in a clinical study in depressed patients [5]. However, drugs that block DAT may exert positive reinforcing effects that could lead to addiction [6,7]. Therefore, DOV 216,303 and other triple reuptake inhibitors could possess abuse potential that might seriously limit their use in future treatment of depression. For instance, the highly addictive drug cocaine is a triple reuptake inhibitor that is believed to exert its reinforcing effect via DAT blockade, leading to increase of mesolimbic extracellular dopamine levels [8,9].Several other DAT inhibitors have been found to be reinforcing in animal models of addiction, including GBR 12909, RTI-177, BTCP and AHN 1-005. For instance, GBR 12909 was self-administered in a manner similar to cocaine by rats [6]. RTI-177 maintained self-administration behaviour on a second-o...

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Antipsychotic-Like Effect of Retigabine [N-(2-Amino-4-(fluorobenzylamino)-phenyl)carbamic Acid Ester], a KCNQ Potassium Channel Opener, via Modulation of Mesolimbic Dopaminergic Neurotransmission

Cited by 58 publications

References 39 publications

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors

Explaining Delusions: Reducing Uncertainty Through Basic and Computational Neuroscience

Addiction‐Related Effects of DOV 216,303 and Cocaine: A Comparative Study in the Mouse

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Antipsychotic-Like Effect of Retigabine [N-(2-Amino-4-(fluorobenzylamino)-phenyl)carbamic Acid Ester], a KCNQ Potassium Channel Opener, via Modulation of Mesolimbic Dopaminergic Neurotransmission

Cited by 58 publications

References 39 publications

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABAA receptors

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABAA receptors

Explaining Delusions: Reducing Uncertainty Through Basic and Computational Neuroscience

Addiction‐Related Effects of DOV 216,303 and Cocaine: A Comparative Study in the Mouse

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Product

Resources

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A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors

A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA_A receptors