Distinct patterns of ΔFosB induction in brain by drugs of abuse

Abstract

The transcription factor ΔFosB accumulates and persists in brain in response to chronic stimulation. This accumulation after chronic exposure to drugs of abuse has been demonstrated previously by Western blot most dramatically in striatal regions, including dorsal striatum (caudate/putamen) and nucleus accumbens. In the present study, we used immunohistochemistry to define with greater anatomical precision the induction of ΔFosB throughout the rodent brain after chronic drug treatment. We also extended previous research involving cocaine, morphine, and nicotine to two additional drugs of abuse, ethanol and Δ 9 -tetrahydrocannabinol (Δ 9 -THC, the active ingredient in marijuana). We show here that chronic, but not acute, administration of each of four drugs of abuse, cocaine, morphine, ethanol, and Δ 9 -THC, robustly induces ΔFosB in nucleus accumbens, although different patterns in the core vs. shell subregions of this nucleus were apparent for the different drugs. The drugs also differed in their degree of ΔFosB induction in dorsal striatum. In addition, all four drugs induced ΔFosB in prefrontal cortex, with the greatest effects observed with cocaine and ethanol, and all of the drugs induced ΔFosB to a small extent in amygdala. Furthermore, all drugs induced ΔFosB in the hippocampus, and, with the exception of ethanol, most of this induction was seen in the dentate. Lower levels of ΔFosB induction were seen in other brain areas in response to a particular drug treatment. These findings provide further evidence that induction of ΔFosB in nucleus accumbens is a common action of virtually all drugs of abuse and that, beyond nucleus accumbens, each drug induces ΔFosB in a region-specific manner in brain.

Transcriptional mechanisms of addiction: role of ΔFosB

“…The 35-37 kD isoforms of DFosB dimerize predominantly with JunD to form an active and long-lasting AP-1 complex within these brain regions (Chen et al 1997;Hiroi et al 1998;Pérez-Otan o et al 1998). The drug induction of DFosB in the nucleus accumbens seems to be a response to the pharmacological properties of the drug per se and not related to volitional drug intake, since animals that self-administer cocaine or receive yoked drug injections show equivalent induction of this transcription factor in this brain region (Perrotti et al 2008).…”

“…An important question, then, is whether DFosB acting in other brain regions beyond the nucleus accumbens may also influence drug addiction. Indeed, there is now increasing evidence that stimulant and opiate drugs of abuse induce DFosB in several brain regions implicated in diverse aspects of addiction Perrotti et al 2005Perrotti et al , 2008McDaid et al 2006a,b;Liu et al 2007).…”

“…A recent study has systematically compared DFosB induction in these various brain regions across four different drugs of abuse: cocaine; morphine; cannabinoids; and ethanol (table 4; Perrotti et al 2008). All four drugs induce the transcription factor to varying degrees in nucleus accumbens and dorsal striatum as well as in prefrontal cortex, amygdala, hippocampus, bed nucleus of the stria terminalis and interstitial nucleus of the posterior limb of the anterior commissure.…”

“…See Perrotti et al (2008) for this information. b The effect of cocaine, ethanol and cannabinoids on DFosB induction in ventral pallidum has not yet been studied, but such induction has been observed in response to methamphetamine (McDaid et al 2006b).…”

Morphine Regulated Synaptic Networks Revealed by Integrated Proteomics and Network Analysis

“…In addition to these morphological alterations, morphine also regulates the expression of transcription factors that are involved in mechanisms of learning and synaptic plasticity such as CREB (6), ⌬FosB (6,7), and NF--B (8). Prolonged exposure to morphine and other opiates also results in a number of important molecular and electrophysiological changes at synaptic terminals.…”