Restorative properties of chronic lurasidone treatment on emotional dysfunction in rats exposed to chronic unavoidable stress: a role for medial prefrontal cortex - nucleus accumbens network.

Anhedonia, a transdiagnostic symptom prevalent in depressive and psychotic disorders, poses a significant challenge for pharmacological intervention due to its association with impaired motivation. Understanding how psychotropic drugs can modulate this pathological domain and elucidating the molecular mechanisms underlying such effects are crucial endeavors in psychiatric research. In this study, we aimed to investigate the pro-motivational properties of lurasidone in a rat (Sprague Dawley males) model of anhedonia and to unravel the interplay between lurasidone and the brain regions critical for reward processing.

Therapeutic Potential of Saffron Extract in Mild Depression: A Study of Its Role on Anhedonia in Rats and Humans.

Drugs generally used in major depressive disorder are considered inappropriate for the more common milder forms. The efficacy of saffron extracts has been demonstrated in mild to moderate depression and in preclinical models of depression. However, evidence of saffron activity on reduced hedonic responsiveness and motivational anhedonia is limited.

Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease.

Growing preclinical and clinical evidence highlights neurosteroid pathway imbalances in Parkinson's Disease (PD) and L-DOPA-induced dyskinesias (LIDs). We recently reported that 5α-reductase (5AR) inhibitors dampen dyskinesias in parkinsonian rats; however, unraveling which specific neurosteroid mediates this effect is critical to optimize a targeted therapy. Among the 5AR-related neurosteroids, striatal pregnenolone has been shown to be increased in response to 5AR blockade and decreased after 6-OHDA lesions in the rat PD model.

PPARα Signaling: A Candidate Target in Psychiatric Disorder Management.

Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three PPAR isoforms have been identified, PPARα, PPARβ/δ, and PPARγ, which are expressed in different tissues and cell types. Hereinafter, we focus on PPARα involvement in the pathophysiology of neuropsychiatric and neurodegenerative disorders, which is underscored by PPARα localization in neuronal circuits involved in emotion modulation and stress response, and its role in neurodevelopment and neuroinflammation.

Targeting PPARα in the rat valproic acid model of autism: focus on social motivational impairment and sex-related differences.

Background: The social motivational theory of autism spectrum disorder (ASD) focuses on social anhedonia as key causal feature of the impaired peer relationships that characterize ASD patients. ASD prevalence is higher in boys, but increasing evidence suggests underdiagnosis and undertreatment in girls. We showed that stress-induced motivational anhedonia is relieved by repeated treatment with fenofibrate (FBR), a peroxisome proliferator-activated receptor α (PPARα) agonist.

BDNF Overexpression Increases Striatal D3 Receptor Level at Striatal Neurons and Exacerbates D1-Receptor Agonist-Induced Dyskinesia.

Background: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID.

Objective: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists.

Heightened reward response is associated with HCN2 overexpression in the ventral tegmental area in morphine-sensitized rats.

Morphine sensitization is associated with increased locomotion and stereotypies in rats. This persistent condition has been proposed as a model of manic-like symptoms. Modifications in reward threshold are considered a central feature of mania and have been related to changes in mesocorticolimbic dopaminergic transmission.

Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT receptor activation.

The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy.

Noradrenergic terminals are the primary source of α-adrenoceptor mediated dopamine release in the medial prefrontal cortex.

In various psychiatric disorders, deficits in dopaminergic activity in the prefrontal cortex (PFC) are implicated. Treatments involving selective augmentation of dopaminergic activity in the PFC primarily depend on the inhibition of α-adrenoreceptors singly or in combination with the inhibition of the norepinephrine transporter (NET). We aimed to clarify the relative contribution of dopamine (DA) release from noradrenergic and dopaminergic terminals to DA output induced by blockade of α-adrenoreceptors and NET.

Antidepressant and pro-motivational effects of repeated lamotrigine treatment in a rat model of depressive symptoms.

Background: The antiepileptic lamotrigine is approved for maintenance treatment of bipolar disorder and augmentation therapy in treatment-resistant depression. Previous preclinical investigations showed lamotrigine antidepressant-like effects without addressing its possible activity on motivational aspects of anhedonia, a symptom clinically associated with poor treatment response and with blunted mesolimbic dopaminergic responsiveness to salient stimuli in preclinical models. Thus, in rats expressing a depressive-like phenotype we studied whether repeated lamotrigine administration restored behavioral responses to aversive and positive stimuli and the dopaminergic response to sucrose in the nucleus accumbens shell (NAcS), all disrupted by stress exposure.

5alpha-reductase inhibitors dampen L-DOPA-induced dyskinesia via normalization of dopamine D1-receptor signaling pathway and D1-D3 receptor interaction.

Although 1-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay therapy for treating Parkinson's disease (PD), its long-term administration is accompanied by the development of motor complications, particularly L-DOPA induced dyskinesia (LID), that dramatically affects patients' quality of life. LID has consistently been related to an excessive dopamine receptor transmission, particularly at the down-stream signaling of the striatal D receptors (DR), resulting in an exaggerated stimulation of cAMP-dependent protein kinase and extracellular signal-regulated kinase (ERK) pathway. We previously reported that pharmacological blockade of 5alpha-reductase (5AR), the rate-limiting enzyme in neurosteroids synthesis, attenuates the severity of a broad set of behavioral alterations induced by DR and DR activation, without inducing extrapyramidal symptoms.

Making Sense of Rodent Models of Anhedonia.

A markedly reduced interest or pleasure in activities previously considered pleasurable is a main symptom in mood disorder and psychosis and is often present in other psychiatric disorders and neurodegenerative diseases. This condition can be labeled as "anhedonia," although in its most rigorous connotation the term refers to the lost capacity to feel pleasure that is one aspect of the complex phenomenon of processing and responding to reward. The responses to rewarding stimuli are relatively easy to study in rodents, and the experimental conditions that consistently and persistently impair these responses are used to model anhedonia.

DARPP-32 in the orchestration of responses to positive natural stimuli.

Dopamine- and cAMP-regulated phosphoprotein (M 32 kDa, DARPP-32) is an integrator of multiple neuronal signals and plays a crucial role particularly in mediating the dopaminergic component of the systems involved in the evaluation of stimuli and the ensuing elaboration of complex behavioral responses (e.g., responses to reinforcers and stressors).

Steroid 5α-reductase 2 deficiency leads to reduced dominance-related and impulse-control behaviors.

The enzyme steroid 5α-reductase 2 (5αR2) catalyzes the conversion of testosterone into the potent androgen 5α-dihydrotestosterone. Previous investigations showed that 5αR2 is expressed in key brain areas for emotional and socio-affective reactivity, yet the role of this enzyme in behavioral regulation remains mostly unknown. Here, we profiled the behavioral characteristics of 5αR2 heterozygous (HZ) and knockout (KO) mice, as compared with their wild-type (WT) littermates.

Aripiprazole relieves motivational anhedonia in rats.

Background: Anhedonia is considered a relevant feature in depression and psychosis, characterized by poor treatment outcome, and associated with deficits in mesolimbic dopaminergic responsiveness. Clinical studies suggest the potential utility of aripiprazole as adjunctive therapy for resistant depression. Since aripiprazole can stabilize the dopaminergic system, in search of tailored therapeutic strategies for reward dysfunctions, we investigated whether the drug restored motivation toward positive stimuli in a rat model.

Fasting biases μ-opioid receptors toward β-arrestin2-dependent signaling in the accumbens shell.

The μ-opioid receptor (MOR) and dopamine D receptor are co-expressed in the medium spiny neurons of striatal areas and the signaling pathways activated by these two receptors are in functional competition. However, in certain conditions an integrated response mediated by the dopamine D receptor transduction system is observed. In mice, morphine administration induces hypermotility and this response has been described in terms of a β-arrestin2-dependent mechanism that favors prevalent dopamine D receptor activation.

PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors.

Depressive disorders cause a substantial burden for the individual and the society. Key depressive symptoms can be modeled in animals and enable the development of novel therapeutic interventions. Chronic unavoidable stress disrupts rats' competence to escape noxious stimuli and self-administer sucrose, configuring a depression model characterized by escape deficit and motivational anhedonia associated to impaired dopaminergic responses to sucrose in the nucleus accumbens shell (NAcS).

The protective effect of Hypericum connatum on stress-induced escape deficit in rat is related to its flavonoid content.

Context Hypericum perforatum L. (Hypericaceae), used in moderate depression treatment, is active in experimental tests for antidepressant activity. For H.

Impramine, fluoxetine and clozapine differently affected reactivity to positive and negative stimuli in a model of motivational anhedonia in rats.

Anhedonia is a relevant symptom in depression and schizophrenia. Chronic stress exposure induces in rats escape deficit, disrupts the dopaminergic response to palatable food and the competence to acquire sucrose self-administration (SA), thus configuring a possible model of motivational anhedonia. Repeated lithium administration reverts stress effects and brings back to control values the breaking point (BP) score, a measure of reward motivation.

Acquisition and expression of conditioned taste aversion differentially affects extracellular signal regulated kinase and glutamate receptor phosphorylation in rat prefrontal cortex and nucleus accumbens.

Conditioned taste aversion (CTA) can be applied to study associative learning and its relevant underpinning molecular mechanisms in discrete brain regions. The present study examined, by immunohistochemistry and immunocytochemistry, the effects of acquisition and expression of lithium-induced CTA on activated Extracellular signal Regulated Kinase (p-ERK) in the prefrontal cortex (PFCx) and nucleus accumbens (Acb) of male Sprague-Dawley rats. The study also examined, by immunoblotting, whether acquisition and expression of lithium-induced CTA resulted in modified levels of phosphorylation of glutamate receptor subunits (NR1 and GluR1) and Thr(34)- and Thr(75-Dopamine-and-cAMP-Regulated) PhosphoProtein (DARPP-32).

Influence of palatability on motivation to operate for caloric and non-caloric food in non food-deprived and food-deprived rats.

Palatability is the hedonic food component that is considered to override the homeostatic mechanisms that control food intake, and we compared how much effort non food-deprived and food-deprived rats were willing to spend in order to earn a palatable caloric (sucrose) or non-caloric (saccharin) snack. We first studied the dopaminergic response, in terms of dopamine levels and dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32) phosphorylation pattern, to two consecutive palatable caloric or non-caloric snacks in the nucleus accumbens shell (NAcS) of non food-deprived and fasted rats. We report that non food-deprived rats developed rapid habituation in the NAcS dopaminergic response to the second consumption of both caloric and non-caloric palatable food, while food-deprived rats developed rapid habituation only to saccharin.

Anti-anhedonic activity of long-term lithium treatment in rats exposed to repeated unavoidable stress.

Behavioural and neurochemical responses to palatable food exposure represent an index of hedonic competence. In rats, a palatable meal increases extra-neuronal dopamine levels in the nucleus accumbens shell (NAcS) that confers to it incentive salience and reinforcing value. Repeated stress exposure decreases dopamine output and impairs the NAcS dopaminergic response to palatable food and the competence to acquire a vanilla sugar (VS)-reinforced instrumental behaviour [VS-sustained appetitive behaviour (VAB)].

Identification of cancer stem cells from human glioblastomas: growth and differentiation capabilities and CD133/prominin-1 expression.

CD133 can be a marker of tumorigenic CSCs (cancer stem cells) in human GBM (glioblastoma multiforme), although tumorigenic CD133-negative CSCs have been also isolated. Additional evidence indicates that CSCs from GBM exhibit different phenotypes, with increasing interest in the potential significance of the different CSCs with respect to diagnosis, prognosis and the development of novel targets for treatment. We have analysed the expression of CD133 in freshly isolated cells from 15 human GBM specimens.