Elsevier

Neuroscience

Volume 134, Issue 4, 2005, Pages 1391-1397
Neuroscience

Neuropharmacology
Amygdalar vasopressin mRNA increases in acute cocaine withdrawal: Evidence for opioid receptor modulation

https://doi.org/10.1016/j.neuroscience.2005.05.032Get rights and content

Abstract

In humans, stress is recognized as a major factor contributing to relapse to drug abuse in abstinent individuals; drugs of abuse themselves or withdrawal from such drugs act as stressors. In the animals, evidence suggests that centrally released arginine vasopressin in both amygdala and hypothalamus plays an important role in stress-related anxiogenic behaviors. The stress responsive hypothalamic–pituitary–adrenal axis is under tonic inhibition via endogenous opioids, and cocaine withdrawal stimulates hypothalamic–pituitary–adrenal activity. The present studies were undertaken to determine whether: (1) 14-day (chronic) “binge” pattern cocaine administration (45mg/kg/day) or its withdrawal for 3 h (acute), 1 day (subacute) or 10 days (chronic) alters arginine vasopressin mRNA levels in amygdala or hypothalamus; (2) the opioid receptor antagonist naloxone (1mg/kg) alters arginine vasopressin mRNA or hypothalamic–pituitary–adrenal hormonal responses in acute cocaine withdrawal; and (3) there are associated changes of mu opioid receptor or proopiomelanocortin mRNA levels. In amygdala, arginine vasopressin mRNA levels were unchanged after chronic “binge” cocaine, but were increased during acute cocaine withdrawal. Naloxone completely blocked this increase. Neither chronic cocaine nor its acute withdrawal altered amygdalar mu opioid receptor mRNA levels. The increase in amygdalar arginine vasopressin mRNA levels was still observed after subacute withdrawal, but not after chronic withdrawal. Although hypothalamic–pituitary–adrenal tolerance developed with chronic “binge” cocaine, there were modestly elevated plasma adrenocorticotropin hormone levels during acute withdrawal. While naloxone produced modest adrenocorticotropin hormone elevations in cocaine-naïve rats, naloxone failed to elicit an adrenocorticotropin hormone response in cocaine-withdrawn rats. In hypothalamus, neither chronic cocaine nor acute withdrawal altered arginine vasopressin, proopiomelanocortin or mu opioid receptor mRNA levels. These results show that: (1) opioid receptors mediate increased amygdalar arginine vasopressin gene expression during acute cocaine withdrawal, and (2) cocaine withdrawal renders the hypothalamic–pituitary–adrenal axis insensitive to naloxone. Our findings suggest a potential role for amygdalar arginine vasopressin in the aversive consequences of early cocaine withdrawal.

Section snippets

Experimental procedures

Male Fischer rats (190–220g, Charles River Laboratories, Kingston, NY, USA) were housed individually in a stress-minimized facility with free access to food and water. Animals were adapted to a standard 12-h light/dark cycle (lights on from 10:30 h to 22:30 h) for 7 days, and then received i.p. injections of cocaine (3×15mg/kg) or equal volumes of saline for 14 days in their home cages following the “binge” pattern regimen: three times daily at 1 h intervals (11:00, 12:00 and 13:00 h) (Branch

Amygdala

In the chronic cocaine experiment, neither chronic “binge” cocaine administration nor naloxone challenge altered AVP mRNA levels (Fig. 1). In the cocaine withdrawal experiment, two-way ANOVA showed a significant Cocaine×Naloxone interaction (F(1,27)=5.49, P<0.05) (Fig. 1). Acute withdrawal led to a significant increase in AVP mRNA levels (Newman-Keuls post hoc test, P<0.05). When the rats were treated with naloxone during acute withdrawal, the AVP mRNA increase was significantly attenuated (P

Discussion

We found that AVP mRNA levels in the amygdala were not altered after chronic “binge” cocaine. However, acute cocaine withdrawal was associated with increased amygdalar AVP mRNA levels, nearly three-fold that of the control level (Fig. 1). Also, this effect occurred at acute withdrawal stage (3 h), persisted for 1 day into subacute cocaine withdrawal, but not for 10 days of chronic withdrawal (Fig. 3). This novel finding parallels our recent studies demonstrating an increased AVP mRNA level in

Conclusion

The present studies determined the effects of chronic “binge” cocaine and its acute withdrawal on stress responsive AVP gene expression. We found that acute cocaine withdrawal resulted in a significant increase in amygdalar AVP mRNA levels. Of interest, amygdalar AVP gene expression stimulated by acute cocaine withdrawal was completely blocked by a single, moderate dose of naloxone, indicating an opioid receptor activation-mediated mechanism. In line with this finding, we have recently found an

Acknowledgments

The authors would like to thank Dr. G. Aguilera for providing the V1b receptor cDNAs; Dr. G. Uhl for the MOP-r cDNA; Dr. J. Roberts for the POMC cDNA; and Drs. T. Nilsen and P. Maroney for the 18S DNA. The work was supported by NIDA Research Center Grant DA-P60-05130 and DA-00049 (M.J.K.), and by NIH Training Grant GM07524 (J.T.B.).

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