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  • Taken together our results demonstrate that the changes of


    Taken together, our results demonstrate that the changes of striatal dopamine release and locomotor activity observed following chronic nicotine treatment and consequent acute withdrawal are mediated by CRF1, but not CRF2. Previous studies have already indicated that blocking CRF1 would prevent some of the affective symptoms (the dysphoria and the reward deficit) (Bruijnzeel et al., 2009, Bruijnzeel et al., 2012, George et al., 2007, Marcinkiewcz et al., 2009), whereas blocking CRF2 would reverse some sphingosine 1 phosphate receptor of the somatic symptoms (the excessive food intake and the increased body weight) of nicotine withdrawal syndrome in rats (Kamdi et al., 2009). A recent study have also indicated that administration of selective CRF2 agonists could ameliorate the anxiety- and depression-like state developed during acute nicotine withdrawal in mice (Bagosi et al., 2016). The present study completes the previous ones, suggesting that both the rewarding, positive reinforcing effects of nicotine promoted by enhanced striatal dopamine release and the aversive, negative effects of nicotine withdrawal mediated partly by deficient striatal dopamine release could be attenuated by administration of selective CRF1 antagonists. As such, antalarmin may normalize the striatal dopamine release by blocking CRF1 receptors that regulate dopamine neuron firing at the level of the substantia nigra and the ventral tegmental area (Van Pett et al., 2000). Alternatively, antalarmin may inhibit CRF1 receptors located in the dorsal and ventral striatum, but also in the amygdala and hippocampus, from where it can modulate bidirectionally the striatal dopamine release via GABAergic and glutamatergic neurotransmission (Bagosi et al., 2006, Bagosi et al., 2008, Bagosi et al., 2015, Palotai et al., 2013a, Palotai et al., 2013b). The present study does not exclude the possibility that the ability of the selective antagonist of CRF1, but not CRF2, to abolish the behavioral and neurochemical effects of nicotine could simply be due to the differential distribution of CRF1 and CRF2 receptors in the substantia nigra and ventral tegmental area or the dorsal and ventral striatum. Moreover, previous studies demonstrated that CRF1 is expressed abundantly in all these sphingosine 1 phosphate receptor regions, whereas CRF2 is limited centrally to the hypothalamus, amydgala, and hippocampus (Van Pett et al., 2000). However, a recent study reported an increased expression of CRF2 in the dorsal striatum after the development of nicotine-induced sensitization in rats (Carboni et al., 2018). In this order of thoughts, both CRF1 and CRF2 must be considered potential targets in the therapy of nicotine addiction.
    Experimental procedures
    Introduction Drug addiction is a chronic, relapsing disorder in part due to the strong associations formed between drugs and stimuli associated with drug abuse through Pavlovian conditioning (Robbins and Everitt, 2002). These stimuli become strong drivers of continuous drugs use and relapse after abstinence. Extensive evidence supports that some of the most important features of drug addiction reflect abnormalities in traditional memory circuits, with long-term memories of the drug experience serving as potent drivers of addiction pathology (Robbins et al., 2008). One of the factors responsible for this vulnerability is reactivation of withdrawal memories or conditioned withdrawal, which consists in somatic and/or affective withdrawal signs elicited in the presence of cues that were previously paired with drug withdrawal (O'Brien et al., 1977). The conditioned-place aversion (CPA) paradigm is a highly sensitive animal model for measurement of the negative affective component of drug withdrawal, as well as for investigating neural substrates underlying the aversive memory associated with withdrawal (Myers et al., 2012; Stinus et al., 2000). CPA triggers association between negative affective consequences of withdrawal with context (aversive memory formation or consolidation). When the animals are re-exposed to the paired environment in a drug-free state, they avoid the paired environment due to the association between the context and aversive memories of drug withdrawal (aversive memory retrieval). Among the limbic structures that are likely to mediate these components of drug addiction, the basolateral amygdala (BLA) and the hippocampus represent critical neural substrates (Frenois et al., 2005; Lucas et al., 2008). It is well established that the hippocampus is crucially important for memory encoding/consolidation but also for episodic memory retrieval. In this context, much experimental evidence has demonstrated that the granular zone of the hippocampal dentate gyrus (DG) has a critical role in learning and memory function (Aimone et al., 2011; Kee et al., 2007). In addition, the BLA is correlated with the acquisition and recall of opiate-related associative memories (Frenois et al., 2005), indicating a critical role for this area during opiate-related learning and memory (Fuchs and See, 2002).