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Rigid reduced successor representation as a potential mechanism for addiction

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Official websites use. Share sensitive information only on official, secure websites. Corresponding author. Repurposing of antihypertensive drugs to treat mental disorders is thus being explored. A systematic knowledge of the mechanisms of action and clinical consequences of the use of antihypertensive agents on neuropsychiatric functions has not been achieved yet. In addition, we review pharmacokinetics brain penetration of drugs and pharmacogenetics data that add important information to assess risks and benefits of antihypertensive drugs in neuropsychiatric settings. Renin-angiotensin system modulators exert protective effects on cognition, depression, and anxiety, and the loop diuretic bumetanide reduced the core symptoms of autism in a subset of patients. There is no evidence of clear benefits of calcium channel blockers in mood disorders in the scientific literature. These findings are mainly from preclinical studies; clinical data are still insufficient or of anecdotal nature and seldom systematic. The information herewith provided can support a better therapeutic approach to hypertension, tailored to patients with, or with high susceptibility to, psychiatric illness. It may prompt clinical studies exploring the potential benefit of antihypertensive drugs in selected patients with neuropsychiatric comorbidities that include outcomes of neuropsychiatric interest and specifically assess undesirable effects or interactions. Keywords: Antihypertensive drugs, Neuropsychiatric disorders, Personalized medicine. The mind—heart—body relationship, specifically the connection between mental disorders and cardiovascular diseases, has received considerable attention in the last decades. Consistent evidence indicates that patients suffering of both cardiovascular diseases and psychiatric disorders e. Hypertensive patients are more likely to have a recorded diagnosis of mental disorders, and hypertension increases the severity of psychological distress. Conversely, prospective studies showed that psychiatric disorders are independent risk factors for hypertension. Mental disorders can cause continuous activation of the sympathetic nervous system and dysfunction of the hypothalamus-pituitary-adrenaline axis, thus increasing vascular tone and blood pressure and leading to pathological hypertension disorders. Proper psychiatric and hypertensive management may be crucial to prevent complications in these patients. In this review, we provide an overview of essential aspects of the pharmacokinetics and pharmacogenetics of the different pharmacological classes of antihypertensive drugs. For each class, we describe the receptors and molecular mechanisms through which antihypertensive drugs generate neuropsychiatric effects in preclinical models, highlighting those that, in our opinion, are desirable and potentially exploitable in therapy. We then discuss drug-drug interactions with commonly prescribed psychiatric drugs, focussing only on psychiatric aspects, while metabolic issues are reviewed elsewhere. In this context, we describe the psychiatric effects of antihypertensive drugs and, where relevant, the pharmacological aspects that may influence such effects. This article aims to stimulate future clinical research studies and promote a conscious tailored therapeutic approach to hypertension in patients with, or with high susceptibility to, psychiatric illness. However, the extent of brain penetration for these drugs depends also on the protein binding in blood and brain. Brain penetration of anti-hypertensive and other drugs. Brain penetration of anti-hypertensive drugs is regulated by some intrinsic chemical properties, including molecular weight, partition coefficient, and distribution volume: these regulate the overall permeability of drugs through biological membranes. Once drugs are absorbed and distributed in the blood flow, they are bound by plasma proteins. The unbound fraction can cross the BBB either passively or actively, and it is often sent back to the blood flow by drug transporters. Once in the cerebrospinal fluid CSF or brain interstitial fluids, again drugs can be bound. Unbound fractions in the brain can actually bind their receptors and produce effects. Created with BioRender. Furthermore, efflux transporters such as P-glycoprotein P-gp , organic anionic transporters OATPs , and breast cancer resistance protein BCRP protect the brain from penetration of harmful substances. Therefore, if a drug is substrate of these efflux transporters, it is less likely to penetrate into the brain Table 1. Physico-chemical and pharmacokinetic features of the main anti-hypertensives from different classes. Table 1 provides the main physico-chemical and pharmacokinetic features of some antihypertensive drugs, which can be used to predict their ability to cross the brain barriers. This table is not intended to be exhaustive of all the antihypertensive drugs on the market; it aims to show that the capacity to penetrate the CNS can vary for molecules belonging to the same therapeutic category based on their chemical, physical, and pharmacokinetic characteristics. All antihypertensive drugs are small molecules and, therefore, potential candidates for passive diffusion. However, even within the same drug class, important differences exist in the lipophilicity of the different compounds. For instance, among the ACE inhibitors ACEIs , lisinopril has low lipophilicity and thus, theoretically, less propensity to cross the brain barriers than ramipril, which has high lipophilicity. The picture is further complicated by key differences in the protein binding, with lisinopril largely circulating as a free drug and ramipril been mostly bound to plasma proteins. Based on these considerations, lisinopril could entry the brain to a higher extent than ramipril. One of the most evident limitations in Table 1 is the lack of data on CNS penetration for most of the molecules. Since the CSF levels of these agents, both free and bound, were much lower than the corresponding concentrations in serum, the Authors concluded that the observed CNS adverse events were unlikely mediated primarily via direct effects of these drugs in the brain. These data suggest that the CNS concentrations reached by these antihypertensive drugs at therapeutic dosages are likely too low to carry out beneficial actions at a central level. These adrenergic receptors are integrated in the Cortico-Striato-Thalamo-Cortical CSTC neurocircuitry, 19 where they regulate arousal, attention, anxiety, and emotional trauma through the norepinephrine signalling among other neurotransmission systems. Although the adrenal medulla can release norepinephrine in the bloodstream, the locus coeruleus LC is the primary source of norepinephrine for the brain, since it innervates several areas of the cortex and can efficiently alter the CSTC function. The amount of released norepinephrine is proportional to the amount and intensity of stimuli received from sensory organs, and correlates directly with the overall activity of the CSTC. AM, active metabolite; ISA, intrinsic sympathomimetic activity. BindingDB in A public database for medicinal chemistry, computational chemistry and systems pharmacology Nucleic Acids Research DD \]. Main mechanisms of action of anti-hypertensive drugs in the brain. For each drug class, we reported on the brain surface the main molecular target in the brain; downstream, we reported the intermediate mechanisms of action; terminally, we reported the higher-level final mechanisms of action. The aspects and localizations of receptors and mechanisms are purely graphical and do not indicate molecular structures or anatomical localizations. Sharp-headed arrows indicate stimulation; flat-headed arrows indicate inhibition; circular-headed arrows indicate modulation. During sleep, norepinephrine release from the LC is almost absent. As a consequence, the CSTC is in a resting condition. In the presence of external stimuli, low tonic norepinephrine release from the LC maintains wakefulness and allows the allocation of attention to distinct stimuli. In these circumstances, the CSTC directs attention towards salient stimuli. Based on their lipophilicity, noradrenergic antihypertensive drugs have different propensity to enter the brain and exert psychoactive effects Figure 1. A possible side effect of these drugs is fatigue. They induce symptoms of fatigue and lethargy, putatively due to their inhibitory activity on neuronal plasticity; they can alter sleep and cause nightmares in unclear ways; in rare cases, they can cause hallucination, possibly by disrupting dopaminergic signals. More recently, these drugs have been tested to treat a variety of psychiatric conditions beyond their approved indication. The main characteristics of studies reporting beneficial vs harmful effects of each antihypertensive drug class in the neuropsychiatric clinic are detailed in the Supplementary material online , Table S1. In adult ADHD patients, 3 RCTs showed that guanfacine produced clinically relevant improvements in core symptoms, executive function, and quality of life. Clonidine and guanfacine showed other promising neuropsychiatric effects; however, these were reported in non-controlled studies and require verification in randomized blinded trials. Other off-label use of clonidine includes the management of obsessive-compulsive disorder OCD symptoms 54 and clinically relevant sleep problems in paediatric patients affected by neurodevelopmental disorders. Clinical evidence on neuropsychiatric effects of antihypertensive drugs is briefly summarized in Table 3. Beneficial vs harmful effects of adrenergic antihypertensive drugs in the neuropsychiatric clinic. PTSD symptoms, nightmares and sleep quality and content, both in adults 61—66 and children 67 Prazosin. Clonidine and guanfacine are approved treatment for ADHD in children, long-acting formulations only. The detailed list of references is reported in the Supplementary material online , Table S1. A large amount of literature is available regarding the use of prazosin for sleep disturbances, specifically in the context of PTSD see Supplementary material online , Table S1. The currently available systematic reviews and meta-analyses addressing adults have found predominantly positive findings on overall PTSD symptoms, nightmares, and sleep quality and content, supporting the use of prazosin as a good pharmacological option to treat PTSD. A systematic review showed that prazosin may also be promising for PTSD-related nightmares in children and adolescents; 66 however, only sporadic case reports are currently available, supporting the need for well-designed placebo-controlled trials. Another potential pharmacogenetic marker for substance use disorder was described in a week placebo controlled clinical trial, focussed on the genetic variant rs c. In this trial, the T-allele carriers had a greater reduction of cocaine use after treatment with doxazosin. Ser49Gly rs and p. The effects of adrenergic modulators depend on the receptor engaged in the brain. Diuretic drugs act on molecular targets that are class-specific or even drug-specific. Diuretics alter the electrolyte content and, consequently, the excitability of neurones, thus producing changes in neurotransmission and potential neuropsychiatric effects. Diuretics have very different neuropsychiatric profiles depending on which receptor they engage. Among potassium sparing diuretics, amiloride and triamterene have their main target in the epithelial sodium channel ENaC Figure 2 , which is in the same superfamily as acid sensing ion channels ASICs. Spironolactone is a highly lipophilic mineralocorticoid antagonist with minor action on the androgen receptor, and a much less potent antagonist of the oestrogen and glucocorticoid receptors. The loop diuretics furosemide and bumetanide act by inhibiting the sodium-potassium-chloride co-transporter NKCC2; they also target its isoform NKCC1, expressed in the juvenile brain, which becomes increasingly silenced with neuronal development. This mechanism is considered important for brain synchronization and synapse wiring during brain development stages. Later, the electrochemical potential of chloride generates by the potassium-chloride co-transporter KCC2, which orients GABA-triggered chloride currents outside-in and allows the inhibitory activity of GABA that is typical of adult neurones. A neuropsychiatric effect of thiazides is not known. Moreover, the lipophilic metolazone might alter electrolyte levels in the brain more efficiently than other non-lipophilic thiazides. The role of CAs has been increasingly studied with respect to synaptic function, spatial learning, memory, and altering the function of GABA receptor channels. Some lipophilic thiazides indapamide, metolazone may contrast seizures through their inhibitory action on CAs, similarly to some antiepileptic drugs that inhibit CAs e. Among potassium sparing diuretics, amiloride and triamterene are scantly lipophilic. Therefore, at therapeutic dosages, these drugs would unlikely reach significant concentrations in the brain. There is ongoing research with respect to intranasal administrations of amiloride, which should reach the brain more efficiently, but its effects are yet to be defined. Mineralocorticoid receptors are not currently associated with any neuropsychiatric effect. However, several observations suggest that they are involved in neurogenesis aspects that establish anxious responses to stress. The possible role of NKCC1 dysregulation in the aetiopathogenesis of several neuropsychiatric disorders has been investigated. NKCC1 may be a promising target for the treatment of specific epilepsies, , neurodevelopmental disorders including autism spectrum disorders and tuberous sclerosis, and neuropsychiatric disorders including schizophrenia, anxiety, pain, and brain degeneration or injury. One bumetanide lipophilic prodrug, its dimethylaminoethyl ester BMU5 , showed promising results in increasing the seizure threshold after epileptogenic brain insults. Most of the existing data on the role of diuretics in psychiatry are related to the use of bumetanide for treating core symptoms of ASD. Additional anecdotal evidence came from studies on emotion recognition , and reports of single cases of success, for instance in a boy with Fragile X. Phase 3 international trials failed to show significant effect of bumetanide over placebo on any outcome in the latest interim analyses, thus leading to a disappointing stop in drug development. CA-inhibiting lipophilic thiazides may have neuropsychiatric effects on mood and cognition, yet to be thoroughly investigated in preclinical models. Agonism at the NKCC1 receptor is the only mechanism currently targeted in clinical applications for the treatment of autism spectrum disorders and epilepsy of specific aetiology. Thus, the use of bumetanide is limited to subpopulations of patients. Except for pharmacokinetic effects based on volaemic changes, no interactions with neuropsychiatric drugs are known or expected from diuretics. The data obtained by the genetic modification of brain LTCCs suggest behavioural effects and anxiolytic-like features for CCBs, which are possibly related to the modulation of neurotransmitters release. However, evidence in hypertensive patients suggests that therapeutic doses of these drugs do not affect brain function. In a study carried out in mice that had been treated with CCBs acutely, verapamil and diltiazem facilitated depression, presumably through an off-target decrease of the release in norepinephrine and serotonin at higher dosages. Conversely, nifedipine showed an antidepressant-like behaviour, in line with a previous paper reporting an antidepressant profile for nifedipine and other DPHs, such as nicardipine, nitrendipine, isradipine, felodipine, and nimodipine. The involvement of the LTCCs in this event was further confirmed by the finding that an activator of the channels, Bay K, reduced the effect of nifedipine. Noteworthy, CCBs may interact pharmacodynamically with diverse psychoactive drugs. Up-regulation of LTCCs has been reported in rat brain after repeated administration of psychostimulant drugs such as methamphetamine, cocaine, and opioids e. Isradipine was effective in improving schizophrenia symptoms in two recent RCTs; 97 , 98 however, no clear evidence of a role of CCBs in neurocognition is currently available. There is a significant association of this polymorphism with bipolar disorders, major depressive disorders, schizophrenia, and ADHD. At molecular level, rs is correlated with changes in CACNA1C expression and an increased L-type current in induced human neurones derived from individuals carrying rs To date, observational studies have reported contradictory associations between CCBs intake and mood disorders see Supplementary material online , Table S1. The preclinical evidence suggests that CCBs might have therapeutic value in the treatment of neuropsychiatric disorders, neurodegenerative diseases, and drug dependence. However, human clinical studies are not conclusive about an association between CCBs intake and mood disorders therapy. This might be due to a low CFS drug concentration at the dosage used for cardiovascular disease treatment. Within the brain, renin has been found within neurones and astrocytes, while angiotensinogen is mainly produced and secreted by astrocytes. Neurones can produce an intracellular form of renin and secrete the precursor form of renin, prorenin; both can bind to prorenin receptors PRRs , which are also expressed in neurones and lead to angiotensinogen cleavage. Plasma membrane AT2R regulates neuronal excitability and differentiation, and promotes neurite outgrowth and cell survival through the activation of multiple pathways. AT1R activation in astrocytes has both negative and positive outcomes. In neurones and microglia, it leads to the increase of ROS generation via the NOX pathway, to oxidative stress, and to cell death. However, AT1R activation decreases the permeability and maintenance of the BBB through the mobilization of occludin, a protein of the tight junctions, in the lipid rafts of the brain endothelial cell. Regarding the role of brain RAS in hypertension, accumulating evidence indicates that RAS constituents and mediators of inflammation act on the brain within a neural network to increase the sympathetic nervous system activity and, consequently, blood pressure. The brain RAS modulates also sensory information processing, learning and memory, and emotional responses. In a recent study in mice, the ACEI captopril and lisinopril showed a rapid and long-lasting beneficial effect on stress-induced depressive-like behaviours. The beneficial effect of pharmacological modulation of RAS in schizophrenia mainly depends on the neuroprotective properties of ARBs. Regarding treatment of schizophrenia-related cognitive impairment with irbesartan, losartan, and telmisartan, a novel mechanism of action has been hypothesized, which involves the negative regulation of the kynurenine aminotransferase II and the reduction of kynurenic acid. It prevented behavioural alterations with a mechanism that appeared to be independent of AT1R activation and presumably consistent with a direct antioxidant effect of the molecule. Although it has been reported that ACEIs have positive effects on mood when compared with patients taking other antihypertensive drugs, 99 , — there is scant evidence on the use of ACEIs in the field of neuropsychiatry see Supplementary material online , Table S1. Associations between ACE polymorphisms and depression have been described, , and altered methylation of the regulatory region of the ACE gene has been reported in depression. Furthermore, through a summary-based Mendelian randomization analysis, they showed an association of decreased ACE expression in blood with increased risk of schizophrenia. This analysis parallel with the findings of another Mendelian randomization study that suggested an association of lower levels of ACE messenger RNA and protein with decreased systolic blood pressure SBP on one side, and with an increased risk of schizophrenia on the other side. Beside major depressive disorder, SNPs within the ACE gene were also significantly associated with acute stress response and higher mortality following a major trauma. With regard to ARBs, data in humans are currently very limited. Clinical reports and observational studies recently reported encouraging findings in psychotic patients; , protective effects of ARBs on cognition, , depression, and anxiety have also been reported see Supplementary material online , Table S1. Noteworthy, in a recent week randomized, double-blind, placebo-controlled study, the adjunctive treatment with telmisartan improved schizophrenia symptoms in 22 patients receiving either clozapine or olanzapine. In a nested case-control study investigating all antihypertensive drug classes, suicide risk was associated only with ARB use OR: 3. Increasing preclinical evidence supports the antidepressant and antipsychotic effects of drugs targeting the RAS. Particularly interesting are ARBs, with their neuroprotective properties exerted through the stimulation of AT1R and its downstream pathways. The available clinical evidence further points to a psychotropic role of RAS modulators. However, the intrinsic limitations of the studies that have addressed the topic e. Such studies should aim to characterize the beneficial effects of RAS-acting agents on psychopathology, cognition, and safety in patients with schizophrenia and mood disorders, along with the potential mechanism mediating these effects and pharmacogenetic aspects. The blood vessel dilating drugs hydralazine and minoxidil have important off-target activities in the brain that do not involve vasodilation; however, since preclinical and clinical evidence is scant, we only provide a summary of the available data. The hydrophilic drug hydralazine is thought to act as an antioxidant by preventing the degradation of NO and thereby increasing its activity. Hydralazine can also inhibit inositol-triphosphate channels, which control calcium release from intracellular storages. Calcium concentrations in the neurone participate in controlling survival, structural, and functional aspects, which are connected also with memory and neurodegeneration. Minoxidil is a lipophilic opener of ATP-sensitive potassium channels K ATP , which can trigger the relaxation of blood vessels smooth muscles and play a crucial role in peripheral and hypothalamic glycaemic regulation. Beside these roles, K ATP channels can couple the electrical activity of neurones with a check of energy availability, possibly playing a role in brain injury following ischaemia or hypoxia. Indeed, K ATP channels dysfunction has been putatively connected with neurodegeneration, in particular of dopaminergic neurones. Reserpine is a lipophilic monoamine depleting agent that irreversibly inhibits the vesicular monoamine transporter VMAT , which reuptakes norepinephrine, serotonin, and dopamine from the cytosol into presynaptic vesicles Figure 2. The consequent increase in the cytosolic concentration of monoamines leads to their degradation by monoamine oxidase and to depletion. Subsequently, monoamines have to be synthesized anew. This action of reserpine is depressant. In addition, reserpine may also induce neurone loss, due to an increased energy expenditure for neurotransmitter synthesis. Indeed, there are pathological models of pain, depression, and neurodegeneration induced by reserpine treatment. Notable exceptions are lipophilic noradrenergic antihypertensive drugs, which cause symptoms attributable to depression, and bumetanide, which may obtain a therapeutic placement for autism or epilepsy in specific patients. When treating psychiatric comorbid patients, knowledge of the neuropsychiatric mechanisms of action and effects of antihypertensive drugs can help discriminate between psychiatric comorbidity and the adverse effects or unexpected positive effects that may occur. Overall, the effects of adrenergic modulators depend on the engaged receptors. Prazosin, thanks to its anxiolytic effect, is used to treat PTSD by reducing the overall burden of disease symptoms. Limited data are available on the effects of diuretic drugs in the field of neuropsychiatry. CCBs are associated with a relative low rate of psychiatric complications, but also with a poor positive effect on brain function. Under debate is their potential role in improving or worsening cognitive functions and mood disorders. CCBs seem to reduce psychiatric hospitalization in patients with schizophrenia, whereas no evidence supports their role to improve acute mania and bipolar disorders, or an antidepressant effect. Evidence of neuropsychiatric effects of drugs targeting RAS is currently almost absent. However, ACEIs and ARBs rescue anxiety- and depression-like phenotypes in animal models, and seem to improve mental health and schizophrenia symptoms in human. Open questions regard on the one hand how to avoid undesirable effects or interactions with neuropsychiatric drugs and, on the other hand, how to exploit these additional mechanisms for neuropsychiatric treatment. Adverse effects can be avoided by switching drugs, for instance to a less lipophilic equivalent, or by choosing the proper combination between antihypertensive and neuropsychiatric drugs to avoid undesired interactions. Therapeutic development of antihypertensive drugs can be pursued firstly by solving the bioavailability issue, since most have limited penetration in the CNS. There are three different approaches to improve the pharmacological profile of these drugs. One is to use lipophilic prodrugs that more easily penetrate the brain barriers and are subsequently metabolized, once within the CNS, to release the active moieties. The second approach is to design lipophilic derivatives of antihypertensive drugs that cross the brain barriers more easily than the parent compound. The third is to modify those antihypertensive drugs that have different targets in the CNS, reducing their antihypertensive potential that may be excessive or untoward when considering neuropsychiatric applications. Future studies should include outcomes of neuropsychiatric interest, because previous studies have focussed on cardiovascular outcomes and only reported anecdotal evidence on neuropsychiatric aspects. The Mendelian randomization approach may provide an additional piece of evidence about the effects of drugs on certain neurological diseases, especially since RCTs are sometimes too expensive or even impossible to perform. Some studies have already applied this approach to investigate the effects of antihypertensive drugs in the context of neuropsychiatric diseases. Supplementary material is available at Cardiovascular Research online. The funding public institutions had no role in any part of the work. Data derived from sources in the public domain. Reference details are provided in full both in the Main text and in the Supplementary Material online. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Cardiovasc Res. Find articles by Carla Carnovale. Find articles by Cristiana Perrotta. Find articles by Sara Baldelli. Find articles by Dario Cattaneo. Find articles by Cristina Montrasio. Find articles by Silvia S Barbieri. Find articles by Giulio Pompilio. Find articles by Chiara Vantaggiato. Find articles by Emilio Clementi. Find articles by Marco Pozzi. This article has been corrected. See Cardiovasc Res. Open in a new tab. CCB, calcium channel blockers; P-gp, P-glycoprotein. Binding profile of antihypertensive drugs at selected receptors of neuropsychiatric interest. Anhyd Kir6. Minoxidil Ki? CCBs Positive effects on: acute bipolar mania All, particularly verapamil 95 , 96 verbal memory, attention dysfunction and functional capacity in patients with schizophraenia Isradipine 97 , 98 cognitive function in elderly hypertensive people All. Click here for additional data file. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Alpha 2 agonists a. Usually dose-related and reversible: dizziness, drowsiness, somnolence, and other depressive symptoms All. Positive effects on: PTSD symptoms, nightmares and sleep quality and content, both in adults 61—66 and children 67 Prazosin drug dreams in patients with substance use disorder Prazosin. Sleep disorders up to insomnia, nightmares, visual hallucinations, delirium or psychosis All. Positive effects on: acute bipolar mania All, particularly verapamil 95 , 96 verbal memory, attention dysfunction and functional capacity in patients with schizophraenia Isradipine 97 , 98 cognitive function in elderly hypertensive people All. Dizziness, difficulty sleeping and decreased energy in symptomatically-stable patients with schizophraenia Isradipine. Positive effects on: depressed mood when compared with patients taking other antihypertensive drugs All 99 , — mental health outcomes overall quality of life, positive wellbeing, mental and anxiety domains of quality of life All cognitive function in adult patients affected by cardiovascular disease All. Visual hallucinations, paranoid delusions, confusion, disorientation, anxiety Quinalapril. Positive effects on: schizophraenia symptoms Telmisartan , depression and anxiety and functional statuses Valsartan b cognitive function in older patients with hypertension Candesartan. Risk for suicide All.

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