We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at -opioid receptors) in NAc neurons, these findings raised the possibility that -receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the -antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at -receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar -antagonists: 5Ј-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5Ј-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the -antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the -agonist) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the -ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective -antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc "triggers" immobility behavior in the FST. Furthermore, they raise the possibility that -antagonists may have efficacy as antidepressants, but lack stimulant or rewardrelated effects.The neurobiology of depression is not understood. Because most antidepressants with clinical efficacy act upon monoamines [primarily norepinephrine (NE) and serotonin (5HT)], much research on depression has focused upon interactions between these neurotransmitters and their reuptake transporters and receptor proteins. However, recent research has become progressively focused upon the intracellular mechanisms of depression and antidepressant treatments (Manji et al., 2001;Duman, 2002;Nestler et al., 2002), with the goal of developing novel therapeutics that act faster, are more efficacious, and have fewer side effects. This approach has led to the study of brain circuits typically associated with reward-related processes, including the mesolimbic dopamine (DA) system Newton et al., 2002).The mesolimbic DA system projects from the ventral tegmental area of the midbrain to the nucleus accumbens (NAc) of the basal forebrain, and is modulated directly and indirectly by noradrenergic and serotonergic inputs (Pasquier et al., 1977). This circuitry contributes importantly to the hedonic (rewarding) effects of food, sexual behavior, and addictive drugs (Carlezon and Wise, 1996b;Kreek and Koob, 1998;Wise, 1998...

Since the inception of radiosurgery, the management of brain metastases has become a common problem for neurosurgeons. Although the use of stereotactic radiosurgery and/or whole brain radiation therapy serves to control the majority of disease burden, patients who survive longer than 6-8 months sometimes face the problem of symptomatic radiographically regrowing lesions with few treatment options. Here we investigate the feasibility of use of MRI-guided stereotactic laser induced thermotherapy (LITT) as a novel treatment option for these lesions. Six patients who had previously undergone gamma knife stereotactic radiosurgery for brain metastases were selected. All patients had an initial favorable response to radiosurgery but subsequently developed regrowth of at least one lesion associated with recurrent edema and progressive neurological symptoms requiring ongoing steroids for symptom control. All lesions were evaluated for craniotomy, but were deemed unresectable due to deep location or patient's comorbidities. Stereotactic biopsies were performed prior to the thermotherapy procedure in all cases. LITT was performed using the Visualase system and follow-up MRI imaging was used to determine treatment response. In all six patients biopsy results were negative for tumor and consistent with adverse radiation effects also known as radiation necrosis. Patients tolerated the procedure well and were discharged from the hospital within 48 h of the procedure. In 4/6 cases there was durable improvement of neurological symptoms until death. In all cases steroids were weaned off within 2 months. One patient died from systemic causes related to his cancer a month after the procedure. One patient had regrowth of the lesion 3 months after the procedure and required re-initiation of steroids and standard craniotomy for surgical resection. There were no complications directly related to the thermocoagulation procedure. Stereotactic laser induced thermotherapy is a feasible alternative for the treatment of symptomatic regrowing metastatic lesions after radiosurgery. The procedure carries minimal morbidity and, in this small series, shows some effectiveness in the symptomatic relief of edema and neurological symptoms paralleled by radiographic lesional control. Further studies are necessary to elucidate the safety of this technology.

No abstract

Background Marijuana use by teenagers often predates the use of harder drugs, but the neurobiological underpinnings of such vulnerability are unknown. Animal studies suggest enhanced heroin self-administration (SA) and dysregulation of the endogenous opioid system in the nucleus accumbens shell (NAcsh) of adults following adolescent Δ9-tetrahydrocannabinol (THC) exposure. However, a causal link between Penk expression and vulnerability to heroin has yet to be established. Methods To investigate the functional significance of NAcsh Penk tone, selective viral-mediated knockdown and overexpression of Penk was performed, followed by analysis of subsequent heroin SA behavior. To determine whether adolescent THC exposure was associated with chromatin alteration, we analyzed levels of histone H3 methylation in the NAcsh via ChIP at five sites flanking the Penk gene transcription start site. Results Here, we show that regulation of the proenkephalin (Penk) opioid neuropeptide gene in NAcsh directly regulates heroin SA behavior. Selective viral-mediated knockdown of Penk in striatopallidal neurons attenuates heroin SA in adolescent THC-exposed rats, whereas Penk overexpression potentiates heroin SA in THC-naïve rats. Furthermore, we report that adolescent THC exposure mediates Penk upregulation through reduction of histone H3 lysine 9 (H3K9) methylation in the NAcsh, thereby disrupting the normal developmental pattern of H3K9 methylation. Conclusions These data establish a direct association between THC-induced NAcsh Penk upregulation and heroin SA and indicate that epigenetic dysregulation of Penk underlies the long-term effects of THC.