Drug abuse during adolescence may predispose towards later adult substance abuse and major depressive disorders (Brook et al., 2002). The purpose of the present study was to characterize whether behavioural sensitization to amphetamine occurred in adult rats following adolescent exposure to amphetamine [low (2 mg/kg.d) or high (10 mg/kg.d) i.p. for 10 d] and the pattern of neural activation associated with sensitized behaviour, in male Sprague-Dawley rats. Following initial treatment (post-natal days 33-41) and a subsequent 4-wk period of abstinence, rats initially treated with either amphetamine regime showed a similar sensitized locomotor activity upon re-challenge with amphetamine (1.5 mg/kg i.p.) compared to rats acutely challenged with this dose of amphetamine. Fos-IR expression in the "high" sensitized group was significantly greater than acutely challenged rats in all quadrants of the CPu. Both "low" and "high" sensitized groups demonstrated heightened Fos expression relative to acutely challenged rats in the medial and central amygdala, as well as rostroventrolateral medulla, whereas Fos-IR in the locus coeruleus and substantia nigra pars reticulata was significantly increased only in the "high" sensitized group compared to acute. Double-labelling for tyrosine hydroxylase confirmed an absence of Fos-IR in A9 and A10 regions. The present study has shown a robust and persistent sensitization in adulthood to amphetamine re-challenge following initial adolescent exposure in rats. This manifestation of sensitization apparently results in widespread neural activation in limbic and autonomic structures.

Transcriptional changes in neurons underpin the long-lived cellular response to environmental stimuli, and cAMP-responsive element-binding protein (CREB1) has been implicated in this process. Exposure to psychostimulants such as cocaine results in persistent neuronal plasticity in cortical circuitry that likely modulates the motivation to use the drug again. To examine whether CREB1 in cortical glutamatergic neurons was implicated in cocaine use, we developed conditional CREB1 mutants that exhibit ablation of functional CREB1 in the cortex and hippocampus. Here we report that CREB1 mutants show normal locomotor responses to acute and chronic cocaine and develop a place preference for cocaine. However, CREB1 mutants demonstrate a diminished drive to self-administer cocaine under operant conditions. We conclude that there is a specific role for CREB1 in telencephalic glutamatergic neurons regulating the motivational properties of cocaine.

Addiction involves complex physiological processes, and is characterised not only by broad phenotypic and behavioural traits, but also by ongoing molecular and cellular adaptations. In recent years, increasingly effective and novel techniques have been developed to unravel the molecular implications of addiction. Increasing evidence has supported a contribution of the nuclear transcription factor CREB in the development of addiction, both in contribution to phenotype and expression in brain regions critical to various aspects of drug-seeking behaviour and drug reward. Abstracting from this, models have exploited these data by removing the CREB gene from the developing or developed mouse, to crucially determine its impact upon addiction-related processes. More recent models, however, hold greater promise in unveiling the contribution of CREB to disorders such as addiction.

In the present study, using rats, we have examined acute, contextual, and sensitized patterns of activated or phosphorylated cAMP response element-binding protein (pCREB) expression in parallel, assaying across multiple nuclei that have been implicated in addiction. The paradigm used included a comparison of pretreatment dose of amphetamine upon patterns of cellular activation, following rechallenge. Because efferent orexinergic projections synapse on many targets through the mammalian brain, including mesotelencephalic regions and limbic systems involved in drug reward and reinforcement, we examined for coexpression of pCREB or c-Fos double labeling within orexin A-immunopositive neurons following sensitization. Acute challenge with amphetamine (1.5 mg/kg i.p.) resulted in an increase in the number of pCREB-immunoreactive (-IR) cells within the substantia nigra but a decrease of pCREB-IR cells in the central and medial subnuclei of the amygdala. Contextual re-exposure to the drug treatment environment altered pCREB expression, particularly in the basal ganglia and hypothalamus, although these effects were dictated by pretreatment dose of amphetamine. Sensitization to amphetamine resulted in robust increases in pCREB-IR cell numbers in the basal ganglia and lateral septum of rats that had been pretreated with high-dose (10 mg/kg i.p.) but not low-dose (2 mg/kg i.p.) amphetamine, despite a similar behavioral response. Orexin A-containing cells in the hypothalamus of sensitized rats did not coexpress pCREB; however, these cells double-labeled for c-Fos and orexin A. These data suggest that orexinergic neurons are activated during the expression of behavioral sensitization, although in a heterogenous manner with regard to afferent topologies and functional roles in the nervous system.