Striatal adenosine A2A receptor involvement in normal and large nest building deer mice: Perspectives on compulsivity and anxiety.

Obsessive-compulsive disorder (OCD) is characterized by recurring obsessive thoughts and repetitive behaviors that are often associated with anxiety and perturbations in cortico-striatal signaling. Given the suboptimal response of OCD to current serotonergic interventions, there is a need to better understand the psychobiological mechanisms that may underlie the disorder. In this regard, investigations into adenosinergic processes might be fruitful. Indeed, adenosine modulates both anxiety- and motor behavioral output. Thus, we aimed to explore the potential associations between compulsive-like large nest building (LNB) behavior in deer mice, anxiety and adenosinergic processes. From an initial pool of 120 adult deer mice, 34 normal nest building (NNB)- and 32 LNB-expressing mice of both sexes were selected and exposed to either a normal water (wCTRL) or vehicle control (vCTRL), lorazepam (LOR) or istradefylline (ISTRA) for 7- (LOR) or 28 days after which nesting assessment was repeated and animals screened for anxiety-like behavior in an anxiogenic open field. Mice were then euthanized, the striatal tissue removed on ice and the adenosine A2A receptor expression quantified. Our findings indicate that NNB and LNB behavior are not distinctly associated with measures of generalized anxiety and that ISTRA-induced changes in nesting expression are dissociated from changes in anxiety scores. Further, data from this investigation show that nesting in deer mice is directly related to striatal adenosine signaling, and that LNB is founded upon a lower degree of adenosinergic A2A stimulation.

Dopaminergic and serotonergic modulation of social reward appraisal in zebrafish (Danio rerio) under circumstances of motivational conflict: Towards a screening test for anti-compulsive drug action.

Cognitive flexibility, shown to be impaired in patients presenting with compulsions, is dependent on balanced dopaminergic and serotonergic interaction. Towards the development of a zebrafish (Danio rerio) screening test for anti-compulsive drug action, we manipulated social reward appraisal under different contexts by means of dopaminergic (apomorphine) and serotonergic (escitalopram) intervention. Seven groups of zebrafish (n = 6 per group) were exposed for 24 days (1 h per day) to either control (normal tank water), apomorphine (50 or 100 µg/L), escitalopram (500 or 1000 µg/L) or a combination (A100/E500 or A100/E1000 µg/L). Contextual reward appraisal was assessed over three phases i.e. Phase 1 (contingency association), Phase 2 (dissociative testing), and Phase 3 (re-associative testing). We demonstrate that 1) sight of social conspecifics is an inadequate motivational reinforcer under circumstances of motivational conflict, 2) dopaminergic and serotonergic intervention lessens the importance of an aversive stimulus, increasing the motivational valence of social reward, 3) while serotoninergic intervention maintains reward directed behavior, high-dose dopaminergic intervention bolsters cue-directed responses and 4) high-dose escitalopram reversed apomorphine-induced behavioral inflexibility. The results reported here are supportive of current dopamine-serotonin opponency theories and confirm the zebrafish as a potentially useful species in which to investigate compulsive-like behaviors.