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Background The claustrum, a subcortical structure densely expressing 5-hydroxytryptamine 2 A (5-HT2A) receptors, has been implicated in sensory integration, emotional regulation, salience, and attention. Despite its hypothesized involvement in the effects of serotonergic psychedelics, the neurochemical impact of these substances on claustral neurotransmission remains unexplored. This study aimed to investigate how psilocin — a tryptamine and the active metabolite of psilocybin — and 4-Iodo-2, 5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) — a phenethylamine and new psychoactive substance (NPS) — modulate extracellular neurotransmitter levels in the rat claustrum, as well as to examine their effects on wet dog shake behavior, a well-established proxy for hallucinogenic activity. Methods Adult male Wistar Han rats were used for in vivo brain microdialysis experiments. Microdialysis probes were stereotaxically implanted into the claustrum. Rats received local administration of either psilocin (100 or 500 µM) or 25I-NBOMe (500 µM) through the microdialysis probe. Dialysate samples were collected and analyzed using high-performance liquid chromatography (HPLC) with electrochemical detection to quantify extracellular levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT), glutamate (GLU), gamma-aminobutyric acid (GABA), and acetylcholine (ACh). A behavioral test defined as wet dog shakes (WDS) was conducted after drugs administration, to infer psychedelic-like activity. Results In vivo microdialysis performed in freely moving rats revealed that both substances markedly altered extracellular levels of DA, NA, 5-HT, GLU, GABA, and ACh. Psilocin, at both administered doses, was the only compound to significantly elevate NA and produced the most pronounced enhancement of cholinergic signaling across all neurotransmitter systems examined. By contrast, 25I-NBOMe induced a more substantial shift toward excitatory dominance, accompanied by the greatest increase in 5-HT release. Overall, psilocin generated a comparatively balanced excitatory–inhibitory neurochemical profile, reflecting its combined engagement of 5-HT2A and 5-HT1A receptors, whereas 25I-NBOMe produced an excitation-biased pattern consistent with its selective, high-affinity 5-HT2A agonism. Conclusions These findings highlight the claustrum as a neurochemical convergence point for psychedelic action and demonstrate that psilocin engages this circuitry in a regulated, receptor-balanced manner, whereas 25I-NBOMe drives a markedly more excitatory and less compensated profile, underscoring their fundamentally distinct therapeutic and toxicological potentials.

In recent decades, psilocybin has gained attention as a potential drug for several mental disorders. Clinical and preclinical studies have provided evidence that psilocybin can be used as a fast-acting antidepressant. However, the exact mechanisms of action of psilocybin have not been clearly defined. Data show that psilocybin as an agonist of 5-HT2A receptors located in cortical pyramidal cells exerted a significant effect on glutamate (GLU) extracellular levels in both the frontal cortex and hippocampus. Increased GLU release from pyramidal cells in the prefrontal cortex results in increased activity of γ-aminobutyric acid (GABA)ergic interneurons and, consequently, increased release of the GABA neurotransmitter. It seems that this mechanism appears to promote the antidepressant effects of psilocybin. By interacting with the glutamatergic pathway, psilocybin seems to participate also in the process of neuroplasticity. Therefore, the aim of this mini-review is to discuss the available literature data indicating the impact of psilocybin on glutamatergic neurotransmission and its therapeutic effects in the treatment of depression and other diseases of the nervous system.

One of the major roles of glutamic acid (Glu) is to serve as an excitatory neurotransmitter within the central nervous system (CNS). This amino acid influences the activity of several brain areas, including the thalamus, brainstem, spinal cord, basal ganglia, and pons. Catecholamines (CAs) are synthesized in the brain and adrenal medulla and by some sympathetic nerve fibers. CAs, including dopamine (DA), norepinephrine (NE), and epinephrine (E), are the principal neurotransmitters that mediate a variety of CNS functions, such as motor control, cognition, emotion, memory processing, pain, stress, and endocrine modulation. This study aims to investigate the effects of the application of various Glu concentrates (5, 50, and 200 µM) on CAs release from rabbit medial prefrontal cortex (mPFC) slices and compare any resulting correlations with CAs released from the hypothalamus during 90 min of incubation. Medial prefrontal cortex samples were dissected from decapitated, twelve-week-old female rabbits. The results demonstrated that Glu differentially influences the direct release of CAs from the mPFC and the indirect release of CAs from the hypothalamus. When under stress, the hypothalamus, a central brain structure of the HPA axis, induces and adapts such processes. Generally, there was an inhibitory effect of Glu on CAs release from mPFC slices. Our findings show that the effect arises from Glu’s action on higher-order motivational structures, which may indicate its contribution to the stress response by modulating the amount of CAs released.

Glutamic acid decarboxylase (GAD) is an enzyme that catalyses the formation of γ-aminobutyric acid (GABA), the most important inhibitory neurotransmitter, from glutamic acid (Glu), which is considered the most important excitatory transmitter in the central and peripheral nervous systems. GAD is a key enzyme that provides a balance between Glu and GABA concentration. Hence, it can be assumed that if the GAD executes the synthesis of GABA from Glu, it is important in the stress response, and thus also in triggering the emotional states of the body that accompany stress. The aim of the study was to investigate the concentration of the GAD in motivational structures in the brain of the rabbit (Oryctolagus cuniculus) under altered homeostatic conditions caused by stress and variable availability of Glu. Summarising, the experimental results clearly showed variable concentrations of GAD in the motivational structures of the rabbit brain. The highest concentration of GAD was found in the hypothalamus, which suggests a strong effect of Glu and GABA on the activity of this brain structure. The GAD concentrations in individual experimental groups depended to a greater extent on blocking the activity of glutamate receptors than on the effects of a single stress exposure. The results obtained clearly support the possibility that a rapid change in the concentration of GAD could shift bodily responses to quickly achieve homeostasis, especially in this species. Further studies are necessary to reveal the role of the Glu–GAD–GABA system in the modulation of stress situations as well as in body homeostasis.