The motivation for exercise over palatable food is dictated by cannabinoid type-1 receptors.

The lack of intrinsic motivation to engage in, and adhere to, physical exercise has major health consequences. However, the neurobiological bases of exercise motivation are still unknown. This study aimed at examining whether the endocannabinoid system (ECS) is involved in this process. To do so, we developed an operant conditioning paradigm wherein mice unlocked a running wheel with nose pokes. Using pharmacological tools and conditional mutants for cannabinoid type-1 (CB1) receptors, we provide evidence that CB1 receptors located on GABAergic neurons are both necessary and sufficient to positively control running motivation. Conversely, this receptor population proved dispensable for the modulation of running duration per rewarded sequence. Although the ECS mediated the motivation for another reward, namely palatable food, such a regulation was independent from CB1 receptors on GABAergic neurons. In addition, we report that the lack of CB1 receptors on GABAergic neurons decreases the preference for running over palatable food when mice were proposed an exclusive choice between the two rewards. Beyond providing a paradigm that enables motivation processes for exercise to be dissected either singly or in concurrence, this study is the first to our knowledge to identify a neurobiological mechanism that might contribute to sedentary behavior.

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.

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 (1mg/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.

Fasting biases µ-opioid receptors toward ß-arrestin2-dependent signaling in the accumbens shell.

The µ-opioid receptor (MOR) and dopamine D1 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 D1 receptor transduction system is observed. In mice, morphine administration induces hypermotility and this response has been described in terms of a ß-arrestin2-dependent mechanism that favors prevalent dopamine D1 receptor activation. In rats, acute morphine administration induces hypermotility only when the animals are food-deprived (FD). We aimed to further investigate the functional interaction between the MOR and dopamine D1 receptors in striatal areas and we studied the effects of acute pharmacological MOR stimulation on motility and nucleus accumbens shell (NAcS) dopamine D1 receptor signaling in control rats and rats with reduced ß-arrestin2 expression in the NAcS, either non food-deprived (NFD) or FD. Motility and dopamine D1 receptor signaling increased only in FD rats in a ß-arrestin2-dependent way. Moreover, FD rats showed a ß-arrestin2-dependent increase in the levels of MOR-dopamine D1 receptor heteromeric complexes in the NAcS. Sucrose consumption is accompanied by release of endogenous opioids and dopamine in the NAcS. We then examined MOR-dopamine D1 receptor interactions after sucrose consumption. Sucrose increased NAcS dopamine D1 receptor signaling in NFD and FD rats, and a reduction in ß-arrestin2 expression prevented this effect selectively in FD rats. These results show the ß-arrestin2-dependent prevalence of dopamine D1 receptor signaling in response to acute morphine or sucrose consumption elicited by food deprivation in rats.

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). Repeated treatments that restore these responses also relieve behavioral symptoms. Ventral tegmental area (VTA) dopamine neurons encode reward and motivation and are implicated in the neuropathology of depressive-like behaviors. Peroxisome proliferator-activated receptors type-α (PPARα) acutely regulate VTA dopamine neuron firing via ß2 subunit-containing nicotinic acetylcholine receptors (ß2*nAChRs) through phosphorylation and this effect is predictive of antidepressant-like effects. Here, by combining behavioral, electrophysiological and biochemical techniques, we studied the effects of repeated PPARα stimulation by fenofibrate on mesolimbic dopamine system. We found decreased ß2*nAChRs phosphorylation levels and a switch from tonic to phasic activity of dopamine cells in the VTA, and increased phosphorylation of dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32) in the NAcS. We then investigated whether long-term fenofibrate administration to stressed rats reinstated the decreased DARPP-32 response to sucrose and whether this effect translated into antidepressant-like properties. Fenofibrate restored dopaminergic responses to appetitive stimuli, reactivity to aversive stimuli and motivation to self-administer sucrose. Overall, this study suggests PPARα as new targets for antidepressant therapies endowed with motivational anti-anhedonic properties, further supporting the role of an unbalanced mesolimbic dopamine system in pathophysiology of depressive disorders.

The protective effect of Hypericum connatum on stress-induced escape deficit in rat is related to its flavonoid content.

Context Hypericum perforatum L. (Hypericaceae), used in moderate depression treatment, is active in experimental tests for antidepressant activity. For H. connatum Lam., a South American species lacking hyperforin, antidepressant effects have not been demonstrated. Objective This study evaluates the antidepressant-like effect of H. connatum in rats and identifies the components involved in this activity. Materials and methods First, the effects of acute and 14-d oral administrations of an extract derived from H. connatum aerial parts were studied using the Escape Deficit (ED) test. Next, methanol-extracted flavonoid-enriched fractions B and C and fraction-purified flavonoids (quercetin, rutin and isoquercitrin) were evaluated in the ED test after acute administration. To rule out possible confounding effects of the flavonoids, we examined nociceptive threshold using the tail-flick test and anxious behaviour using the elevated plus maze (EPM) test. Results Hypericum connatum increased reactivity of unavoidable stress-exposed rats after acute (0.5 and 1 g/kg: ED = 18.6/30 and 19.8/30, respectively) and repeated administration (0.5 g/kg twice daily: ED = 17.8/30). Protective effects were observed for fractions B and C (250 mg/kg: ED = 18.1/30 and 18.8/30, respectively), quercetin (2.5, 5 and 10 mg/kg: ED = 15.3/30, 18.3/30 and 21.6/30, respectively), rutin (5 and 10 mg/kg: ED = 15.4/30 and 13.0/30, respectively) and isoquercitrin (2.5 mg/kg: ED = 19.2/30). The flavonoids did not modify nociceptive threshold or performance in the EPM test. Discussion and conclusion Hypericum connatum showed protective activity in the ED test, a correlate of potential antidepressant-like effects that appeared to be related to the flavonoid components of this species.