Differential effects of cariprazine, LY379268 and donepezil on EEG oscillations and auditory steady-state response in MK-801-treated rats: relevance for schizophrenia drug development

Article

作者: Maurin, Anne ; Chassignolle, Morgane ; Carvalho, Kevin ; Herbel, Heloise ; Viardot, Geoffrey ; Delpy, Eric ; Adraoui, Florian W ; Violas, Maëlle ; L'Hostis, Philippe ; Tugler, Samuel ; Rochelle, Christophe Drieu La ; Hettak, Kenza

Treating patients affected by schizophrenia (SZ) remains highly challenging for drug developers. While available antipsychotics mostly reduce positive symptoms, their effects on cognitive and social deficits as well as their underlying pathophysiology remain insufficient. Disinhibition in SZ patients' cortex is considered a key player in the genesis of these symptoms and would result from N-methyl-D-aspartate receptor (NMDAr) hypofunction on interneurons. Besides, electroencephalography-based biomarkers of these mechanisms including spontaneous and evoked gamma oscillations have been highlighted. These strongly depend on NMDAr function, associate with symptoms and therefore represent translational tools for drug development. However, reversing these circuit abnormalities is challenging for the field and finding drugs engaging them would constitute a major milestone. Here, we tested three different drugs whose features attract scientists for restoration of excitation/inhibition balance: cariprazine (D2/D3 receptor partial agonist and 5-HT_2A receptor antagonist), LY379268 (mGlur2/3 receptor agonist) and donepezil (acetylcholinesterase inhibitor). We investigated their effects on spontaneous oscillations and auditory steady-state responses (ASSR, measuring evoked gamma oscillations) in a rat model of SZ induced by MK-801, a selective NMDAr blocker. MK-801 increased locomotor activity, impaired spontaneous and evoked gamma oscillations and altered spontaneous oscillations in delta, alpha and beta frequencies of male Sprague Dawley rats. Remarkably, both cariprazine and LY379268 normalized spontaneous gamma oscillations. Moreover, cariprazine normalized alpha and beta waves and LY379268 selectively corrected delta activity. Interestingly, only cariprazine mitigated the ASSR deficit. These differential normalization profiles, including cariprazine's unique broad-spectrum signature, reveal distinct patterns of circuit engagement and provide a translational pharmaco-EEG framework for circuit-level target engagement in SZ drug development.

2026-04-01·MOLECULAR PSYCHIATRY

Psilocybin mitigates chronic behavioral and neurobiological alterations in a rat model of recurrent intimate partner violence-related brain injury

Article

作者: Shultz, Sandy R ; Sun, Mujun ; Dames, Shannon ; Christie, Brian R ; Baker, Tamara L ; McDonald, Stuart J ; Kryskow, Pamela ; Allen, Josh

Intimate partner violence (IPV) poses a significant medical concern, predominantly affecting females. IPV-related brain injuries (IPV-BI), such as mild traumatic brain injury (mTBI) and non-fatal strangulation (NFS), sustained during physical attacks are common and often repetitive. Chronic neurobehavioral sequalae from IPV-BI are associated with neuroinflammation and impaired neuroplasticity, and effective treatment options are scarce, particularly in the context of IPV. However, psilocybin, a 5-HT_2A receptor agonist with therapeutic potential in psychiatric disorders that share overlapping pathophysiology as BI, is a promising candidate. This study evaluated psilocybin's effects on behavior, cognition, and neurobiology in a novel rat model of recurrent IPV-BI. Female rats underwent daily mTBI (lateral impact) followed by NFS (90 s) for five days, followed by 16 weeks of recovery. Rats then received a single intraperitoneal injection of psilocybin (1 mg/kg) or saline, with behavioral testing 24 h later. To investigate whether psilocybin's effects were 5-HT_2A receptor dependent, additional rats received pre-treatment with selective 5-HT_2A receptor antagonist M100907 (1.5 mg/kg) one hour before psilocybin administration. Psilocybin recovered mTBI+NFS-induced abnormalities in the elevated plus-maze, increased sucrose preference when administered without M100907, and improved reversal learning in the water maze and spatial memory in the Y-maze. In the dorsal hippocampus, mTBI+NFS rats treated with saline, but not those treated with psilocybin, exhibited an increased number of microglial cells in the molecular layer and fewer reelin-positive cells in the subgranular zone. These findings suggest psilocybin's antidepressant, pro-cognitive, anti-inflammatory, and neuroplasticity-enhancing effects hold promise for improving chronic IPV-BI outcomes and highlight the critical role of 5-HT_2A receptors in mediating psilocybin's therapeutic benefits.

2026-02-20·Current Neuropharmacology

Long-Term Benefits of Chronic 5-HT2A Antagonist and 5-HT1A Agonist Treatment on ADHD Behavior in Juvenile Spontaneously Hypertensive Rats

Article

作者: Rao, Muddanna S. ; Madhyastha, Sampath

Introduction::

Norepinephrine and Dopamine (DA) are critical brain amines in Attention Deficit Hyperactivity Disorder (ADHD), with treatments targeting their neuroreceptors often causing adverse effects, particularly in the motor system through DA receptors. Our earlier study suggested that chronic treatment with a 5-HT1A receptor agonist or a 5-HT2A receptor antagonist in juvenile spontaneously hypertensive rats (SHRs) may improve ADHD-like symptoms by potentially modulating DA receptors. This study investigated the long-term impacts of these serotonergic receptor manipulations on ADHD behavior.

Methods::

Male SHRs (15 days old) received either ipsapirone (a 5-HT1A agonist) or MDL100907 (a 5-HT2A antagonist) from postnatal day (PND) 15 to 42, in parallel with similarly aged Wistar Kyoto rats (WKY). After eight weeks of undisturbed observation, we assessed hyperlocomotor activity, anxiety, and impulsivity. On PND 122, rats were sacrificed, and the striatum and prefrontal cortex (PFC) were analyzed for DA-D1, DA-D2, 5-HT1A, and 5-HT2A receptor proteins and DA levels.

Results::

The results showed that both treatments had lasting positive effects on ADHD behaviors, linked to increased 5-HT1A and 5-HT2A receptors in the PFC and striatum. Ipsapirone (5-HT1A agonist) did not alter DA receptor expression but reduced DA levels, while the 5-HT2A antagonist reduced DA-D2 and increased DA-D1 expression, with enhanced DA content levels. In the striatum, both treatments increased DA-D2 and reduced DA-D1 receptors, but the 5-HT1A agonist lowered DA content.

Discussion::

Striatal DA-D2 dysregulation appears to contribute to hyperlocomotor activity, while attentional impairments are associated with enhanced striatal DA-D2 receptor expression. Enhancing 5-HT activity either through 5-HT2A antagonists or 5-HT1A agonists effectively alleviates core ADHD symptoms in SHRs, likely by indirectly modulating DA signaling. These serotonergic agents may influence DA pathway activity via cortical mechanisms, providing therapeutic benefits without the long-term adverse effects typically associated with direct DA receptor blockade.

Conclusion::

These findings suggest that dysregulation of 5-HT1A and DA-D2 receptors may contribute to ADHD, and monotherapy with either a 5-HT1A receptor stimulator or a 5-HT2A receptor inhibitor can effectively alleviate core ADHD symptoms long-term, likely through indirect DA system modulation.

100 项与 5-HT2A receptor antagonists(Korea Research Institute of Chemical Technology) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
结直肠癌	临床前	韩国	Korea Research Institute of Chemical Technology	2025-01-06
结直肠癌	临床前	韩国	Gwangju Institute of Science & Technology	2025-01-06