Prefrontal dopamine efflux during exposure to drug-associated contextual cues in rats with prior repeated methamphetamine
Introduction
Among mammalians, various brain areas are known for being capable of dopamine releasing as induced by drugs of abuse, and the mesocorticolimbic dopaminergic projections are widely believed to play a critical role in the incentive properties of such motivational stimuli [23], [26], [53]. It has been postulated that environmental stimuli reminiscent of previous drug reward can provoke drug craving and precipitate drug relapse in human addicts even after prolonged periods of abstinence [35], [54]. In animal models, contextual cues associated with availability of natural reward (chocolate), as well as sensory cues associated with addictive substance (cocaine or nicotine), induced specific activation (Fos expression) in the prefrontal cortical (PFC) and limbic regions of rats [6], [39]. Dopamine (DA) is implicated to be involved in the formation of associations between salient contextual stimuli and reinforcing experience [44].
Conditioned place preference (CPP) is a model widely used for assessment of cue-eliciting craving and drug reward [49]. Animals receiving substance of salient reward in one distinctive chamber of a place preference apparatus acquire associative learning of the rewarding effects of the substance with the context of the chamber. Once this association is established via classical conditioning, animals placed in the CPP apparatus spend more time in the chamber paired with previous rewarding experience.
Emerging evidence indicates that the mPFC plays an important role in drug reinforcement. PFC is involved in associative learning, as well as in conducting visuomotor conditional tasks and cue-response association [2], [55]. Rats self-administer cocaine, but not amphetamine, directly into the mPFC [13]. Lesions of the mPFC disrupt CPP to cocaine, however, they did not affect the amphetamine or morphine-induced reward as measured by CPP paradigm, indicating a substance- or pharmacology-specific action on the responsiveness of mPFC to drug reward [19], [52]. Previous repeated, intermittent exposure to psychostimulant (sensitization) can enhance subsequent appetitive conditioning or drug reward behavior, as revealed by the CPP [17], [34], [43]. In addition to behavioral responses, the DA efflux in the NAc was enhanced upon subsequent cocaine challenge after prior repeated cocaine administration [58].
Various lines of study indicate involvement of the mPFC in reward-related mechanisms [50, for review] and associative learning [2], [27]. Meanwhile, increased DA neurotransmission, especially in the nucleus accumbens (NAc), can be triggered by encounters with stimuli associated with previous rewarding experience and has been suggested to be responsible for the manifested drug reward to psychostimulants [9], [28]. However, neurochemical changes in the PFC DA level during a conditioned response to cues paired with an addictive drug have relatively been under-reported. Besides, dissociations have also been noted in pattern of neural responses between the mPFC and NAc, e.g., in DA release during classical aversive conditioning [56] or Fos activation following exposure to a cocaine-paired environment [5]. Moreover, in non-food-deprived animals, cues associated with food availability do not modify DA efflux in the nucleus accumbens, but DA is increased in the PFC. It was thus suggested that there were differences between mPFC and NAc in response to stimuli of various properties [3].
Still, the profile of DA efflux in the mPFC responding to contextual cues that were conditioned to previous psychostimulant use in the animals having prior repeated exposures to psychostimulant has not been reported. In the present study we sought to evaluate the influence of a prior sensitization state on subsequent drug reward behavior and prefrontal DA efflux when the animals were re-exposed to contextual stimuli previously paired with MA administration. CPP drug reward response and DA outflow in the mPFC were measured and compared in another two groups of rat; both undertook the same CPP protocol and microdialysis study, one with prior MA sensitizing regimens while the other without.
Section snippets
Subjects
Male Sprague–Dawley rats (140–160 g on arrival) were obtained from Experimental Animal Center of Yang-Ming University (Taipei, Taiwan). Rats were housed three-four per cage under a 12 h light–dark cycle in room temperature (22 ± 1 °C) with standard laboratory chow and water freely available. All animal use procedures were approved by the Institutional Animal Care and Use Committee (National Yang-Ming University, Taipei, Taiwan) and were performed in accordance with the provisions of the Guide for
Behavioral sensitisation
Fig. 1 shows that the LMA, after a challenge dose of MA (1 mg/kg, i.p.), as measured by total travel distance in the MA-pretreated group as compared to the saline control. The peak increases appeared during the period 30–40 min post the MA administration. A two-way ANOVA with repeated measure over time revealed significantly different profiles between these two treatments [F(1,20) = 7.555, p < 0.05]. And total travel distance was significantly increased in the MA-pretreated group, compared to the
Discussion
The present study demonstrates that the profile of DA efflux in the mPFC during exposure to contextual cues, which were associated with previous drug reinforcing experience can be altered by a pre-existing drug-sensitized state. Also, our results show that prior sensitization to MA further augments subsequent CPP response. This latter finding can supplement previous reports that reward-seeking behavior, which is triggered by environmental stimuli in expectancy or reminiscence of past rewarding
Conclusions
The present study indicates a phasic increase in the mPFC DA efflux, under a drug-free state, as triggered via expectancy or reminiscence of drug experience that is related to stimulus-reward association. Prior repeated exposures to a drug of abuse can result in sensitization of stimulus-reward associations coupled with diminished inhibitory control that normally govern motivational behavior and hence robustly enhances subsequent reward-seeking behavior provoked by stimuli presentation. The
Acknowledgements
This study is supported in part by the research grants of NSC 92-2321-B-109-002, NSC 92-2314-B-109-002, NSC 93-2314-B-109-004 from National Science Council, and a grant from Ministry of Education, Aim for the Top University Plan, Taiwan, ROC.
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2019, Neurochemistry InternationalCitation Excerpt :MA is a substrate for the DAT, and increases synaptic DA concentration through the inhibition of DA uptake as well as the induction of DA efflux (reverse transport) via the DAT (Kazahaya et al., 1989; Stephans and Yamamoto, 1995; Yamada et al., 1988). MA-induced synaptic DA release plays a pivotal role in its neuropsychotoxicity (Hamamura et al., 1991; Lin et al., 2007; O'Dell et al., 1993). It has long been recognized that there is a so-called “PKC domain” at the N-terminus of the DAT structure in which several serine residues can be phosphorylated by PKC (Foster et al., 2002; Lin et al., 2003).
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2011, Pharmacology Biochemistry and BehaviorCitation Excerpt :This would be consistent with the view that a primary function of mesotelencephalic dopamine is to modulate the vigor or frequency of behavioral activation in a given situation, and that the function of this activation is to enhance behaviors appropriate to the upcoming availability of a reinforcer or goal object (Everitt et al., 2008; Everitt and Robbins, 2005; Robbins and Everitt, 1992, 2002). Direct observations of dopaminergic activity in sensitized animals within the prefrontal cortex (Lin et al., 2007; Peleg-Raibstein and Feldon, 2008), nucleus accumbens (Afanas'ev et al., 2000; Duvauchelle et al., 2000) or amygdala (Harmer and Phillips, 1999b; Phillips et al., 2003c) confirm a greatly elevated and widespread dopaminergic response specifically to stimuli of acquired motivational significance. Alternatively, an additional mechanism termed ‘incentive salience’ may be necessary fully to account for the role of dopamine in rewarded behaviors (Berridge, 2007; Robinson and Berridge, 2003; 2008; Robinson and Flagel, 2009), and dopaminergic activation is thought to enhance ‘wanting’ of conditioned stimuli and to govern approach towards such stimuli through facilitating their ability to act as ‘motivational magnets’ (Berridge, 2001).