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.

No abstract

No abstract

Rats exposed to acute unavoidable stress develop a de®cit 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 de®cit 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 de®cit and reduced DA output in the NAcS were still signi®cant 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 signi®cant increase beyond control values at day 14; (iii) a signi®cant reduction in 5-HT extraneuronal basal levels at day 3, but not at day 14. Finally, a signi®cant 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 modi®cations.

No abstract

Ventral tegmental area dopamine neurons control reward-driven learning, and their dysregulation can lead to psychiatric disorders. Tonic and phasic activity of these dopaminergic neurons depends on cholinergic tone and activation of nicotinic acetylcholine receptors (nAChRs), particularly those containing the ␤2 subunit (␤2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-␣ (PPAR␣) tonically regulate ␤2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPAR␣ endogenous ligands are synthesized by dopamine cells. Using ex vivo and in vivo electrophysiological techniques combined with biochemical and behavioral analysis, we show that activation of ␣7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the ␤2 subunit of nAChRs and the levels of two PPAR␣ endogenous ligands in a Ca 2ϩ -dependent manner. Accordingly, in vivo production of endogenous PPAR␣ ligands, triggered by ␣7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPAR␣ ligands are effectors of ␣7-nAChRs and that their neuromodulatory properties depend on phosphorylation of ␤2*-nAChRs on VTA dopamine cells. This reveals an autoinhibitory mechanism aimed at reducing dopamine cell overexcitation engaged during hypercholinergic drive. Our results unveil important physiological functions of nAChR/PPAR␣ signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPAR␣ as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.

No abstract

No abstract