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Psychological resilience and hyperthymia: Is there a link?
No full textHighlights
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Resilience, the ability to adaptively rebound from stress, is associated with creativity, optimism and eudaimonic traits.
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These traits are also key features of hyperthymia
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Recent research shows that hyperthymic individuals are protected from depression as discussed in Ogura et al., 2023
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Thus, we advocate for future research on potential links between hyperthymia and resilience
DARPP-32 in the orchestration of responses to positive natural stimuli
No full textDopamine- and cAMP-regulated phosphoprotein (Mr 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). Dopamine neurons can fire tonically or phasically in distinct timescales and in specific brain regions to code different behaviorally relevant information. Dopamine signaling is mediated mainly through the regulation of adenylyl cyclase activity, stimulated by D1-like or inhibited by D2-like receptors, respectively, that modulates cAMP-dependent protein kinase (PKA) function. The activity of DARPP-32 is finely regulated by its phosphorylation at multiple sites. Phosphorylation at the threonine (Thr) 34 residue by PKA converts DARPP-32 into an inhibitor of protein phosphatase 1, while the phosphorylation at the Thr75 residue turns it into an inhibitor of PKA. Thus, DARPP-32 is critically implicated in regulating striatal output in response to the convergent pathways that influence signaling of the cAMP/PKA pathway. This review summarizes some of the landmark and recent studies of DARPP-32-mediated signaling in the attempt to clarify the role played by DARPP-32 in the response to rewarding natural stimuli. Particularly, the review deals with data derived from rodents studies and discusses the involvement of the cAMP/PKA/DARPP-32 pathway in: 1) appetitive food-sustained motivated behaviors, 2) motivated behaviors sustained by social reward, 3) sexual behavior, and 4) responses to environmental enrichment
Making Sense of Rodent Models of Anhedonia
Full text linkA 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. To this end, long-term exposure to environmental aversive conditions is primarily used, and the resulting deficits in reward responses are often accompanied by other deficits that are mainly reminiscent of clinical depressive symptoms. The different components of impaired reward responses induced by environmental aversive events can be assessed by different tests or protocols that require different degrees of time allocation, technical resources, and equipment. Rodent models of anhedonia are valuable tools in the study of the neurobiological mechanisms underpinning impaired behavioral responses and in the screening and characterization of drugs that may reverse these behavioral deficits. In particular, the antianhedonic or promotivational effects are relevant features in the spectrum of activities of drugs used in mood disorders or psychosis. Thus, more than the model, it is the choice of tests that is crucial since it influences which facets of anhedonia will be detected and should be tuned to the purpose of the study
Neurobiological Aspects of Ethanol-Derived Salsolinol in NEUROSCIENCE OF ALCOHOL: Mechanisms and Treatment
No full textSUMMARY POINTS
1. Ethanol acts through glutamate and GABA, but indirectly necessitates dopamine, opioid peptides, adenosine, and serotonin neurotransmission.
2. Ethanol acts through the involvement of ethanol- derived acetaldehyde.
3. Acetaldehyde is a highly reactive, electrophilic molecule.
4. Tetrahydroisoquinolines are the acetaldehyde’s condensation products with biogenic monoamines.
5. Salsolinol, the condensation product of acetaldehyde and dopamine, has been implicated in the neurobiological basis of alcoholism and in the emergence of neurological disorders.
6. Ethanol may act both as a pro-drug and a pro-toxic agent
Aripiprazole relieves motivational anhedonia in rats
No full textBackground 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. Methods Anhedonia is modeled in non food-deprived 9-week old male Sprague-Dawley rats by exposing them to a chronic unavoidable stress protocol, consisting in repeated exposure to tail-shock or restrain, which disrupts the motivation to acquire a reward-directed behavior and the competence to escape aversive stimuli. We evaluated whether long-term aripiprazole administration (1 mg/kg/day, i.p.) restored in chronically stressed rats, a) the disrupted dopaminergic response to sucrose consumption measuring DARPP-32 phosphorylation levels in the nucleus accumbens shell by immunoblotting; b) the motivation to operate in a sucrose self-administration protocol. Results Long-term aripiprazole administration restored DARPP-32 phosphorylation changes in response to sucrose and reinstated the motivational drive to acquire the reward in the progressive ratio task. However, it did not restore reactivity to aversive stimuli. Limitations The results obtained in our model may not fully translate to the clinic, as anhedonia is a complex construct in patients, where motivational aspects represent a central but not unique feature. Conclusions This study demonstrates that aripiprazole relieved motivational anhedonia in a stress-induced model and warrants further studies to ascertain whether this activity is clinically relevant for antipsychotic or adjunctive antidepressant treatments
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
No full textSardinian 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. In the mPFC, Wistar and sNP rats showed similar serotonin increases after two vanilla sugar meals, while sP rats, which had low serotonin basal levels, did not show a serotonergic response. When presented with a 10% ethanol solution, Wistar and sP rats rapidly consumed it, while sNP rats did not. In the NAcS, Wistar and sP rats presented dopamine and serotonin increases in response to ethanol. However, while Wistar rats showed habituation in their response, sP rats did not. In the mPFC, ethanol induced similar dopamine increases in Wistar and sP rats; serotonin increases were observed only in Wistar rats. In conclusion, all three lines showed increased serotonin release in response to palatable food, but they profoundly differed in their response to ethanol. In fact, only Wistar and sP rats drank ethanol, Wistar rats showed a monoaminergic response similar to that obtained after palatable food, while sP rats did not develop habituation, suggesting that they perceived ethanol as a more relevant stimulus
Impramine, fluoxetine and clozapine differently affected reactivity to positive and negative stimuli in a model of motivational anhedonia in rats
Full text linkAnhedonia 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. In this study, we tested on this model two antidepressants, imipramine and fluoxetine, and two antipsychotics, haloperidol and clozapine. The dopaminergic response to sucrose consumption was studied in non food-deprived rats in terms of dopamine D1 receptor signaling in the nucleus accumbens shell (NAcS). More specifically, we studied the modifications in dopamine and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32) phosphorylation pattern following sucrose consumption. Fluoxetine reverted the escape deficit and showed no effects on dopaminergic response and sucrose SA. Imipramine reverted sucrose SA and dopamine response deficit in half of the rats and the escape deficit in all animals. Haloperidol did not affect stress-induced deficits. Clozapine-treated rats recovered the dopaminergic response to sucrose consumption and the competence to acquire sucrose SA, although they still showed the escape deficit, thus confirming that motivation toward reward may be dissociated from that to punishment escape. These results indicate that imipramine or fluoxetine are not endowed with a rapid onset antianhedonic effect. On the other hand, clozapine treatment showed a motivational antianhedonic activity similar to that observed after lithium treatment
Dopamine and cyclic AMP-regulated phosphoprotein-32 phosphorylation pattern in cocaine and morphine-sensitized rats
No full textThis study reports some of the modifications in dopaminergic signalling that accompany cocaine and morphine behavioural sensitization. Cocaine-sensitized rats showed increased phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein Mr 32 kDa (DARPP-32) at threonine-75 (Thr75) and decreased DARPP-32 phosphorylation at Thr34, in the caudate–putamen (CPu) and nucleus accumbens (NAc) 7 days after sensitization assessment. Conversely, in morphine-sensitized rats, no apparent modifications in DARPP-32 phosphorylation pattern were observed. Morphine-sensitized rats have increased binding and coupling of µ-opioid receptors and increased dopaminergic transmission in striatal areas and, upon morphine challenge, exhibit dopamine D1 receptor-dependent stereotypies. Thus, the DARPP-32 phosphorylation pattern was studied in morphine-sensitized rats at different times after morphine challenge. Morphine challenge increased levels of phospho-Thr75 DARPP-32 and decreased levels of phospho-Thr34 DARPP-32 in a time-dependent manner in the CPu and NAc. In order to assess whether these modifications were related to modified cyclic AMP-dependent protein kinase (PKA) activity, the phosphorylation levels of two other PKA substrates were examined, the GluR1 and NR1 subunits of α-amino-3-hydroxy-5-methylisoxazole-4-propionate and NMDA receptors respectively. The phosphorylation levels of GluR1 and NR1 subunits decreased in parallel with those of phospho-Thr-34 DARPP-32, supporting the hypothesis that morphine challenge elicited a decrease in PKA activity in morphine-sensitized rats
Expanding the therapeutic potential of neuro(active)steroids : a promising strategy for hyperdopaminergic behavioral phenotypes
Full text linkImbalances in dopamine activity significantly contribute to the pathophysiology of several neuropsychiatric disorders, including addiction, ADHD, schizophrenia, impulse control disorders, and Parkinson's Disease. Neuro(active)steroids, comprising endogenous steroids that finely modulate neuronal activity, are considered crucial regulators of brain function and behavior, with implications in various physiological processes and pathological conditions. Specifically, subclasses of Neuro(active)steroids belonging to the 5α reductase pathway are prominently involved in brain disorders characterized by dopaminergic signaling imbalances. This review highlights the neuromodulatory effects of Neuro(active)steroids on the dopamine system and related aberrant behavioral phenotypes. We critically appraise the role of pregnenolone, progesterone, and allopregnanolone on dopamine signaling. Additionally, we discuss the impact of pharmacological interventions targeting 5α reductase activity in neuropsychiatric conditions characterized by excessive activation of the dopaminergic system, ranging from psychotic (endo)phenotypes and motor complications to decision-making problems and addiction
Targeting PPARα in the rat valproic acid model of autism: Focus on social motivational impairment and sex-related differences
Full text linkBackground 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 alpha (PPAR alpha) agonist. Here, we used the valproic acid (VPA) model of ASD in rats to examine male and female phenotypes and assess whether FBR administration from weaning to young adulthood relieved social impairments. Methods Male and female rats exposed to saline or VPA at gestational day 12.5 received standard or FBR-enriched diet from postnatal day 21 to 48-53, when behavioral tests and ex vivo neurochemical analyses were performed. Phosphorylation levels of DARPP-32 in response to social and nonsocial cues, as index of dopamine D(1)receptor activation, levels of expression of PPAR alpha, vesicular glutamatergic and GABAergic transporters, and postsynaptic density protein PSD-95 were analyzed by immunoblotting in selected brain regions. Results FBR administration relieved social impairment and perseverative behavior in VPA-exposed male and female rats, but it was only effective on female stereotypies. Dopamine D(1)receptor signaling triggered by social interaction in the nucleus accumbens shell was blunted in VPA-exposed rats, and it was rescued by FBR treatment only in males. VPA-exposed rats of both sexes exhibited an increased ratio of striatal excitatory over inhibitory synaptic markers that was normalized by FBR treatment. Limitations This study did not directly address the extent of motivational deficit in VPA-exposed rats and whether FBR administration restored the likely decreased motivation to operate for social reward. Future studies using operant behavior protocols will address this relevant issue. Conclusions The results support the involvement of impaired motivational mechanisms in ASD-like social deficits and suggest the rationale for a possible pharmacological treatment. Moreover, the study highlights sex-related differences in the expression of ASD-like symptoms and their differential responses to FBR treatment
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