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Astrocytic-secreted matricellular proteins have been shown to influence various aspects of synaptic function. More recently, they have been found altered in animal models of psychiatric disorders such as drug addiction. Hevin (also known as Sparc-like 1) is a matricellular protein highly expressed in the adult brain that has been implicated in resilience to stress, suggesting a role in motivated behaviors. To address the possible role of hevin in drug addiction, we quantified its expression in human postmortem brains and in animal models of alcohol abuse. Hevin mRNA and protein expression were analyzed in the postmortem human brain of subjects with an antemortem diagnosis of alcohol use disorder (AUD, n = 25) and controls (n = 25). All the studied brain regions (prefrontal cortex, hippocampus, caudate nucleus and cerebellum) in AUD subjects showed an increase in hevin levels either at mRNA or/and protein levels. To test if this alteration was the result of alcohol exposure or indicative of a susceptibility factor to alcohol consumption, mice were exposed to different regimens of intraperitoneal alcohol administration. Hevin protein expression was increased in the nucleus accumbens after withdrawal followed by a ethanol challenge. The role of hevin in AUD was determined using an RNA interference strategy to downregulate hevin expression in nucleus accumbens astrocytes, which led to increased ethanol consumption. Additionally, ethanol challenge after withdrawal increased hevin levels in blood plasma. Altogether, these results support a novel role for hevin in the neurobiology of AUD.

The peculiar neurochemical profile of the adolescent brain renders it differently susceptible to several stimuli, including stress and/or drug exposure. Among several stress mediators, nitric oxide (NO) has a role in stress responses. We have demonstrated that adolescent mice are less sensitive to ethanol-induced sensitization than adult mice. The present study investigated whether chronic unpredictable stress (CUS) induces behavioral sensitization to ethanol in adolescent and adult Swiss mice, and investigated the influence of Ca2+-dependent nitric oxide synthase (NOS) activity in the phenomenon. Adolescent and adult mice were exposed to repeated 1.8 g/kg ethanol or CUS and challenged with saline or ethanol. A neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7NI), was administered along with ethanol and CUS to test its effects on behavioral sensitization. Both adolescent and adult mice displayed cross-sensitization between CUS and ethanol in adult mice, with adolescents showing a lower degree of sensitization than adults. nNOS inhibition by 7NI reduced both ethanol sensitization and cross-sensitization. All age differences in the Ca2+-dependent NOS activity in the hippocampus and prefrontal cortex were in the direction of greater activity in adults than in adolescents. Adolescents showed lower sensitivity to cross-sensitization between CUS and ethanol, and the nitric oxide (NO) system seems to have a pivotal role in ethanol-induced behavioral sensitization and cross-sensitization in both adolescent and adult mice.

The peculiar neurochemical profile of the adolescent brain renders it differently susceptible to several stimuli, including stress and/or drug exposure. Among several stress mediators, nitric oxide (NO) has a role in stress responses. We have demonstrated that adolescent mice are less sensitive to ethanol-induced sensitization than adult mice. The present study investigated whether chronic unpredictable stress (CUS) induces behavioral sensitization to ethanol in adolescent and adult Swiss mice, and investigated the influence of Ca2+-dependent nitric oxide synthase (NOS) activity in the phenomenon. Adolescent and adult mice were exposed to repeated 1.8 g/kg ethanol or CUS and challenged with saline or ethanol. A neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7NI), was administered along with ethanol and CUS to test its effects on behavioral sensitization. Both adolescent and adult mice displayed cross-sensitization between CUS and ethanol in adult mice, with adolescents showing a lower degree of sensitization than adults. nNOS inhibition by 7NI reduced both ethanol sensitization and cross-sensitization. All age differences in the Ca2+-dependent NOS activity in the hippocampus and prefrontal cortex were in the direction of greater activity in adults than in adolescents. Adolescents showed lower sensitivity to cross-sensitization between CUS and ethanol, and the nitric oxide (NO) system seems to have a pivotal role in ethanol-induced behavioral sensitization and cross-sensitization in both adolescent and adult mice.

RATIONALE: The neurobiological systems that mediate the discriminative stimulus effects of self-administered drugs are largely unknown. The present study examined the discriminative stimulus effects of self-administered ethanol. METHODS: Rats were trained to discriminate ethanol (1 g/kg, IP) from saline on a two-lever drug discrimination task with sucrose (10% w/v) reinforcement. Test sessions were conducted with ethanol (0 or 10% v/v) added to the sucrose reinforcement to determine if self-administered ethanol would interact with the discriminative stimulus effects of investigator-administered ethanol, or with the ethanol-like discriminative stimulus effects of the GABAA-positive modulator pentobarbital or the non-competitive NMDA antagonist MK-801. RESULTS: During a saline test session, ethanol (10% v/v) was added to the sucrose reinforcement. Responding by all animals began accurately on the saline-appropriate lever and then switched to the ethanol-appropriate lever after rats self-administered a mean dose of 1.2 +/- 0.14 g/kg ethanol. During cumulative self-administration trials, responding initially occurred on the saline lever and then switched to the ethanol-appropriate lever after ethanol (0.68 +/- 0.13 g/kg) was self-administered. Investigator-administered MK-801 (0.01-1.0 mg/kg, cumulative IP) and pentobarbital (0.3-10.0 mg/kg, cumulative IP) dose-dependently substituted for ethanol. When ethanol (10% v/v) was added to the sucrose reinforcer, MK-801 and pentobarbital dose-response curves were shifted significantly to the left. CONCLUSIONS: Self-administered ethanol substituted for and potentiated the stimulus effects of investigator-administered ethanol, suggesting that the discriminative stimulus effects of self-administered ethanol are similar to those produced by investigator-administered ethanol. Self-administered ethanol enhanced the ethanol-like discriminative stimulus effects of MK-801 and pentobarbital, which suggests that the discriminative stimul