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.

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.

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).

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).

PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings.

Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in α4 or β2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine.

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)].

Morphine sensitization as a model of mania: comparative study of the effects of repeated lithium or carbamazepine administration.

Repeated unavoidable stress induces in rats decreased reactivity to avoidable stressors and an anhedonia-like condition that are reverted by long-term antidepressant treatments and regarded as models of core symptoms of depression. Morphine-sensitized rats present resilience to stress-induced behavioral deficits and, if hyporeactivity to stress models a depressive symptom, stress resistance can be regarded as a manic symptom. This hypothesis is supported by the observation that long-term lithium administration reinstates sensitivity to stress in sensitized rats.

Effects of the 5-HT(6) receptor agonist ST 1936 on depression- and anhedonia-like experimental models.

Serotonin 5-HT(6) receptor agonists and antagonists have been proposed as possible useful compounds in the treatment of psychiatric disorders such as depression. This study was aimed at characterizing ST 1936, a new 5-HT(6) receptor agonist, as a possible antidepressant/anti-anhedonic drug by studying its effects on three experimental models of depression. These models are based on the behavioral sequelae induced in rats by unavoidable stressors that result in decreased reactivity to avoidable stressors (escape deficit, ED) and an anhedonia-like condition based on the disruptive effect of stress on the competence to acquire an instrumental vanilla sugar-sustained appetitive behavior (VAB).

Cocaine sensitization models an anhedonia-like condition in rats.

Anhedonia is a core symptom of depression that also characterizes substance abuse-related mood disorders, in particular those secondary to stimulant abuse. This study investigated the long-lasting condition of cocaine sensitization as an inducing condition for anhedonia in rats. Cortical-mesolimbic dopamine plays a central role in assessing the incentive value of a stimulus and an increased dopamine output in these areas after a novel palatable meal seems to correlate with the ability to acquire an instrumental behaviour aimed at earning it again.

Modifications in DARPP-32 phosphorylation pattern after repeated palatable food consumption undergo rapid habituation in the nucleus accumbens shell of non-food-deprived rats.

In non-food-deprived rats a palatable meal induces a transient increase in dopamine output in the prefrontal cortex and nucleus accumbens shell and core; habituation to this response develops with a second palatable meal, selectively in the shell, unless animals are food-deprived. A palatable meal also induces time-dependent modifications in the dopamine and cAMP-regulated phosphoprotein of Mr 32 000 (DARPP-32) phosphorylation pattern that are prevented when SCH 23390, a selective dopamine D(1) receptor antagonist, is administered shortly after the meal. This study investigated whether dopaminergic habituation in the shell had a counterpart in DARPP-32 phosphorylation changes.

F2-isoprostane receptors on hepatic stellate cells.

F2-isoprostanes are considered as the most reliable markers of oxidative stress and can be used to evaluate the oxidative status in a number of human pathologies. Besides being markers of oxidative stress, F2-isoprostanes proved to be mediators of important biological effects and would act through the activation of receptors analogous to those for thromboxane A2. In a previous work, we provided evidence that F(2)-isoprostanes, generated during carbon tetrachloride-induced hepatic fibrosis, mediate hepatic stellate cell (HSC) proliferation and collagen hyperproduction.

Behavioral expression of cocaine sensitization in rats is accompanied by a distinct pattern of modifications in the PKA/DARPP-32 signaling pathway.

Repeated cocaine administration induces behavioral sensitization and modifications in the phosphorylation pattern of dopamine and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32), characterized by a tonic increase in the Thr75 phosphorylated form, and a decrease in the Thr34 phosphorylated form. This study further investigated the correlations between cocaine sensitization and modifications in the DARPP-32 phosphorylation pattern, cAMP-dependent protein kinase (PKA) activity, and mGluR5 tone in the medial prefrontal cortex and nucleus accumbens. Behavioral sensitization and modifications in these neurochemical markers followed a similar temporal pattern.

The mesolimbic dopaminergic response to novel palatable food consumption increases dopamine-D1 receptor-mediated signalling with complex modifications of the DARPP-32 phosphorylation pattern.

Acute cocaine administration increases extraneuronal dopamine and Thr34 phosphorylation of dopamine- and cAMP-regulated phosphoprotein (M(r) 32 kDa; DARPP-32) in striatal and cortical areas. Novel palatable food consumption increases extraneuronal dopamine in the same areas. We examined the DARPP-32 phosphorylation pattern in food non-deprived rats at different times after vanilla sugar consumption.

Sardinian alcohol-preferring rats show low 5-HT extraneuronal levels in the mPFC and no habituation in monoaminergic response to repeated ethanol consumption in the NAcS.

Sardinian ethanol-preferring (sP), non-preferring (sNP), and Wistar rats show similar dopaminergic response to vanilla sugar consumption in nucleus accumbens shell (NAcS) and medial prefrontal cortex (mPFC), and similarly learn a vanilla sugar-sustained appetitive behavior. In this study we investigated whether in satiated sP, sNP, and Wistar rats vanilla sugar would also elicit a serotonergic response in NAcS and mPFC, and whether in these areas voluntary ethanol consumption would elicit dopaminergic and/or serotoninergic responses. In the NAcS, all rats showed similar serotonin increases in response to the two meals and similar development of rapid habituation.

Synthetic peptides in the form of dendrimers become resistant to protease activity.

In previous papers, we observed that dendrimers of peptide mimotopes of the nicotinic receptor ligand site are strong antidotes against the lethality of the nicotinic receptor ligand alpha-bungarotoxin. Although their in vitro activity is identical to that of dendrimers, the corresponding monomeric peptide mimotopes are not effective in vivo. Because the higher in vivo efficiency of dendrimers could not in this case be related to polyvalent interaction, the stability to blood protease activity of monomeric versus tetrabranched dendrimeric mimotope peptides was compared here by incubating three different mimotopes with human plasma and serum.

Acquisition of an appetitive behavior prevents development of stress-induced neurochemical modifications in rat nucleus accumbens.

In rats, exposure to chronic unavoidable stress produces a decrease in dopamine output in the nucleus accumbens shell that is accompanied by a decreased density of the dopamine transporter and an increased activity of the dopamine-D(1) receptor complex. These modifications have been hypothesized to be adaptive to decreased dopamine output in stressed rats. We investigated whether the learning of an appetitive behavior sustained by palatable food, which is associated with increased dopamine output in the nucleus accumbens shell as measured by microdialysis experiments, would affect the modifications induced by chronic stress exposure on dopamine transporter density and dopamine-D(1) receptor complex activity in the nucleus accumbens.

Sardinian alcohol-preferring and non-preferring rats show different reactivity to aversive stimuli and a similar response to a natural reward.

Sardinian alcohol-preferring (sP) and non-preferring (sNP) rats were studied to ascertain whether some behavioral and/or neurochemical traits, beyond ethanol preference, differentiated the two lines. Spontaneous reactivity of Wistar, sP and sNP rats to aversive or pleasurable stimuli was examined in an avoidance test, an elevated plus maze test, and in response to palatable food presentation. As the mesocorticolimbic dopaminergic system plays a relevant role in the response to rewarding or aversive stimuli, extraneuronal dopamine levels and cocaine-induced dopamine accumulation in the nucleus accumbens shell (NAcS) and medial prefrontal cortex (mPFC) were studied by microdialysis in the three groups of rats.

Selective modifications in the nucleus accumbens of dopamine synaptic transmission in rats exposed to chronic stress.

Stressful events are accompanied by modifications in dopaminergic transmission in distinct brain regions. As the activity of the neuronal dopamine (DA) transporter (DAT) is considered to be a critical mechanism for determining the extent of DA receptor activation, we investigated whether a 3-week exposure to unavoidable stress, which produces a reduction in DA output in the nucleus accumbens shell (NAcS) and medial prefrontal cortex (mPFC), would affect DAT density and DA D1 receptor complex activity in the NAcS, mPFC and caudate-putamen (CPu). Rats exposed to unavoidable stress showed a decreased DA output in the NAcS accompanied by a decrease in the number of DAT binding sites, and an increase in the number of DA D1 binding sites and Vmax of SKF 38393-stimulated adenylyl cyclase.