Cocaine Up-Regulates Fra-2 and σ-1 Receptor Gene and Protein Expression in Brain Regions Involved in Addiction and Reward

Abstract

Receptors have recently been implicated in the actions of cocaine, and antagonists of these receptors prevent many acute and subchronic cocaine effects. A previous study revealed that the immediate early gene fra-2 is up-regulated after cocaine administration, and this effect is prevented by the -1In the present study, the effects of cocaine and BD1063 on the expression of six fos and jun genes were evaluated in mouse brains using cDNA microarrays. Several of these genes were altered by cocaine, but only the alteration in fra-2 was prevented by BD1063. The time courses of fra-2 and -1 receptor gene and protein expression in different brain regions were also determined. Cocaine up-regulated fra-2, which was followed by a later up-regulation of -1 receptors. The cocaine-induced up-regulation of fra-2 and -1 receptor genes and proteins were detected in whole brain, striatum, and cortex, but not in cerebellum. All of these cocaine-induced effects were prevented by BD1063. The interaction between cocaine, fra-2, and -1 receptors involves brain regions that are established components of the neural circuit for reward, suggesting that they may contribute to the enduring changes that underlie the cellular basis of drug abuse.

Reinforcing Effects of σ-Receptor Agonists in Rats Trained to Self-Administer Cocaine

“…That sensitization can be blocked by cotreatment with the R antago- nists, BMY 14802, rimcazole (Ujike et al, 1992a(Ujike et al, , 1996, or the flavone-derivative R antagonist, NPC 16377 (Witkin et al, 1993). More recently, Liu et al (2005) and Liu and Matsumoto (2008) reported that treatment with cocaine upregulated several immediate early genes, among them fra-2 and 1 R genes, and protein levels. Those effects were prevented by coadministration of BD 1063.…”

Differential Effects of σ1 Receptor Blockade on Self-Administration and Conditioned Reinstatement Motivated by Cocaine vs Natural Reward

“…A more likely interpretation for the differential effects of BD1047 on cocaine S + vs SCM S + -induced reinstatement is related to upregulation of s 1 receptor function after cocaine treatment. Acute cocaine administration has been shown to upregulate s 1 receptor gene expression and protein levels in whole brain, striatum, and cortex (Liu et al, 2005). Moreover, 4 days of intermittent cocaine exposure during place conditioning increased in vivo binding levels of the s 1 receptor agonist [ 3 H]( + )-SKF-10,047 in the olfactory bulb, hippocampus, hypothalamus, cortex, and striatumFa change that was sustained during extinction of CPPFindicative of persistent functional s 1 receptor upregulation (Romieu et al, 2004).…”

Alterations in Fos-Related Antigen 2 and σ1 Receptor Gene and Protein Expression Are Associated with the Development of Cocaine-Induced Behavioral Sensitization: Time Course and Regional Distribution Studies

“…BD1063 (Tocris Bioscience, Ellisville, MO) was injected at a dosage of 30 mg/kg (3 mg/ml solution i.p.). In earlier studies, this dose of BD1063 produced robust attenuation of the locomotor stimulatory effects of the -active psychomotor stimulants cocaine (Matsumoto et al, 2001;Liu et al, 2005), methamphetamine (Nguyen et al, 2005), and 3,4-methylenedioxymethamphetamine (Brammer et al, 2006). It also attenuated cocaine-induced toxicities, such as convulsions and lethality (Matsumoto et al, 2001).…”

“…In an earlier study combining behavioral pharmacological approaches with cDNA microarray analysis and reverse transcription-polymerase chain reaction (PCR) confirmations (Matsumoto et al, 2003;Liu et al, 2005), fos-related antigen 2 (fra-2), an immediate-early gene (IEG) and member of the fos family of transcription factors, was discovered to be upregulated by cocaine and prevented by behavioral protective doses of BD1063, a 1 receptor antagonist (Matsumoto et al, 2003;Liu et al, 2005). The ability of drugs to induce IEGs has been proposed to represent an early step in a chain of molecular events leading to synaptic reorganization, which underlie drug experience-dependent behavioral plasticity (Hyman and Malenka, 2001;McClung and Nestler, 2008).…”