5-HT2A and mGlu2 receptor binding levels are related to differences in impulsive behavior in the Roman Low- (RLA) and High- (RHA) avoidance rat strains

Klein, Anders Bue; Ultved, Lene; Adamsen, Dea; Santini, Martin A.; Tobeña, Adolf; Fernandez-Teruel, Alberto; Flores, Pilar; Moreno, Margarita; Cardona, Diana M.; Knudsen, Gitte M.; Aznar, Susana; Mikkelsen, Jens D.

doi:10.1016/j.neuroscience.2013.12.063

Cited by 62 publications

(56 citation statements)

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“…Moreover, systemic administration of M100907 in rats impairs spatial reversal learning, increasing perseverative responses (Boulougouris et al 2008). Alterations in 5-HT 2A receptor levels have also been observed in Roman high-avoidance (RHA) rats (Klein et al 2014), an inbred strain characterized by a compulsive drinking profile on SIP, impulsivity on the delay-discounting task and poor inhibitory control in the 5-CSRT task (Moreno et al 2010). In humans, neuroimaging studies have also linked differences in 5-HT 2A receptor levels to the development of compulsive spectrum disorders.…”

Section: Discussionmentioning

confidence: 99%

“…The protocol was modified from Klein et al (2014). The 5-HT 2A autoradiography protocol was performed using 3 H-MDL100907 [R(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorphenyl)-ethyl]-4-piperidin-methanol] (specific activity, 2.8 TBq/mmol, Novandi Chemistry, Sweden; and non-specific binding was determined using 10 μM ketanserin tartrate (3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]-ethyl]-2,4[1H,3H] quinazolinedione tartrate) (Tocris Cookson Ltd., Bristol, UK).…”

Section: Methodsmentioning

confidence: 99%

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Tryptophan depletion affects compulsive behaviour in rats: strain dependent effects and associated neuromechanisms

et al. 2017

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RationaleCompulsive behaviour, present in different psychiatric disorders, such as obsessive-compulsive disorder, schizophrenia and drug abuse, is associated with altered levels of monoamines, particularly serotonin (5-hydroxytryptamine) and its receptor system.ObjectivesThe present study investigated whether 5-HT manipulation, through a tryptophan (TRP) depletion by diet in Wistar and Lister Hooded rats, modulates compulsive drinking in schedule-induced polydipsia (SIP) and locomotor activity in the open-field test. The levels of dopamine, noradrenaline, serotonin and its metabolite were evaluated, as well as the 5-HT2A and 5-HT1A receptor binding, in different brain regions.MethodsWistar rats were selected as high (HD) or low (LD) drinkers according to their SIP behaviour, while Lister hooded rats did not show SIP acquisition. Both strains were fed for 14 days with either a TRP-free diet (T−) or a TRP-supplemented diet (T+)ResultsThe TRP depletion diet effectively reduced 5-HT levels in the frontal cortex, amygdala and hippocampus in both strains of rats. The TRP-depleted HD Wistar rats were more sensitive to 5-HT manipulation, exhibiting more licks on SIP than did the non-depleted HD Wistar rats, while the LD Wistar and the Lister Hooded rats did not exhibit differences in SIP. In contrast, the TRP-depleted Lister Hooded rats increased locomotor activity compared to the non-depleted rats, while no differences were found in the Wistar rats. Serotonin 2A receptor binding in the striatum was significantly reduced in the TRP-depleted HD Wistar rats.ConclusionsThese results suggest that alterations of the serotonergic system could be involved in compulsive behaviour in vulnerable populations.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Tryptophan depletion affects compulsive behaviour in rats: strain dependent effects and associated neuromechanisms

et al. 2017

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“…During the SRTT rodents must attend to multiple apertures while waiting for a visual stimulus, which is then reported by a poke into the aperture and rewarded by delivery of a reinforcer. Multiple response errors can be measured, including: premature selection of an aperture, a measure of impulsivity that is mediated by 5-HT 2A receptor-cortical-cortical activity 9 in the PFC (Klein et al, 2014;Winstanley et al, 2003), incorrect responses (i.e., wrong aperture) and response omissions, which reflect attention deficits that are mediated in part by hypocretin-induced thalamocortical glutamate release (Lambe et al, 2005). Task difficulty can be modulated to enhance measures of attention by reducing stimulus duration or to enhance measures of impulsivity by increasing ITI (Figure 5e and f, respectively).…”

Section: Glyx-13 Increases C-fos Immunolabelling In Mpfcmentioning

confidence: 99%

GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine

Liu

Duman

Kato

et al. 2016

Neuropsychopharmacol

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GLYX-13 is a putative NMDA receptor modulator with glycine-site partial agonist properties that produces rapid antidepressant effects, but without the psychotomimetic side effects of ketamine. Studies were conducted to examine the molecular, cellular, and behavioral actions of GLYX-13 to further characterize the mechanisms underlying the antidepressant actions of this agent. The results demonstrate that a single dose of GLYX-13 rapidly activates the mTORC1 pathway in the prefrontal cortex (PFC), and that infusion of the selective mTORC1 inhibitor rapamycin into the medial PFC (mPFC) blocks the antidepressant behavioral actions of GLYX-13, indicating a requirement for mTORC1 similar to ketamine. The results also demonstrate that GLYX-13 rapidly increases the number and function of spine synapses in the apical dendritic tuft of layer V pyramidal neurons in the mPFC. Notably, GLYX-13 significantly increased the synaptic responses to hypocretin, a measure of thalamocortical synapses, compared with its effects on 5-HT responses, a measure of cortical-cortical responses mediated by the 5-HT receptor. Behavioral studies further demonstrate that GLYX-13 does not influence 5-HT receptor induced head twitch response or impulsivity in a serial reaction time task (SRTT), whereas ketamine increased responses in both tests. In contrast, both GLYX-13 and ketamine increased attention in the SRTT task, which is linked to hypocretin-thalamocortical responses. The differences in the 5-HT receptor synaptic and behavioral responses may be related to the lack of psychotomimetic side effects of GLYX-13 compared with ketamine, whereas regulation of the hypocretin responses may contribute to the therapeutic benefits of both rapid acting antidepressants.

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“…There is extensive evidence showing that RHA/RLA rats display differential schizophrenia-relevant features. For instance, the RHA strain/line displays impaired performance in several learning/memory tasks (Aguilar et al 2002; Driscoll et al 1995; Escorihuela et al 1995b; Nil and Bättig 1981; Oliveras et al 2015) and enhanced impulsive behavior in the 5-CSRTT and DRL-20 operant tasks (Klein et al 2014; Moreno et al 2010; Zeier et al 1978). RHA rats exhibit deficits in latent inhibition (Fernandez-Teruel et al 2006; Esnal et al 2016), augmented mesocortical dopaminergic response to stress (Giorgi et al 2003), and enhanced locomotor as well as mesolimbic dopaminergic sensitization upon the repeated administration of dopaminergic psychostimulants (Corda et al 2005; Giorgi et al 2007; Guitart-Masip et al 2008a, b), a more robust functional tone of nigrostriatal and mesolimbic dopamine neurons (Tournier et al 2013) and neurochemical and neuromorphological evidence of decreased hippocampal function (Garcia-Falgueras et al 2012; Meyza et al 2009; Salles et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats

et al. 2017

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Rationale Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders. Objectives We have carried out a pharmacological characterization of the Roman high-(RHA-I) and low-avoidance (RLA-I) rat strains with different acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages). Results RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 70 dB prepulse intensities) and reduced locomotion in both strains. The atypical antipsychotic clozapine (serotonin/dopamine receptor antagonist) did not affect PPI in either strain, but decreased locomotion in a dose-dependent manner in both rat strains. The mixed dopamine D1/D2 agonist, apomorphine, at the dose of 0.05 mg/kg, decreased PPI in RHA-I, but not RLA-I rats. The hallucinogen drug DOI (5-HT2A agonist; 0.1–1.0 mg/kg) disrupted PPI in RLA-I rats in a dose-dependent manner at the 70 dB prepulse intensity, while in RHA-Irats, only the 0.5 mg/kg dose impaired PPI at the 80 dB prepulse intensity. DOI slightly decreased locomotion in both strains. Finally, clozapine attenuated the PPI impairment induced by the NMDA receptor antagonist MK-801 only in RLA-I rats. Conclusions These results add experimental evidence to the view that RHA-I rats represent a model with predictive and construct validity of some dopamine and 5-HT2A receptor-related features of schizophrenia.

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5-HT2A and mGlu2 receptor binding levels are related to differences in impulsive behavior in the Roman Low- (RLA) and High- (RHA) avoidance rat strains

Cited by 62 publications

References 39 publications

Tryptophan depletion affects compulsive behaviour in rats: strain dependent effects and associated neuromechanisms

Tryptophan depletion affects compulsive behaviour in rats: strain dependent effects and associated neuromechanisms

GLYX-13 Produces Rapid Antidepressant Responses with Key Synaptic and Behavioral Effects Distinct from Ketamine

Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats

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