Antipsychotic-like effects of TAAR1 agonists and D2 receptor blockers are mediated through distinct modulation of striatal neuronal dynamics.

Dopamine D2 receptor dependent and independent structural, intrinsic and synaptic adaptations in experimental parkinsonism.

The main motor symptoms of Parkinson's disease (PD) emerge following dopamine depletion in the dorsal striatum and are associated with structural and functional adaptations of striatal medium spiny neurons (MSN). Although the indirect pathway MSN (iMSN) selectively expresses dopamine D2 receptors (D2R), the contribution of D2R signaling to these adaptations remains incompletely understood. Here, we examined neuronal morphology, dendritic spine density, corticostriatal transmission, and intrinsic excitability in direct pathway MSN (dMSN) and iMSN from constitutive D2R knockout mice, with or without chronic nigrostriatal lesions induced by 6-hydroxydopamine. D2R ablation reduced dendritic length and complexity in both MSN subtypes, although the effects were markedly greater in iMSN. In iMSN, D2R ablation also reduced spine density and increased intrinsic excitability, reproducing well known effects of nigrostriatal lesions and largely occluding additional effects of dopamine denervation. In contrast, D2R ablation produced only modest changes in dMSN spine density and excitability and did not prevent the additional spine loss and hyperexcitability induced by 6-OHDA lesions. Basal corticostriatal transmission remained largely preserved after D2R ablation in either MSN subtype, except for a slower excitatory postsynaptic current decay in iMSN, which was not enhanced further by the dopamine depleting lesion. Remarkably, nigrostriatal lesions continued to depress corticostriatal excitatory postsynaptic currents in D2R-deficient mice, indicating that this synaptic adaptation does not require D2R signaling. Together, these findings identify D2R signaling as a major determinant of iMSN structural and intrinsic physiological integrity and demonstrate that global loss of D2R function reproduces many of the adaptations induced by dopamine depletion. More broadly, they indicate that dopamine depletion drives distinct forms of plasticity through separable D2R dependent and independent mechanisms, with depression of corticostriatal synaptic currents in iMSN arising independently of D2R signaling.

852. Preclinical models of non dopaminergic antipsychotics

Abstract Background Current antipsychotic treatments primarily rely on dopamine D2 receptor antagonism and show limited efficacy for negative and cognitive symptoms, as well as in treatment-resistant schizophrenia. Trace amine-associated receptor 1 (TAAR1) agonists represent a promising non-dopaminergic approach with a distinct mechanism of action. Aims & Objectives To investigate the pharmacological and translational potential of TAAR1 agonists using preclinical models, and to evaluate their relevance for domains poorly addressed by current antipsychotics. Method Preclinical models integrating behavioural, neurochemical, and pharmacological approaches to assess TAAR1 agonists. These models were used to examine modulation of dopaminergic, serotonergic, and glutamatergic systems, with particular focus on dopamine synthesis and monoaminergic regulation. Results TAAR1 activation modulated dopamine synthesis and broader monoaminergic signalling, producing effects across behavioural paradigms relevant to psychosis, including domains related to negative and cognitive symptoms. These findings are consistent with emerging clinical data on TAAR1 agonists such as ulotaront, although Phase 3 results remain mixed. Discussion & Conclusions TAAR1 agonists provide a mechanistically distinct alternative to D2 antagonists, with potential advantages in tolerability and metabolic profile. Preclinical models support their relevance for symptom domains inadequately targeted by current therapies. Further clinical investigation is warranted to clarify their therapeutic role and broader applicability, including in bipolar spectrum disorders.

Hippocampal synaptic transmission and Ca2⁺ signaling are altered by the selective 5-HT2A receptor agonist, 25CN-NBOH.

Classical psychedelics exert therapeutic effects on affective disorders, with serotonin 5-HT2A receptor activation thought to play a central role. The cellular mechanisms by which 5-HT2A signaling modulates neural circuits remain incompletely understood and may differ across mood-regulating brain regions. While psychedelic actions have been extensively studied in the medial prefrontal cortex, the hippocampus which is critical for mood, and memory has received less attention, and effects of selective 5-HT2A agonists on hippocampal neurons remain poorly characterized. Here, we examined the effects of the selective 5-HT2A agonist 25CN-NBOH on synaptic transmission, intrinsic excitability, and intracellular calcium in mouse hippocampal CA1 pyramidal neurons using whole-cell patch-clamp electrophysiology and Fura-2 AM imaging. 25CN-NBOH (10 μM) increased both spontaneous excitatory and inhibitory synaptic transmission, as indicated by elevated sEPSC and sIPSC frequency and amplitude, without affecting miniature events, suggesting action potential-dependent mechanisms. These synaptic effects persisted in the presence of the 5-HT2A antagonist MDL-100907, indicating 5-HT2A -independent synaptic facilitation. Despite increased synaptic drive, neuronal firing and action potential properties were unchanged, consistent with balanced excitation and inhibition. In contrast, 25CN-NBOH induced robust intracellular calcium elevations in CA1 neurons that were significantly reduced by MDL-100907, as well as by TTX and AMPA/NMDA receptor blockade, indicating dependence on both 5-HT2A receptor activation and glutamatergic presynaptic activity. Together, these findings reveal separable mechanisms of action: 5-HT2A-independent, presynaptic facilitation, and 5-HT2A-dependent calcium signaling. These results highlight distinct modes of hippocampal modulation by a selective 5-HT2A receptor agonist and suggest mechanisms through which psychedelics may promote plasticity-related processes.

403. Sustained administration of the full and partial agonists of trace amine associated receptor 1 (TAAR1) induces different effects on the excitability of central monoaminergic neurons

Abstract Background Trace amine associated receptor 1 (TAAR1) is a promising target for the next generation of the central nervous system (CNS) drugs. It has been previously shown that the full (RO5256390) and partial (RO5263397) agonists of TAAR1 had anti-addictive, pro-cognitive, and antipsychotic- and antidepressant-like effects; these beneficial effects of TAAR1 ligands were linked, at least in part, with the altered excitability of serotonergic (5-HT) neurons of the dorsal raphe nucleus (DRN) and dopaminergic neurons of the ventral terminal area (VTA; Revel et al Mol Psychiatry 18:543, 2013). Aims & Objectives This study aimed to examine the effects of sustained administration of RO5256390 and RO5263397 on the excitability of 5-HT neurons of the DRN and dopaminergic neurons of the VTA in vivo conditions. Method Male Wistar rats, weighing 250-350 g, were pre-treated with RO5256390, RO5263397 (orally, 1.5 mg/kg, twice a day at 09:00 and 17:00) or with corresponding vehicles (0.3% polysorbate-80 in 0.9% NaCl) for 14 consecutive days. On the 15th day, one hour after the morning RO5256390, RO5263397, or vehicle administration, rats were anesthetized with chloralhydrate (0.4 g/kg) and mounted in a stereotaxic frame. Borosilicate electrodes filled with 2M NaCl (impedance 4-6 MΩ) were inserted into the DRN or VTA. Spontaneously active 5-HT and dopaminergic neurons were identified by the waveform of their action potentials and pattern of their generation. Since the burst-like, or phasic firing of 5-HT (Gartside et al Neuroscience 98:295, 2000) and dopaminergic (Cooper Neurochem Int 41:333, 2002) neurons results in increased release of corresponding neurotransmitter from the nerve terminals, the excitability mode of monoaminergic neurons was assessed. The onset of a burst was signified by the occurrence of two spikes with and inter-spike interval (ISI) < 0.08 s for dopaminergic and ISI < 0.01 s for 5-HT neurons. The termination of a burst was defined as an ISI > 0.16 s for dopaminergic and ISI > 0.010 s for 5-HT neurons. Results Sustained administration of RO5256390 had no effect on the mean basal firing rate of 5-HT neurons. It however increased the frequency of the phasic activity of these neurons. With respect to dopaminergic neurons, sustained treatment with RO5256390 stimulated their mean spontaneous basal firing rate, as well as the burst/phasic mode of activity. Sustained administration of RO5263397 increased the mean spontaneous basal firing rate of 5-HT neurons. The mode of their activity, however, was not altered. With respect to dopaminergic neurons, sustained treatment with RO5263397 did not affect their mean basal firing rate or mode of their activity. Discussion & Conclusions Chronic treatment with the full agonists of TAAR1 might have a robust stimulatory effect on the central dopaminergic neurotransmission. It may also stimulate 5-HT neurotransmission. Chronic treatment with the partial agonists of TAAR1 might have strong stimulatory effect on 5-HT, but they may have lesser effect on dopaminergic neurotransmission. This work was supported by the grants APVV-22-0061, APVV-24-0131, VEGA-2/0045/24, and VEGA- 2/0126/26. RO5256390 and RO5263397 were provided as a gift from Roche Innovation Center Basel.

Dopamine D2 receptors bypass canonical signaling to directly tune NMDA receptor function and aversive learning

It is shown that D2Rs can bypass second messenger systems to tune glutamatergic transmission through receptor-receptor interactions, providing a mechanism by which dopamine selectively gates specific glutamatergic inputs to control striatal plasticity and behavioral adaptation.

Striatal Dopamine D2 Receptors Contribute to N-Ethylpentylone-Induced Arousal in Mice