• addiction
• anxiety
• cocaine
• depression
• Dopamine
• drug abuse
• Hippocampus
• HPA axis
• metabotropic Glutamate receptors
• Nucleus Accumbens
• Prenatal restraint stress
• self-medication

BACKGROUND: It is recognized that exposure to an adverse environment during fetal period may have lifelong programming effects on different body functions with a considerable impact on disease susceptibility. Prenatal restraint stress (PRS) in rat is a well-documented model of early life stress (Maccari et al., 1995) known to induce long-lasting neurobiological and behavioral alterations (reviewed by Darnaudéry and Maccari, 2008). This model is a clear example of early programming of vulnerability to stress -related disorders, such as anxiety, depression or drug abuse (Zuena et al., 2008; Morley-Fletcher et al., 2011; Marrocco et al., 2012; Deminière et al., 1992; Koehl et al., 2000; Morley-Fletcher et al., 2004; Kippin et al., 2008). An impairment in the glutamatergic machinery and metabotropic glutamate receptors system lies at the core of the PRS phenotype (Marrocco et al., 2012; Morley-Fletcher et al., 2011) and antidepressant (ATD) treatment was able to correct behavioral abnormalities and alterations in glutamatergic system (Marrocco et al., 2014). Interestingly, PRS induces a clear-cut sex effect for anxiety-like behavior with PRS male rats being more anxious and females less anxious in comparison to control animals (Zuena et al., 2008), while an enhancement in depressive-like profile was observed both in male and female PRS animals. We have also recently shown a sex effect in the response of PRS rats to natural reward (Reynaert et al., in revision).

AIMS: Here, we investigate a sex effect in rats response to the psychostimulant drug cocaine in a conditioned place preference (CPP) paradigm and in a locomotor activity test. We also aimed to address whether behavioral sensitization with cocaine could have a beneficial impact on the anxious/depressive phenotype in PRS rats and be responsible for increased preference for the drug.

MATERIALS AND METHODS: Behavioral and neurochemical analysis were performed on Control and PRS male and female rats treated or not with cocaine. Preference for a cocaine-paired environment and psychomotor activation inducted by cocaine administration were studied, as well as anxiety- and depressive-like phenotypes.


Behavioral analysis:

- CPP: To measure cocaine reinforcing properties. On D1 (20 min, pretest) spontaneous preference for a one of the two compartments of the apparatus (one grey, one white) is evaluated. During daily conditioning sessions (D2 – D9), rats are alternatively injected intraperitoneally with vehicle (saline) or cocaine and placed in the appropriate chamber for 30 min (cocaine is paired to least preferred side). During the test (D10), realized like the pretest (D1), rats preference is measured.

- Locomotor activity: Animals during a chronic sensitization protocol with increasing doses of cocaine were tested for the psychomotor effects of cocaine on day1(15 mg/Kg) and on day 6 (30 mg/Kg). Locomotor activity in standard rat cages was registered over a period of 90 min.

- Light and dark test : An apparatus, composed of a white and a black boxes, separated by a small door allowing the rat to visit the 2 boxes, allows an evaluation of the anxious-like behavior. Rats are injected with vehicle or cocaine on day 7 of chronic sensitization with cocaine and the time spent in the light box, anxiogenic, and the latency to enter this box are recorded.

- Forced swim test : Animals are subjected to two trials during which they are placed in an inescapable situation represented by a cylinder filled with water. The first trial lasts 15 min. Then, after 24 h, a 2nd trial is performed for 5 min. The time spent in immobility and the latency to immobility are recorded. This test is classically performed for the screening of ATD drugs (Porsolt, 1978). Rats are injected with cocaine before being placed in the test (pretest: D9 of chronic sensitization protocol; test on D10).


Biochemical Analysis:

24 h after FST test, sacrifices are done, and Nucleus Accumbens (NAc) are dissected and keep at -80°C until use. A subcellular fractioning is performed on NAc samples. The effect of PRS, sex and cocaine on the expression of neurobiological key markers such as mGlu receptors and DAD receptors is analyzed in synaptosomal fractions by Western Blot.


RESULTS: We report that PRS enhances cocaine-induced CPP in both sexes with respect to unstressed rats. Remarkably, cocaine exerts an anxiolytic effect in PRS males and has anti-depressive properties in both males and female PRS rats. Interestingly, the reversal of the PRS behavioral phenotype induced by chronic cocaine treatment is mainly associated to neurobiological changes in metabotropic glutamate receptors in the NAc. Enhanced response to cocaine would be thus a self-medication strategy to counteract the PRS-induced anxious/depressive phenotype.