Stress and cocaine interact to modulate basic fibroblast growth factor (FGF-2) expression in rat brain.

RATIONALE: Our laboratory has previously demonstrated that the expression of basic fibroblast growth factor (FGF-2), a protein involved in survival and maintenance of several cell phenotypes as well as in synaptic plasticity, is modulated by stress (Molteni et al., Brain Res Rev 37:249-258, 2001; Fumagalli et al., Neurobiol Dis 20:731-737, 2005) and cocaine (Fumagalli et al., J Neurochem 96:996-1004, 2006). OBJECTIVES: Since it is widely recognized that stress influences drug seeking, we decided to investigate whether stress, acute or repeated, could influence the changes in FGF-2 gene expression brought about by cocaine. RESULTS: Our data demonstrate that stress and cocaine interact to produce significant changes on FGF-2 expression in rat prefrontal cortex and striatum. In prefrontal cortex, our experiments demonstrated that a single exposure to stress potentiated cocaine-induced FGF-2 elevation, whereas prolonged stress prevented the modulation of the trophic factor in response to cocaine. In striatum, the magnitude of cocaine-induced FGF-2 response is enhanced by repeated stress, whereas no interaction was observed when acute stress and single exposure to cocaine were combined. CONCLUSIONS: Our findings demonstrate that stress interacts with cocaine to alter the pattern of FGF-2 expression in a way that depends on whether stress is acute or chronic and in a regionally selective fashion. These results identify a potential molecular target through which stress alters cellular sensitivity to cocaine and might prove useful in understanding the mechanisms underlying brain vulnerability to stress.

Repeated exposure to cocaine differently modulates BDNF mRNA and protein levels in rat striatum and prefrontal cortex.

In this report we investigated the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) following single or repeated injections with cocaine. Dose-response experiments revealed that a single dose of cocaine (5 mg/kg) is sufficient to upregulate BDNF mRNA levels selectively in rat prefrontal cortex 2 h after the injection, an effect that persists at least for 24 h and is paralleled by enhanced expression of mature (m)BDNF protein. Five consecutive injections of the psychostimulant (5 mg/kg) potentiate the increase of BDNF mRNA levels 2 h after the last treatment, presumably as a result of the enhancement of cAMP response element-binding protein (CREB) phosphorylation, an effect that vanishes 72 h later. Conversely, precursor (pro-) and mBDNF protein forms were markedly reduced 2 h and 72 h post-injection in the prefrontal cortex. Interestingly, in the striatum we found that repeated cocaine injection increased pro-BDNF levels without altering the mature form of the neurotrophin. Our results suggest that cocaine differently affects BDNF transcription and translation in a region-selective manner, but might also alter neurotrophin processing. These data further support the notion that the corticostriatal network is highly vulnerable to the effects of cocaine, and suggest that abnormal regulation of BDNF expression could contribute, at least in part, to the functional defects observed in drug abusers.

Corticostriatal up-regulation of activity-regulated cytoskeletal-associated protein expression after repeated exposure to cocaine.

We provide evidence that cocaine evokes short- and long-lasting increases in activity-regulated cytoskeletal-associated protein (Arc) expression after a finely tuned, time-dependent and regional-selective expression profile. Acute experiments revealed that cocaine up-regulates Arc expression primarily in striatum and prefrontal cortex through a dopamine D1-dependent mechanism and a combination of D1- and D2-dependent mechanisms, respectively. Aside from cocaine-dependent Arc elevation, we show for the first time that D1 and D2 receptors tonically regulate basal Arc expression following a regional-selective profile. As opposed to the effects of a single cocaine injection on Arc expression, which dissipate within 24 h, subchronic (five daily injections) or chronic (14 daily injections) cocaine administration, with animals sacrificed hours or days after the last treatment, demonstrated that Arc expression is still up-regulated long after treatment cessation, suggesting that adaptive changes have been set in motion by the prolonged administration of the psychostimulant. In summary, our findings are the first to demonstrate that repeated exposure to cocaine leads to long-lasting dysregulation of Arc expression in the corticostriatal network, thus establishing a molecular basis to explain, at least partially, the impaired synaptic transmission caused by cocaine abuse at this level. Furthermore, given the role exerted by Arc in cytoarchitectural rearrangements, it is conceivable to speculate that it mediates changes in synaptic connectivity brought about by cocaine. Our findings thus pinpoint this molecule as a neuropathological underpinning and molecular bridge that connects short- and long-term neuronal modifications associated with cocaine abuse.

Involvement of fractalkine and macrophage inflammatory protein-1 alpha in moderate-severe depression.

Moderate-severe depression (MSD) is linked to overexpression of proinflammatory cytokines and chemokines. Fractalkine (FKN) and macrophage inflammatory protein-1 alpha (MIP-1alpha) are, respectively, members of CX3C and C-C chemokines, and both are involved in recruiting and activating mononuclear phagocytes in the central nervous system. We analysed the presence of FKN and MIP-1alpha in sera of untreated MSD patients and healthy donors. High FKN levels were observed in all MSD patients as compared with values only detectable in 26% of healthy donors. MIP-1alpha was measurable in 20% of patients, while no healthy donors showed detectable chemokine levels. In conclusion, we describe a previously unknown involvement of FKN in the pathogenesis of MSD, suggesting that FKN may represent a target for a specific immune therapy of this disease.