The Pharmacological Profile of Second Generation Pyrovalerone Cathinones and Related Cathinone Derivative

Pyrovalerone cathinones are potent psychoactive substances that possess a pyrrolidine moiety. Pyrovalerone-type novel psychoactive substances (NPS) are continuously detected but their pharmacology and toxicology are largely unknown. We assessed several pyrovalerone and related cathinone derivatives at the human norepinephrine (NET), dopamine (DAT), and serotonin (SERT) uptake transporters using HEK293 cells overexpressing each respective transporter. We examined the transporter-mediated monoamine efflux in preloaded cells. The receptor binding and activation potency was also assessed at the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors. All pyrovalerone cathinones were potent DAT (IC50 = 0.02–8.7 μM) and NET inhibitors (IC50 = 0.03–4.6 μM), and exhibited no SERT activity at concentrations < 10 μM. None of the compounds induced monoamine efflux. NEH was a potent DAT/NET inhibitor (IC50 = 0.17–0.18 μM). 4F-PBP and NEH exhibited a high selectivity for the DAT (DAT/SERT ratio = 264–356). Extension of the alkyl chain enhanced NET and DAT inhibition potency, while presence of a 3,4-methylenedioxy moiety increased SERT inhibition potency. Most compounds did not exhibit any relevant activity at other monoamine receptors. In conclusion, 4F-PBP and NEH were selective DAT/NET inhibitors indicating that these substances likely produce strong psychostimulant effects and have a high abuse liability.

Antagonization of monoamine reuptake transporters by agmatine improves anxiolytic and locomotive behaviors commensurate with fluoxetine and methylphenidate

Background Agmatine (AGM) is known for its protective effects including neuroprotection, nephroprotection, gastroprotection, cardioprotection, and glucoprotection. Studies have validated the neuroprotective role of AGM as antidepressant, anxiolytic, locomotive, and antipsychotic agent in psychopathologies. Fluoxetine (FLX) is the most extensively prescribed antidepressant while methylphenidate (MPD) is the most frequently prescribed psychoactive stimulant for ADHD (attention deficit hyperactivity disorder) treatment worldwide. The mechanism of action of FLX and MPD involves reuptake inhibition of serotonin and dopamine and norepinephrine at presynaptic transporters. Present study was designed to determine the safety and efficacy of AGM administration along with conventional antidepressant and psychostimulative drugs. The study also aimed to establish underlying mechanism of action of AGM at monoamine reuptake transporters. Results AGM significantly ameliorated locomotion in activity box and open field while anxiolytic behaviors in light/dark transition box and EPM were also improved (p<0.01). The growth and appetite of animals were enhanced along with antidepressive behavior in FST (p<0.01). Moreover, co-administration of AGM with FLX or MPD improved rats’ behaviors as compared to single AGM administration. Conclusion Present study determined the significant anxiolytic, locomotor, and antidepressive effects of AGM compared with FLX and MPD. The study also showed improved behaviors of rats treated with combined doses of AGM with FLX or MPD along with food intake and body weights. This study has also proposed the potential mechanism of action of AGM at monoamine receptors that may lead to inhibition of monoamine reuptake transporters that may lead to increase in 5-HT, D, and NE concentrations at synaptic level.

Heterogeneity of the mechanisms of action of antidepressants

The article discusses the heterogeneous mechanisms of the pharmacodynamics of antidepressants that underlie the therapeutic response. Sharing the similar clinical activity, antidepressants determine the development of drug-induced homeostasis by means of different molecular mechanisms (selective or nonselective blockade of monoamine reuptake, inhibition of monoamine oxidase, blockade of certain monoamine receptors). However, an increase of serotonin and other monoamines concentrations in the synapses of the central nervous system is only the initiating factor in the development of specific clinical effects. The latter are probably determined by other neurochemical effects, including changes in the density of postsynaptic receptors and an increase in the synthesis of neurotrophic factors. However, the primary mechanisms that increase monoamine concentrations in the synapses might not always “work properly”, leading to the lack of efficacy of the initial antidepressant, while the probability of the therapeutic response to the subsequent antidepressant remains rather high. Thus, the efficacy of an antidepressant may depend on the baseline differences in the neurochemical state contributing to the pathological “depressive” homeostasis. The heterogeneous neurochemical effects of antidepressants can determine the dissociation of existing neuronal interactions, leading to the development of the new — druginduced — homeostasis. At the same time, it is possible that stimulation of general neurotrophic processes by antidepressants may contribute to the progression and chronicity of pathology due to the ambiguous influence on certain stages of the pathological process. This determines the significance of neurophysiological studies of central disturbances in depression and search of fundamentally new neurochemical targets for the treatment of depressive states associated with various mental disorders.

Alcohol use disorder

Alcohol is one of the most frequently used substances, and alcohol-related disorders are common, especially in western societies. While there is no safe lower drinking level, a clear dose–response relationship has been shown between alcohol intake and organ damage. Conceptualization and diagnostic classification of alcohol use disorders have changed over time, focusing most recently on aspects of craving, loss of control, and continued use despite negative consequences. Alcohol acts via various binding sites in the brain and via downstream effects, including glutamatergic, GABAergic, serotonergic, dopaminergic, opioid, and neuroendocrine pathways. For its long-lasting, habit-forming effects, sensitization within the mesolimbic–mesocortical system is crucial. Psychological treatments traditionally focus on motivational enhancement, cognitive behaviour therapy, and the community reinforcement approach. Pharmacological treatment approaches range from aversive and reward-inhibiting to anti-craving compounds and cognitive enhancers, which target opioid, glutamatergic, and monoamine receptors. Improvement of treatment effects can be achieved by polypharmacy and use of personalized medicine, based on clinical characteristics, biomarkers, and genetic indicators.

The Role of Cannabis within an Emerging Perspective on Schizophrenia

Background: Approximately 0.5% of the population is diagnosed with some form of schizophrenia, under the prevailing view that the pathology is best treated using pharmaceutical medications that act on monoamine receptors. Methods: We briefly review evidence on the impact of environmental forces, particularly the effect of autoimmune activity, in the expression of schizophrenic profiles and the role of Cannabis therapy for regulating immunological functioning. Results: A review of the literature shows that phytocannabinoid consumption may be a safe and effective treatment option for schizophrenia as a primary or adjunctive therapy. Conclusions: Emerging research suggests that Cannabis can be used as a treatment for schizophrenia within a broader etiological perspective that focuses on environmental, autoimmune, and neuroinflammatory causes of the disorder, offering a fresh start and newfound hope for those suffering from this debilitating and poorly understood disease.

The effect of antipsychotic drug on monoamine receptors in peripheral blood mononuclear cells: affinity linked mechanism

Schizophrenia is one of the most serious and common mental disorders, which is characterized by high levels of pathogenic heterogeneity as well as neuroimmune abnormalities, which require treatment with antipsychotic drugs. Monoamines are one of the key neurotransmitters which play an important role in neuroimmune interactions of the human organism. We suggest that the quantity of the monoamine receptors on mononuclear cells of the peripheral blood (PBMCs) can be associated with the cytokine profile of patients. With this quantity being a key component of the mental status correction mechanism in antipsychotic therapy. In this study we measured cytokine levels (IL-6, IL-1b and TGF-b) in blood serum, the protein expression status of the serotonin receptor 5HTR2A and the dopamine receptors D1 (DRD1), DRD2, DRD3 in PBMCs of drug-naive, first episode schizophrenia patients before and after the treatment with olanzapine and haloperidol. This study has shown for the first time that the antipsychotic therapy leads to a decrease in protein levels of monoamine receptors in PBMCs associated with the affinity of the drug used. Blood cytokine levels were significantly higher in serum from studied patients as compared with the reference values. The antipsychotic-linked change of the TGF-b production caused by the therapy is probably associated with the reduction of various monoamine receptors. The relationship between the psychopathological status and the protein level of 5THR2A suggests that the amount of 5HTR2A may serve as a potential biomarker for the personalized appointment of the antipsychotic therapy.

Modulation of neurogenesis and selected neuropeptides expression in the hypothalamus of rats exposed to neuroleptic

Patients treated with neuroleptics suffer from significant weight gain. Hypothalamus consists of neuronal circuits responsible for food intake regulation. Moreover, last finding suggest that adult neurogenesis occurs in the hypothalamus, which could play a role in the energy expenditure control. Considering that neuroleptics affect neural formation in the canonical neurogenic sites, we made a hypothesis that they could modulate hypothalamic neurogenesis and change expression of orexigenic/anorexigenic neuropeptides and their receptors. Experiments were carried out on adult male rats injected intraperitoneally for 1 or 28 days by the neuroleptics: olanzapine, chlorpromazine and haloperidol. Hypothalami were isolated in order to perform RT-PCR reaction and also whole brains were sliced for immunohistochemical assay. We observed that antipsychotics administered chronically supported the origin of newborn cells (Ki67 +) in the hypothalamic regions and affect the number of DCX-positive immature neurons. Furthermore, they have a distinct ability to upregulate preproorexin and orexin A expression and to increase the level of some anorexigenic factors (POMC, α-MSH), at the same time strongly decreasing nesfatin-1 signalling. Our results highlight the role of neuroleptics as potential modulators of the hypothalamic neurogenesis and contribute to better understanding the mechanisms of their side effects. They also underline the complexity of interplay between monoamine receptors, hypothalamic peptidergic pathways and adult neurogenesis which has putative but possible pharmacological applications.