What drugs modify the risk of iatrogenic impulse-control disorders in Parkinson’s disease? A preliminary pharmacoepidemiologic study

Introduction Parkinson’s disease (PD) patients treated with pramipexole (PPX) and ropinirole (ROP) exhibit a higher risk of developing impulse control disorders (ICDs), including gambling disorder, compulsive shopping, and hypersexuality. The management of ICDs in PD is challenging, due to the limited availability of effective therapeutic alternatives or counteractive strategies. Here, we used a pharmacoepidemiological approach to verify whether the risk for PPX/ROP-associated ICDs in PD patients was reduced by drugs that have been posited to exert therapeutic effects on idiopathic ICDs–including atypical antipsychotics (AAs), selective serotonin reuptake inhibitors (SSRIs), and glutamatergic modulators (GMs). Methods To quantify the strength of the associations between PPX/ROP and other medications with respect to ICD risk, odds ratios (ORs) were calculated by multivariable logistic regression, adjusting for age, gender, marital status race, psychiatric comorbidities, and use of cabergoline and levodopa. Results A total of 935 patients were included in the analysis. Use of GMs, SSRIs, and AAs was not associated with a decreased ICD risk in PD patients treated with PPX/ROP; conversely, ICD risk was significantly increased in patients treated with either GMs (Adjusted Odds Ratio, ORa: 14.00 [3.58–54.44]) or SSRIs (ORa: 3.67 [1.07–12.59]). Results were inconclusive for AAs, as available data were insufficient to compute a reliable ORa. Conclusions These results suggest that some of the key pharmacological strategies used to treat idiopathic ICD may not be effective for ICDs associated with PPX and ROP in PD patients. Future studies with larger cohorts are needed to confirm, validate, and extend these findings

Animal Models of Virus-Induced Neurobehavioral Sequelae: Recent Advances, Methodological Issues, and Future Prospects

Converging lines of clinical and epidemiological evidence suggest that viral infections in early developmental stages may be a causal factor in neuropsychiatric disorders such as schizophrenia, bipolar disorder, and autism-spectrum disorders. This etiological link, however, remains controversial in view of the lack of consistent and reproducible associations between viruses and mental illness. Animal models of virus-induced neurobehavioral disturbances afford powerful tools to test etiological hypotheses and explore pathophysiological mechanisms. Prenatal or neonatal inoculations of neurotropic agents (such as herpes-, influenza-, and retroviruses) in rodents result in a broad spectrum of long-term alterations reminiscent of psychiatric abnormalities. Nevertheless, the complexity of these sequelae often poses methodological and interpretational challenges and thwarts their characterization. The recent conceptual advancements in psychiatric nosology and behavioral science may help determine new heuristic criteria to enhance the translational value of these models. A particularly critical issue is the identification of intermediate phenotypes, defined as quantifiable factors representing single neurochemical, neuropsychological, or neuroanatomical aspects of a diagnostic category. In this paper, we examine how the employment of these novel concepts may lead to new methodological refinements in the study of virus-induced neurobehavioral sequelae through animal models

Gene-sex interactions in schizophrenia: focus on dopamine neurotransmission

Schizophrenia is a severe mental disorder, with a highly complex and heterogenous clinical presentation. Our current perspectives posit that the pathogenic mechanisms of this illness lie in complex arrays of gene × environment interactions. Furthermore, several findings indicate that males have a higher susceptibility for schizophrenia, with earlier age of onset and overall poorer clinical prognosis. Based on these premises, several authors have recently begun exploring the possibility that the greater schizophrenia vulnerability in males may reflect specific gene × sex (G×S) interactions. Our knowledge on such G×S interactions in schizophrenia is still rudimentary; nevertheless, the bulk of preclinical evidence suggests that the molecular mechanisms for such interactions are likely contributed by the neurobiological effects of sex steroids on dopamine (DA) neurotransmission. Accordingly, several recent studies suggest a gender-specific association of certain DAergic genes with schizophrenia. These G×S interactions have been particularly documented for catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), the main enzymes catalyzing DA metabolism. In the present review, we will outline the current evidence on the interactions of DA-related genes and sex-related factors, and discuss the potential molecular substrates that may mediate their cooperative actions in schizophrenia pathogenesis

Links Between Stressful Life Events and Proactive and Reactive Functions of Aggression

This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Aggression, Maltreatment and Trauma on June 01, 2017, available online: http://www.tandfonline.com/10.1080/10926771.2017.1322658.Recently, more attention has been devoted to understanding how stressful life events might relate to proactive and reactive aggression. Findings suggest that stressful life events are more strongly linked to reactive, than proactive, aggression; however, it is unclear whether the impact of stressful life events on proactive and reactive aggression might vary as a function of the level of exposure to or type of stressful life event. The current study examined how level of exposure to stressful life events (i.e., witnessed, experienced, and learned about) and stressful life event types (i.e., war zone exposure, sexual victimization, interpersonal violence, and other trauma exposure) related to proactive and reactive aggression. The sample was comprised of 500 undergraduate students (M = 18.96, SD = 1.22, 49.6% male) recruited from a Midwestern university. Findings indicated that all three levels of stressful life event exposure (i.e., experienced, witnesses, and learned) were associated with reactive aggression; however, only witnessed stressful life events were associated with proactive aggression. Clinical implications and future directions are discussed

The Role of Hostile Attributions in the Associations between Child Maltreatment and Reactive and Proactive Aggression

This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Aggression, Maltreatment and Trauma on October 8th, 2016, available online: http://www.tandfonline.com/10.1080/10926771.2016.1231148.The present study examined the relations between child maltreatment and reactive and proactive functions of aggression, and whether hostile attribution biases partially accounted for these associations in a sample of 339 college students (mean age = 19; 51% male). Child maltreatment was associated with reactive, but not proactive, aggression, and instrumental hostile attribution biases accounted for this association. Relational hostile attributions were correlated with both reactive and proactive aggression, but did not play a role in the link between child maltreatment and reactive aggression

Endocannabinoid-dependent decrease of GABAergic transmission on dopaminergic neurons is associated with susceptibility to cocaine stimulant effects in pre-adolescent male MAOA hypomorphic mice exposed to early life stress.

Vulnerability to cocaine use disorder depends upon a combination of genetic and environmental risk factors. While early life adversity is a critical environmental vulnerability factor for drug misuse, allelic variants of the monoamine oxidase A (MAOA) gene have been shown to moderate its influence on the risk of drug-related problems. However, data on the interactions between MAOA variants and early life stress (ES) with respect to predisposition to cocaine abuse are limited. Here, we show that a mouse model capturing the interaction of genetic (low-activity alleles of the Maoa gene; MAOANeo) and environmental (i.e., ES) vulnerability factors displays an increased sensitivity to repeated in vivo cocaine psychomotor stimulant actions associated with a reduction of GABAA receptor-mediated inhibition of dopamine neurons of the ventral tegmental area (VTA). Depolarization-induced suppression of inhibition (DSI), a 2-arachidonoylglycerol (2AG)-dependent form of short-term plasticity, also becomes readily expressed by dopamine neurons from male MAOANeo ES mice repeatedly treated with cocaine. The activation of either dopamine D2 or CB1 receptors contributes to cocaine-induced DSI expression, decreased GABA synaptic efficacy, and hyperlocomotion. Next, in vivo pharmacological enhancement of 2AG signaling during repeated cocaine exposure occludes its actions both in vivo and ex vivo. This data extends our knowledge of the multifaceted sequelae imposed by this gene-environment interaction in VTA dopamine neurons of male pre-adolescent mice and contributes to our understanding of neural mechanisms of vulnerability for early onset cocaine use

Animal models of tic disorders: A translational perspective

Tics are repetitive, sudden movements and/or vocalizations, typically enacted as maladaptive responses to intrusive premonitory urges. The most severe tic disorder, Tourette syndrome (TS), is a childhood-onset condition featuring multiple motor and at least one phonic tic for a duration longer than 1 year. The pharmacological treatment of TS is mainly based on antipsychotic agents; while these drugs are often effective in reducing tic severity and frequency, their therapeutic compliance is limited by serious motor and cognitive side effects. The identification of novel therapeutic targets and development of better treatments for tic disorders is conditional on the development of animal models with high translational validity. In addition, these experimental tools can prove extremely useful to test hypotheses on the etiology and neurobiological bases of TS and related conditions. In recent years, the translational value of these animal models has been enhanced, thanks to a significant re-organization of our conceptual framework of neuropsychiatric disorders, with a greater focus on endophenotypes and quantitative indices, rather than qualitative descriptors. Given the complex and multifactorial nature of TS and other tic disorders, the selection of animal models that can appropriately capture specific symptomatic aspects of these conditions can pose significant theoretical and methodological challenges. In this article, we will review the state of the art on the available animal models of tic disorders, based on genetic mutations, environmental interventions as well as pharmacological manipulations. Furthermore, we will outline emerging lines of translational research showing how some of these experimental preparations have led to significant progress in the identification of novel therapeutic targets for tic disorders

Methionine sulfoxide reductase regulates brain catechol-O-methyl transferase activity

This is the published version. Copyright 2014 Oxford University PressCatechol-O-methyl transferase (COMT) plays a key role in the degradation of brain dopamine (DA). Specifically, low COMT activity results in higher DA levels in the prefrontal cortex (PFC), thereby reducing the vulnerability for attentional and cognitive deficits in both psychotic and healthy individuals. COMT activity is markedly reduced by a non-synonymous single-nucleotide polymorphism (SNP) that generates a valine-to-methionine substitution on the residue 108/158, by means of as-yet incompletely understood post-translational mechanisms. One post-translational modification is methionine sulfoxide, which can be reduced by the methionine sulfoxide reductase (Msr) A and B enzymes. We used recombinant COMT proteins (Val/Met108) and mice (wild-type (WT) and MsrA knockout) to determine the effect of methionine oxidation on COMT activity and COMT interaction with Msr, through a combination of enzymatic activity and Western blot assays. Recombinant COMT activity is positively regulated by MsrA, especially under oxidative conditions, whereas brains of MsrA knockout mice exhibited lower COMT activity (as compared with their WT counterparts). These results suggest that COMT activity may be reduced by methionine oxidation, and point to Msr as a key molecular determinant for the modulation of COMT activity in the brain. The role of Msr in modulating cognitive functions in healthy individuals and schizophrenia patients is yet to be determined

Inhibition of 17α-hydroxylase/C17,20 lyase reduces gating deficits consequent to dopaminergic activation

Cogent evidence points to the involvement of neurosteroids in the regulation of dopamine (DA) neurotransmission and signaling, yet the neurobiological bases of this link remain poorly understood. We previously showed that inhibition of 5α-reductase (5αR), a key neurosteroidogenic enzyme, attenuates the sensorimotor gating deficits induced by DA receptor activation, as measured by the prepulse inhibition (PPI) of the acoustic startle reflex. To extend these findings, the present study was aimed at the assessment of the role of other key neurosteroidogenic enzymes in PPI, such as 17α-hydroxylase/C17,20 lyase (CYP17A1), 3α- and 3β-hydroxysteroid dehydrogenase (HSD), in Sprague-Dawley rats. The PPI deficits induced by the DAergic non-selective agonist apomorphine (APO, 0.25 mg/kg, SC) were dose-dependently attenuated by the selective CYP17A1 inhibitor abiraterone (ABI, 10-50 mg/kg, IP) in a fashion akin to that of the 5αR inhibitor finasteride (FIN, 100 mg/kg, IP). These systemic effects were reproduced by intracerebroventricular injection of ABI (1 μg/1 μl), suggesting the involvement of brain CYP17A1 in PPI regulation. Conversely, the PPI disruption induced by APO was not significantly affected by the 3α- and 3β-HSD inhibitors indomethacin and trilostane. Given that CYP17A1 catalyzes androgen synthesis, we also tested the impact on PPI of the androgen receptor (AR) antagonist flutamide (10 mg/kg, IP). However, this agent failed to reverse APO-induced PPI deficits; furthermore, AR endogenous ligands testosterone and dihydrotestosterone failed to disrupt PPI. Collectively, these data highlight CYP17A1 as a novel target for antipsychotic-like action, and suggest that the DAergic regulation of PPI is modulated by androgenic neurosteroids, through AR-unrelated mechanisms