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

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. Methods: Depressive-like phenotype was induced in non-food-deprived adult male Sprague-Dawley rats by exposure to a chronic protocol of alternating unavoidable tail-shocks or restraint periods. We examined whether lamotrigine administration (7.5 mg/kg twice a day, i.p.) for 14–21 days restored a) the competence to escape aversive stimuli; b) the motivation to operate in sucrose self-administration protocols; c) the dopaminergic response to sucrose consumption, evaluated measuring phosphorylation levels of cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32) in the NAcS, by immunoblotting. Results: Lamotrigine administration restored the response to aversive stimuli and the motivation to operate for sucrose. Moreover, it reinstated NAcS DARPP-32 phosphorylation changes in response to sucrose consumption. Limitations: The pro-motivational effects of lamotrigine that we report may not completely transpose to clinical use, since anhedonia is a multidimensional construct and the motivational aspects, although relevant, are not the only components. Conclusions: This study shows antidepressant-like and pro-motivational effects of repeated lamotrigine administration in a rat model of depressive symptoms

Experimental protocols for the study of stress in animals and humans.

1. Stress is the response of an organism to a stressor of physical, chemical, or emotional nature. 2. Exposure to stressors induces behavioral and neuroendocrine consequences in experimental animals as well as in humans, and this complex response can be adaptive or maladaptive. 3. Experimentally, the exposure to different stressors is used in order to study the evoked responses and the mechanisms underlying them, or to modify the behavior of animals in an attempt to reproduce reliable models of psychiatric symptoms with a stress-related component in humans. 4. In animals of the same species, strain, sex and age maintained in controlled environmental conditions we can expect reproducible behavioral and neuroendocrine responses to stressful protocols, that are proportional to the intensity of the stressor and the duration of the exposure. The reproducibility of the response is crucially bound to the controlled experimental conditions used. 5. In human experiments, the main difficulties in controlling experimental conditions are not related to the stressor (intensity and duration of exposure ethically acceptable), but are mainly related to the large interindividual variability in sensitivity to any kind of traumatic stimulus or event that can sometimes be explained on the basis of genetic variables or particular personal histories

Efficacy in behavioural models of antidepressant activity.

Extracts of Hypericum perforatum have been tested in experimental models of depression in rodents and their efficacy in these models has been demonstrated after acute, subacute, or repeated administration. In order to identify the component responsible for this activity, extracts with different proportions of hyperforin, currently the most likely active antidepressant principle, have been tested. Different groups reported a correlation between efficacy in these models and the hyperforin content of the extract. Moreover, purified hyperforin is active at doses significantly lower than those necessary for observing an activity when the extract is used. In conclusion, we now have convincing experimental evidence of the efficacy of Hypericum perforatum extract in models of depression