Elsevier

Brain Research

Volume 991, Issues 1–2, 21 November 2003, Pages 232-239
Brain Research

Research report
Prolonged effects of repeated cocaine on medial prefrontal cortex dopamine response to cocaine and a stressful predatory odor challenge in rats

https://doi.org/10.1016/j.brainres.2003.03.001Get rights and content

Abstract

The present study examined the effects of seven daily saline (1 ml/kg, ip) or cocaine injections (15 mg/kg, ip) on extracellular dopamine levels in the medial prefrontal cortex (mPFC) after challenge with cocaine or stressful predatory odor presentation given 1 week (early withdrawal) or 3 weeks later (late withdrawal). Cocaine challenge at early withdrawal produced an increase in dopamine levels that was temporally shifted so that maximal levels of dopamine were significantly higher and attained 20 min earlier in the cocaine-pretreated group (maximal levels of saline controls=378% increase, cocaine=494% increase above baseline). Cocaine challenge at late withdrawal produced a similar effect on the temporal shift of maximal dopamine levels, with a significantly higher maximal percent increase of dopamine in cocaine-pretreated rats (saline-pretreated=420% increase, cocaine-pretreated=515% increase). Challenge with TMT, a predatory odor from fox that produces a stress response in rats, produced a maximal 75–200% increase in basal dopamine levels in both groups at both early and late withdrawal times. As with cocaine challenge, daily cocaine produced a leftward shift in the time at which maximal dopamine levels were attained in response to TMT. Cocaine-pretreated animals demonstrated maximal dopamine levels 40–80 min after TMT removal, while saline-pretreated rats showed maximal levels 100–140 min after TMT removal. These results suggest that there are long-term changes in the mPFC dopamine response to subsequent challenge with cocaine as well as a stressful predatory odor. The altered response of mPFC dopamine after repeated daily cocaine may impact relapse to drug-seeking or drug-taking behavior.

Introduction

Accumulating evidence indicates that the medial prefrontal cortex (mPFC) plays an important role in drug reinforcement [2], [3], [7], [15], [16], [26], [27], [28], [34], [38], [46], [56], [57], [58]. Rats self-administer cocaine directly into the mPFC [12] and lesions of the mPFC disrupt conditioned place preference to cocaine, indicating a decrease in the reinforcing properties of this drug [16], [57], [58]. Drug self-administration is closely associated with the firing of mPFC neurons [3], and repeated cocaine given non-contingently over 7 days or self-administered over a longer period produces a decrease in the percentage of mPFC neurons present in the bistable state [55]. Finally, the reinstatement phase of cocaine self-administration induced by cocaine or stress can be stimulated or blocked by manipulation of dopamine within the mPFC [26], [34], [46]. Therefore, a greater understanding of the effects of repeated cocaine administration on the mPFC dopamine response to subsequent cocaine or stress challenge may help to determine whether altered dopamine responses in this region contribute to drug craving.

Repeated exposure to psychostimulants or stress produces the phenomenon of behavioral sensitization, a progressive increase in psychostimulant-induced locomotor activity in rodents. Several laboratories have found that extracellular dopamine levels in the nucleus accumbens are enhanced in rats exhibiting behavioral sensitization, and the increase is believed to partially contribute to the sensitized locomotor response [19], [37], [49], [59]. Several studies have demonstrated that the mPFC is also involved in the sensitization phenomenon [25], [40], [41], [52]. We have previously reported that daily cocaine or stress suppresses the mPFC dopamine elevation in response to subsequent cocaine injection [50], [51]. This tolerance has also been reported by Chefer et al. [4] after a 5-day injection procedure followed by a 3-day withdrawal. These investigators demonstrated a significant increase in basal dopamine levels, resulting in a decrease in the percent increase in dopamine after cocaine challenge. The present study employed a 7-day treatment of cocaine or stress rather than a 5-day regimen, because we believed it might produce a more enduring effect on neurochemical changes, as established for dopamine in the nucleus accumbens [39]. No studies to date have reported the long-term effects of repeated cocaine treatments on mPFC extracellular dopamine levels. Consequently, we measured the effects of repeated cocaine on the mPFC dopamine response to a cocaine challenge 3 weeks later.

We also explored the mPFC extracellular dopamine response to a stressful odor challenge using the predatory odor, 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), which is the primary ingredient in fox odor. Exposure of rats to TMT has been shown to produce increases in the stress hormone, corticosterone, increases in dopamine turnover in the mPFC, and increases in c-Fos expression in ventral tegmental area (VTA), but not substantia nigra dopamine neurons [31], [32], [43]. Given that stress produces reinstatement of cocaine-seeking behavior [1], [9], [45], [46], [47] and that manipulation of dopamine D1 and/or D2 receptor activation alters reinstatement by stress or cocaine [26], [34], [46], it was of great interest to assess whether dopamine levels were altered in the mPFC in response to a stressful odor. The overall goal of these studies was to determine the short- and long-term effects of 7 days of repeated cocaine on the mPFC dopamine response to subsequent cocaine or aversive odor challenge.

Section snippets

Chemicals

TMT was purchased from Phero Tech (Delta, BC, Canada). Cocaine hydrochloride, dopamine, octane sulfonic acid and citric acid were purchased from Sigma (St. Louis, MO, USA). Disodium-EDTA and acetonitrile were from J.T. Baker (Phillipsburg, NJ, USA).

Animal housing and surgery

Experiments were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23, 1996), and experimental protocols were approved by the University Animal Care and Use Committee.

Results

Basal dopamine levels were not different between daily saline and cocaine-pretreated rats; the mean±S.E.M. for all saline-pretreated rats was 8.17±0.42 fmol/20 min sample and for cocaine-pretreated rats was 8.02±0.48 fmol/20 min sample (p=0.82).

Discussion

The results from these studies demonstrate that a sensitizing treatment regimen of seven daily cocaine injections (15 mg/kg, ip) produced temporal shifts in cocaine- and predatory odor-induced elevations in mPFC dopamine levels. When both cocaine and TMT were used as challenge agents, maximal dopamine levels were attained 20–60 min earlier in daily cocaine-pretreated rats compared with daily saline-pretreated controls at both the 1- and 3-week withdrawal times. Moreover, cocaine challenge

Acknowledgements

The authors wish to thank Ms. Jenny Baylon for assistance with the manuscript. This work was supported by NIH Grant DA 11787.

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