Repeated opiate (e.g. heroin) use may result in drug addiction where successful treatment is deterred by high incidences of relapse. Learning processes that enable drug-related stimuli (cues) to become associated with drugs (rewards) represent a contributing factor to craving, and may underlie the relapsing nature of addiction to drugs of abuse (O'Brien and McLellan 1996; Leshner 1997). Brain areas such as the prefrontal cortex (PFC), striatum and amygdala, which are targets of the mesocorticolimbic system, play a pivotal role in associative learning processes, mediating motivated behaviour towards natural rewards (e.g. food and sex; Everitt et al. 1999; Robbins and Everitt 2002), but also in craving and drug seeking. Imaging studies that measure cue-induced cocaine craving in humans have shown that prefrontal and limbic activation correlates with the degree of craving (Maas et al. 1998; Childress et al. 1999). In addition, animal studies have shown that various brain areas, such as the medial prefrontal cortex (mPFC), orbital frontal cortex (OFC), nucleus accumbens core (NAC) and basolateral amygdala (BLA) are implicated in the cue-induced reinstatement of cocaine seeking in animal models for cocaine relapse (Ciccocioppo et al. 2001; McLaughlin and See 2003; Fuchs et al. 2004a,b).
Opiates and psychostimulants alter dopaminergic transmission profoundly, which is thought to underlie the consolidation of drug memories (Di Chiara 1999), and induce various short- and long-term neural adaptations, such as changes in neuronal morphology and gene expression in cortical, striatal and amygdala areas (Nestler 2001; Jacobs et al. 2002; Robinson and Kolb 2004; Spijker et al. 2004). These persistent alterations may be different for natural rewards (Di Chiara 1999; Nestler 2001; Robinson and Kolb 2004; Van den Oever et al. 2005). It is interesting to note that, in humans, various cortical and striatal areas respond to cocaine, but not naturally rewarding (sexual) stimuli (Garavan et al. 2000). We and others have shown that exposure to conditioned cues associated with drugs of abuse (opiates, nicotine) versus natural rewards (chocolate, sucrose) elicit overlapping, but also distinct expression patterns of transcription factor immediate early genes (IEGs) in prefrontal and striatal areas (Schroeder et al. 2000, 2001; Schroeder and Kelley 2002; Schmidt et al. 2005). Therefore, it can be inferred from the aforementioned human and animal studies that neuronal substrates respond differently to drugs versus natural rewards and their related stimuli.
As a further step towards the identification of potential disease targets for the clinical management of opiate relapse, it is necessary to identify the diverse molecular responses associated with cue-induced reinstatement to heroin that do not generalize to a motivated behaviour towards natural rewards. Measuring IEGs are useful in this respect as they are rapidly induced in response to neuronal stimulation and their induction suggests alterations in genomic regulation, neuronal signalling and structure (Herdegen and Leah 1998; Lanahan and Worley 1998). Thus, they are attractive neural reactivity markers, whose simultaneous induction in a brain area can be measured sensitively by real-time quantitative PCR (qPCR). Therefore, the aim of this study was to identify a wider range of alterations in molecular reactivity patterns from mesocorticolimbic target areas underlying cue-induced heroin-seeking behaviour, and to compare them with the patterns observed in cue-induced sucrose (natural reward) seeking.
In this study, rats were trained to self-administer heroin or sucrose associated with a compound audio-visual cue. After a long (approximately 3-week) extinction period, the rats were tested for cue-induced reinstatement of heroin or sucrose seeking. Neural reactivity was measured by detecting changes in multiple IEG transcripts from different functional classes using qPCR. Heroin-seeking behaviour, but not sucrose-seeking behaviour, was associated with IEG induction in the mPFC, OFC and NAC.