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We have previously demonstrated that a single exposure to cocaine during adolescence causes several behavioural and neurobiological changes, highlighting the unique vulnerability of this period of life. The purpose of our work was to investigate whether a single exposure to cocaine during brain development is sufficient to shape a negative emotional state in adolescent rats. A single injection of cocaine during adolescence followed by measurement of sucrose consumption, a measure of anhedonia, identifies two separate groups of rats, i.e. anhedonic (AN) and non anhedonic (NON-AN) rats. AN rats show reduced ability to synthesize, traffic and translate the neurotrophin BDNF at synaptic level, reduced activation of hippocampal BDNF signaling, reduced BDNF plasma levels and a steep rise of corticosterone secretion. Conversely, NON-AN rats exhibit reduced trafficking of BDNF while up-regulating hippocampal BDNF synthesis and stabilizing its downstream signaling with no changes of BDNF and corticosterone plasma levels. Adult rats exposed to cocaine showed no signs of anhedonia, an increase of BDNF both in hippocampus and plasma and decreased levels of corticosterone. In conclusion, our findings reveal a complex central and peripheral dysregulation of BDNF-related mechanisms that instead are preserved in NON-AN rats, suggesting that BDNF modulation dictates behavioural vulnerability vs. resiliency to cocaine-induced anhedonia, a profile uniquely restricted to adolescent rats.

Contains fulltext : 282578.pdf (Publisher’s version ) (Open Access), BACKGROUND AND PURPOSE: It has been well established that glutamate in the nucleus accumbens (NAc) plays a critical role in the motivation to take drugs of abuse. We have previously demonstrated that rats with ablation of the serotonin transporter (SERT(-/-) rats) show increased cocaine intake reminiscent of compulsivity. EXPERIMENTAL APPROACH: By comparing SERT(-/-) to SERT(+/+) rats, we investigated whether SERT deletion influences glutamate homeostasis under control conditions as well as after short access (ShA: 1 h per session) or long access (LgA: 6 h per session) to cocaine self-administration. Rats were killed at 24 h after the last self-administration session for ex vivo molecular analyses of the main determinants of the glutamate system, including transporters (vesicular and glial), receptors (main post-synaptic subunits of NMDA and AMPA receptors together with the metabotropic subunit mGLUR5), and scaffolding proteins (SAP102, SAP97, and GRIP) in the NAc shell (sNAc) KEY RESULTS: In cocaine-naive animals, SERT deletion was associated with changes indicative for a reduction in glutamate signalling. ShA and LgA exposure led to a further dysregulation of the glutamatergic synapse. CONCLUSION: SERT deletion may render the glutamatergic synapses of the NAc shell more responsive to both ShA and LgA intake of cocaine.

Contains fulltext : 282578.pdf (Publisher’s version ) (Open Access), BACKGROUND AND PURPOSE: It has been well established that glutamate in the nucleus accumbens (NAc) plays a critical role in the motivation to take drugs of abuse. We have previously demonstrated that rats with ablation of the serotonin transporter (SERT(-/-) rats) show increased cocaine intake reminiscent of compulsivity. EXPERIMENTAL APPROACH: By comparing SERT(-/-) to SERT(+/+) rats, we investigated whether SERT deletion influences glutamate homeostasis under control conditions as well as after short access (ShA: 1 h per session) or long access (LgA: 6 h per session) to cocaine self-administration. Rats were killed at 24 h after the last self-administration session for ex vivo molecular analyses of the main determinants of the glutamate system, including transporters (vesicular and glial), receptors (main post-synaptic subunits of NMDA and AMPA receptors together with the metabotropic subunit mGLUR5), and scaffolding proteins (SAP102, SAP97, and GRIP) in the NAc shell (sNAc) KEY RESULTS: In cocaine-naive animals, SERT deletion was associated with changes indicative for a reduction in glutamate signalling. ShA and LgA exposure led to a further dysregulation of the glutamatergic synapse. CONCLUSION: SERT deletion may render the glutamatergic synapses of the NAc shell more responsive to both ShA and LgA intake of cocaine.