Search

Cocaine self-administration (SA) in rats dysregulates glutamatergic signaling in the prelimbic (PrL) cortex and glutamate release in the nucleus accumbens (NA) core, promoting cocaine seeking. PrL adaptations that affect relapse to drug seeking emerge during the first week of abstinence, switching from an early (2 h) hypoglutamatergic state to a later (7 days) hyperglutamatergic state. Different interventions that normalize glutamatergic signaling in PrL cortex at each timepoint are necessary to suppress relapse. We hypothesized that plasticity-related proteins that regulate glutamatergic neurotransmission as well as dendritic spine morphology would be biphasically regulated during these two phases of abstinence in PrL cortical neurons projecting to the NA core (PrL-NA core). A combinatorial viral approach was used to selectively label PrL-NA core neurons with an mCherry fluorescent reporter. Male rats underwent 2 weeks of cocaine SA or received yoked-saline infusions and were perfused either 2 h or 7 days after the final SA session. Confocal microscopy and 3D reconstruction analyses were performed for Fos and pCREB immunoreactivity (IR) in the nucleus of layer V PrL-NA core neurons and GluA1-IR and GluA2-IR in apical dendritic spines of the same neurons. Here, we show that cocaine SA decreased PrL-NA core spine head diameter, nuclear Fos-IR and pCREB-IR, and GluA1-IR and GluA2-IR in putative mushroom-type spines 2 h after the end of cocaine SA, whereas the opposite occurred following 1 week of abstinence. Our findings reveal biphasic, abstinence duration-dependent alterations in structural plasticity and relapse-related proteins in the PrL-NA core pathway after cocaine SA.

Rationale and Objectives: Among the changes caused by repeated exposure to drugs of abuse, structural rearrangements play a critical role, setting the stage for maladaptive responses to environmental challenges and sustaining drug-taking and drug-seeking behaviors. Given that adolescents are more vulnerable to drug abuse than adults and based on our recent data showing that a single exposure to cocaine during adolescence is sufficient to change the adolescent brain, we decided to investigate whether acute cocaine exposure may alter actin remodeling in reward-related brain regions., Methods: Accordingly, we decided to evaluate if F-actin/G-actin ratio was altered by a single injection of cocaine (20 mg/kg) at postnatal day 35. We also evaluated whether the first administration of cocaine influences such a ratio in response to a second injection (10 mg/kg) provided 24 h or 7 days later., Results: Within the medial prefrontal cortex, a single cocaine injection increases the F-actin/G-actin ratio. This effect lasts 1 week, and it is not affected by the second injection of cocaine, indicating a persistent effect of the first exposure. In the nucleus accumbens, cocaine reduces the F-actin/G-actin ratio 24 h later. Seven days later, instead, such a ratio is markedly increased: notably, the additional exposure to the psychostimulant normalizes the F-actin/G-actin ratio., Conclusions: These results suggest that a single cocaine injection during adolescence causes possible changes in actin dynamics and influences the response to a second challenge of the psychostimulant, indicating that early cocaine priming might affect mechanisms regulating synaptic structural plasticity in specific brain regions.

Rationale: Although brain-derived neurotrophic factor (BDNF) is part of a homeostatic pathway involved in the development of alcohol dependence, it is not clear whether this is also true after recreational ethanol consumption., Objectives: We examined BDNF expression and signaling in the cortico-striatal network immediately and 24 h after either a single intravenous (i.v.) ethanol operant self-administration session or the last of 14 sessions., Methods: To compare contingent and non-contingent ethanol exposure, we incorporated the "yoked control-operant paradigm" in which rats actively taking ethanol (S-Et) were paired with two yoked controls receiving passive infusions of ethanol (Y-Et) or saline., Results: A single ethanol exposure transiently reduced BDNF mRNA levels in the medial prefrontal cortex (mPFC) of Y-Et. Immediately after the last of 14 sessions, mRNA and mature BDNF protein levels (mBDNF) were reduced in the mPFC in both S-Et and Y-Et while mBDNF expression was raised in the nucleus accumbens (NAc), suggesting enhanced anterograde transport from the mPFC. Conversely, 24 h later mBDNF expression and signaling were raised in the mPFC and NAc of S-Et rats but reduced in the NAc of Y-Et rats, with concomitant reduction of downstream signaling pathways., Conclusions: Our findings indicate that recreational-like i.v. doses of ethanol promote early changes in neurotrophin expression, depending on the length and modality of administration, the brain region investigated, and the presence of the drug. A rapid intervention targeting the BDNF system might be useful to prevent escalation to alcohol abuse.

Rationale: Adolescence is a period of high vulnerability to drugs of abuse and alterations of the proper developmental trajectory via psychostimulant exposure might change the physiological brain homeostasis., Objective: By microdissection of brain areas via punching, we investigated whether repeated exposure to cocaine during adolescence (from postnatal day 28 [PND28] to PND42) has altered fibroblast growth factor-2 (FGF-2) messenger RNA (mRNA) levels in selected brain subregions critical for the action of cocaine., Results: We found a reduction of FGF-2 mRNA levels in ventral tegmental area (VTA), where mesocortical and mesolimbic pathways originate. The analysis of the trophic factor levels in the distal projecting regions revealed a selective reduction of FGF-2 mRNA levels in infralimbic (IL) subregion of the medial prefrontal cortex (the terminal region of the mesocortical pathway) and in the nucleus accumbens core (cNAc) (the terminal region of the mesolimbic pathway). Last, we found reduced FGF-2 mRNA levels also in brain regions which, although in a different manner, contribute to the reward system, i.e., the central nucleus of amygdala (cAmy) and the ventral portion of hippocampus (vHip)., Conclusion: The widespread and coordinated reduction of FGF-2 mRNA levels across the brain's reward neurocircuitry might represent a defensive strategy set in motion to oppose to the psychostimulant properties of cocaine. Moreover, given the role of FGF-2 in modulating mood disorders, the reduced trophic support here observed might sustain the negative emotional state set in motion by repeated exposure to cocaine.

Rationale: During adolescence, the brain is maturing and more sensitive to drugs of abuse that can influence its developmental trajectory. Recently, attention has been focused on basic fibroblast growth factor (FGF-2) given that its administration early in life enhances the acquisition of cocaine self-administration and sensitization at adulthood (Turner et al. (Pharmacol Biochem Behav 92:100-4, 2009), Clinton et al. (Pharmacol Biochem Behav103:6-17, 2012)). Additionally, we found that abstinence from adolescent cocaine exposure long lastingly dysregulates FGF-2 transcription (Giannotti et al. (Psychopharmacology (Berl) 225:553-60, 2013 )., Objectives: The objectives of the study are to evaluate if (1) a single injection of cocaine (20 mg/kg) at postnatal day 35 alters FGF-2 messenger RNA (mRNA) levels and (2) the first injection influences the trophic response to a second injection (10 mg/kg) provided 24 h or 7 days later., Results: We found regional differences in the FGF-2 expression pattern as either the first or the second injection of cocaine by themselves upregulated FGF-2 mRNA in the medial prefrontal cortex and nucleus accumbens while downregulating it in the hippocampus. The first injection influences the trophic response of the second. Of note, 24 h after the first injection, accumbal and hippocampal FGF-2 changes produced by cocaine in saline-pretreated rats were prevented in cocaine-pretreated rats. Conversely, in the medial prefrontal cortex and hippocampus 7 days after the first injection, the cocaine-induced FGF-2 changes were modified by the subsequent exposure to the psychostimulant., Conclusions: These findings show that a single cocaine injection is sufficient to produce enduring changes in the adolescent brain and indicate that early cocaine priming alters the mechanisms regulating the trophic response in a brain region-specific fashion.

Rationale: Our study stems from four related lines of evidence: (1) FGF-2 is expressed in the developing brain; (2) psychostimulants modulate FGF-2 expression; (3) stress alters FGF-2 expression; and (4) exogenous administration of FGF-2 long-lastingly alters cocaine acquisition of self-administration., Objectives: This research aims to study the effects of adolescent cocaine exposure on FGF-2 mRNA levels and its influence on the response to stress., Materials and Methods: Rats were treated subcutaneously with saline or cocaine from postnatal day (PND) 28 to PND 42, a period that roughly approximates adolescence in humans. At PND 45 and PND 90, rats were exposed to an acute stress. Real-time PCRs were performed on total RNA extracted from the prefrontal cortex, hippocampus, nucleus accumbens and striatum., Results: In the prefrontal cortex, repeated cocaine treatment during adolescence increased FGF-2 mRNA levels in PND 90 rats and altered its response to an acute stress in both PND 45 and PND 90 rats. In the hippocampus of PND 45 rats, we found an increase of FGF-2 mRNA levels following repeated cocaine administration. No changes in the trophic factor gene expression were found in the striatum and nucleus accumbens., Conclusions: Our data show that cocaine exposure during adolescence alters FGF-2 mRNA levels throughout life in rat prefrontal cortex and modulates its response to an adverse event. These results point to FGF-2 as a potential molecular target through which exposure to cocaine early in life may dynamically and persistently alter brain homeostasis.