Elsevier

Brain Research Bulletin

Volume 71, Issue 4, 9 January 2007, Pages 365-371
Brain Research Bulletin

Prefrontal dopamine efflux during exposure to drug-associated contextual cues in rats with prior repeated methamphetamine

https://doi.org/10.1016/j.brainresbull.2006.10.001Get rights and content

Abstract

Conditioned stimulus-reward response and prefrontal dopamine efflux under context previously paired with methamphetamine administration were assessed in rats with or without prior sensitizing regimen. Sensitizing pretreatment was administered with methamphetamine (1 mg/kg, every other day for six sessions) for behavioral sensitization. The animals received methamphetamine (1 mg/kg) or saline injection (each for six sessions) to pair with distinct contexts on alternate days to induce conditioned place preference. Then, dopamine outflows in the medial prefrontal cortex were analyzed on the next day via microdialysis study as animals exposed to the methamphetamine or saline-paired context, respectively. Prefrontal DA efflux increased in those rats without sensitizing pretreatment, while they occupied the methamphetamine-paired chamber. The rats with prior sensitizing regimen demonstrated more robust conditioned place preference than those without pretreatment, however, their dopamine efflux was attenuated, while remaining in methamphetamine-paired context. It is suggested that the attenuated responsiveness of mesocortical dopamine transmission in prior sensitized rats may, at least in part, be responsible for their augmented conditioned place preference, which resulted from activation of related brain areas that together strengthen the associative learning to drug-related stimuli. This paradigm may reflect a dysregulated prefrontal function in the methamphetamine abusers.

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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