ABSTRACT
BACKGROUND: Psychostimulants and opiates trigger similar enduring neuroadaptations within the reward circuitry thought to underlie addiction. Transcription factors are key to mediating these enduring behavioral alterations. The facilitation of these maladaptive changes by glucocorticoid hormones suggests that the glucocorticoid receptor (GR), a transcription factor involved in the stress response, could be a common mediator of responses to pharmacologically distinct classes of abused drugs. METHODS: We employed mouse models carrying GR gene inactivation in either dopamine or dopaminoceptive neurons to determine the involvement of this transcription factor in behavioral responses to cocaine and morphine. We then combined microarray analysis, drug-elicited immediate early gene induction, and in vivo microdialysis to elucidate the molecular underpinnings of these responses. RESULTS: Inactivating GR within dopaminoceptive neurons markedly reduces cocaine-induced conditioned place preference and the expression of locomotor sensitization. In striking contrast, GR had no effect on behavioral morphine responses in either dopaminoceptive or dopamine neurons. The dopaminoceptive mutation engenders alterations in the expression of striatal genes that are implicated in glutamatergic transmission and plasticity. Within the nucleus accumbens, impaired cellular responses to cocaine are conspicuous; a pronounced deficit in cocaine-elicited extracellular dopamine release, expression of the key IEGs c-Fos and Zif268, and phosphorylation of extracellular signal-regulated kinases 1/2 in mutants were observed. In contrast, these molecular and neurochemical changes were not observed in response to morphine, mirroring the lack of effect on behavioral responses to morphine. CONCLUSION: Combined behavioral and molecular approaches have identified a subset of neurons in which GR differentially influences cocaine- and morphine-induced responses.
Subject(s)
Central Nervous System Depressants/metabolism , Cocaine/metabolism , Morphine/metabolism , Neurons/metabolism , Receptors, Glucocorticoid/metabolism , Substance-Related Disorders/metabolism , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Brain/metabolism , Dopamine/metabolism , Gene Silencing , Male , Mice , Mice, Inbred C57BL , Mice, Neurologic Mutants , Mutation/genetics , Receptors, Glucocorticoid/genetics , Reinforcement, PsychologyABSTRACT
Merlin is the product of the Nf2 tumor-suppressor gene, and inactivation of Nf2 leads to the development of neural tumors such as schwannomas and meningiomas in humans and mice. Merlin is a member of the ERM (ezrin, radixin and moesin) family of proteins that function as organizers of the actin cytoskeleton. Merlin structure is thought to be similar to that of the ERM proteins, and is held in a closed clamp conformation via intramolecular interactions of its N-terminal FERM (four-point-one, ERM) domain with an alpha-helical C-terminal domain. Like ERMs, merlin can remodel actin-rich cortical structures, yet merlin uniquely inhibits the proliferation of many different cell types. Here, we report that the F2 subdomain of the FERM domain and a domain close to the C-terminus that is defined by residues 532-579 are essential for merlin-mediated inhibition of primary Schwann cell proliferation. Furthermore, we demonstrate that the F1 subdomain of the merlin FERM domain is required for actin colocalization, proper regulation of merlin C-terminal phosphorylation and for remodeling the cytoskeleton, yet is not required for the inhibition of Schwann cell proliferation. Thus, tumor suppression by merlin is independent of its role as an organizer of the actin cytoskeleton in Schwann cells.
