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. 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

The Steroidogenesis Inhibitor Finasteride Reduces the Response to Both Stressful and Rewarding Stimuli

This work is licensed under a Creative Commons Attribution 4.0 International License.Finasteride (FIN) is the prototypical inhibitor of steroid 5α-reductase (5αR), the enzyme that catalyzes the rate-limiting step of the conversion of progesterone and testosterone into their main neuroactive metabolites. FIN is clinically approved for the treatment of benign prostatic hyperplasia and male baldness; while often well-tolerated, FIN has also been shown to cause or exacerbate psychological problems in vulnerable subjects. Evidence on the psychological effects of FIN, however, remains controversial, in view of inconsistent clinical reports. Here, we tested the effects of FIN in a battery of tests aimed at capturing complementary aspects of mood regulation and stress reactivity in rats. FIN reduced exploratory, incentive, prosocial, and risk-taking behavior; furthermore, it decreased stress coping, as revealed by increased immobility in the forced-swim test (FST). This last effect was also observed in female and orchiectomized male rats, suggesting that the mechanism of action of FIN does not primarily reflect changes in gonadal steroids. The effects of FIN on FST responses were associated with a dramatic decrease in corticotropin release hormone (CRH) mRNA and adrenocorticotropic hormone (ACTH) levels. These results suggest that FIN impairs stress reactivity and reduces behavioral activation and impulsive behavior by altering the function of the hypothalamus–pituitary–adrenal (HPA) axis

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 a4 or b2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-a (PPARa), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing b2 subunits. On these bases, we tested whether PPARa agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ,100% of mice. A single dose of the synthetic PPARa agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARa antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARa agonists abolished nicotine-induced sIPSC increases. PPARa within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role

Psychological resilience and hyperthymia: Is there a link?

Highlights • Resilience, the ability to adaptively rebound from stress, is associated with creativity, optimism and eudaimonic traits. • These traits are also key features of hyperthymia • Recent research shows that hyperthymic individuals are protected from depression as discussed in Ogura et al., 2023 • Thus, we advocate for future research on potential links between hyperthymia and resilience

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

Dopamine- 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

Long-term behavioral and neurochemical effects of chronic stress exposure in rats

Rats exposed to acute unavoidable stress develop a deficit in escaping avoidable aversive stimuli that lasts as long as unavoidable stress exposure is repeated. A 3-week exposure to unavoidable stress also reduces dopamine (DA) output in the nucleus accumbens shell (NAcS). This study showed that a 7-day exposure to unavoidable stress induced in rats an escape deficit and a decrease in extraneuronal DA basal concentration in the NAcS. Moreover, animals had reduced DA and serotonin (5-HT) accumulation after cocaine administration in the medial pre-frontal cortex (mPFC) and NAcS, compared with control animals. After a 3-week exposure to unavoidable stress, escape deficit and reduced DA output in the NAcS were still significant at day 14 after the last stress administration. In the mPFC we observed: (i) a short-term reduction in DA basal levels that was back to control values at day 14; (ii) a decrease in DA accumulation at day 3 followed by a significant increase beyond control values at day 14; (iii) a significant reduction in 5-HT extraneuronal basal levels at day 3, but not at day 14. Finally, a significant decrease in 5-HT accumulation following cocaine administration was present in the NAcS and mPFC at day 3, but not at day 14. In conclusion, a long-term stress exposure induced long-lasting behavioral sequelae associated with reproducible neurochemical modifications

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. 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

Animal models for the study of antidepressant activity

5noreservedThree behavioral paradigms are presented for the study of the mechanism of action of antidepressant treatments and for the screening of new antidepressant drugs. The first model (acute escape deficit) exploits the decreased ability of a rat exposed to an unavoidable stress to avoid a noxious stimulus, and it allows us to evaluate the preventive activity of a treatment on the development of escape deficit. The second paradigm (chronic escape deficit) begins as acute escape deficit, that is then indefinitely sustained by the repeated administration of mild stressors; this model allows us to evaluate the efficacy of a treatment to revert the escape deficit. The third is a model of anhedonia based on the finding that exposure to repeated unavoidable stress prevents the acquisition of an appetitive behavior induced and maintained by a highly palatable food (vanilla sugar) in rats fed ad libitum; this paradigm assesses the efficacy of a treatment to restore an animal's motivation. A long-term (2 to 3 week) treatment with classical antidepressants, such as imipramine or fluoxetine, resulted in a clear-cut preventive and/or revertant activity in the three models. © 2001 Elsevier Science B.V.mixedGAMBARANA, C.; SCHEGGI, S.; TAGLIAMONTE, A.; TOLU, P.L.; DE MONTIS, M.G.Gambarana, C.; Scheggi, S.; Tagliamonte, A.; Tolu, P. L.; DE MONTIS, M. G

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. A multiplicity of downstream pathways modulated by PPARα activation, including glutamatergic neurotransmission, upregulation of brain-derived neurotrophic factor, and neurosteroidogenic effects, encompass mechanisms underlying behavioral regulation. Modulation of dopamine neuronal firing in the ventral tegmental area likely contributes to PPARα effects in depression, anhedonia, and autism spectrum disorder (ASD). Based on robust preclinical evidence and the initial results of clinical studies, future clinical trials should assess the efficacy of PPARα agonists in the treatment of mood and neurodevelopmental disorders, such as depression, schizophrenia, and ASD

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

5noreservedBehavioural 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)]. Moreover, chronic stress exposure disrupts reactivity to aversive stimuli. A 3-wk treatment with lithium, the gold-standard treatment in bipolar disorder, tonically reduces NAcS dopamine output and the reactivity to aversive stimuli. However, it does not affect the dopaminergic response to VS and the competence to acquire VAB. This study investigated whether repeated lithium administration is endowed with anti-anhedonic activity. The NAcS dopaminergic response to VS and the competence to acquire VAB and sucrose self-administration (SA), in terms of fixed-ratio (FR)1, FR5 and progressive ratio schedules of reinforcement, were studied in saline or lithium-treated groups of non-food-deprived rats exposed or not to repeated unavoidable stress. Chronic stress exposure impaired the NAcS dopaminergic response to VS, acquisition of VAB and sucrose SA, in terms of FR1 and FR5 schedules of reinforcement and breaking point score. Repeated lithium treatment restored these parameters to control group values, even when treatment began in rats already showing an anhedonia-like condition. Since the breaking point defines the reinforcement efficacy of a hedonic stimulus, the present data suggest that lithium treatment is endowed with anti-anhedonic activity in rats. © CINP 2013.mixedMarchese, G.; Scheggi, S.; Secci, M.E.; De Montis, M.G.; Gambarana, C.Marchese, G.; Scheggi, S.; Secci, M. E.; De Montis, M. G.; Gambarana, C