ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

Abstract

DFosB, a FosB gene product, is induced in the prefrontal cortex (PFC) by repeated exposure to several stimuli including antipsychotic drugs such as haloperidol. However, the functional consequences of increased DFosB expression following antipsychotic treatment have not been explored. Here, we assessed whether DFosB induction by haloperidol mediates the positive or negative consequences or clinical-related actions of antipsychotic treatment. We show that individuals with schizophrenia who were medicated with antipsychotic drugs at their time of death display increased DFosB levels in the PFC, an effect that is replicated in rats treated chronically with haloperidol. In contrast, individuals with schizophrenia who were medication-free did not exhibit this effect. Viral-mediated overexpression of DFosB in the PFC of rodents induced cognitive deficits as measured by inhibitory avoidance, increased startle responses in prepulse inhibition tasks, and increased MK-801-induced anxiety-like behaviors. Together, these results suggest that DFosB induction in the PFC by antipsychotic treatment contributes to the deleterious effects of these drugs and not to their therapeutic actions.

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

“…Swerdlow et al 2008). A number of creative strategies have been used to understand this complex genetic landscape and its overlap with brain circuitry, via assessing the PPI-altering effects of gene knockouts, humanized gene insertions (e.g., Risbrough et al 2014), strain differences in regional gene expression (e.g., Shilling et al 2008), drug-induced changes in regional expression of genes identified in postmortem schizophrenia brain tissue (e.g., Dietz et al 2014), and pharmacogenetic manipulations of neural activity in targeted neuron populations via the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) (e.g., Nguyen et al 2014), among other techniques. These strategies are not without potential pitfalls, including the importance of assessing hearing loss in mutant animals as a potential basis for reduced inhibitory effects of auditory prepulses.…”

Accumulation of Highly Stable ΔFosB-Isoforms and Its Targets inside the Reward System of Chronic Drug Abusers - A Source of Dependence-Memory and High Relapse Rate?

“…However, recent findings by Teyssier et al [34] clearly show that the ΔFosB pathway in brain tissue of depressed patients was chronically activated at the mRNA level, suggesting that a more complex genetic response may be involved, at least in the case of humans. Independent of these findings, both Dietz et al [35] and Robison et al [22] were able to detect stable ΔFosB isoforms in NAc of human tissue samples of patients with schizophrenia in the former and of cocaine-dependent individuals in the latter. However, postmortem intervals did not exceed more than one to two days for any of those examinations.…”

SEACOIN 2.0 – an interactive mining and visualization tool for information retrieval, summarization, and knowledge discovery

“…One of the articles supported the hypothesis that schizophrenia, fosb and BMY14802 are linked. In their recently published work, Dietz et al showed that the fosb expression levels increased in schizophrenic patients who were prescribed antipsychotic drugs, while no effect in fosb levels was observed in patients who were medication free (Dietz 2014). This example demonstrates the ability of the system to extract implicit relationships from literature to facilitate hypothesis generation and knowledge discovery.…”