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Contribution of limbic norepinephrine to cannabinoid-induced aversion

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Abstract

Rationale

The cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gaging their actions within the central nervous system that may contribute to the expression of unwanted side effects.

Objectives

In the present study, we investigated whether norepinephrine (NE) in the limbic forebrain is a critical determinant of cannabinoid receptor agonist-induced aversion and anxiety in rats.

Methods

An immunotoxin lesion approach was combined with behavioral analysis using a place conditioning paradigm and the elevated zero maze.

Results

Our results show that the non-selective CB1/CB2 receptor agonist, WIN 55,212-2, produced a significant place aversion in rats. Further, NE in the nucleus accumbens was critical for WIN 55,212-2-induced aversion but did not affect anxiety-like behaviors. Depletion of NE from the bed nucleus of the stria terminalis was ineffective in altering WIN 55,212-2-induced aversion and anxiety.

Conclusions

These results indicate that limbic, specifically accumbal, NE is required for cannabinoid-induced aversion but is not essential to cannabinoid-induced anxiety.

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Abbreviations

Acb:

Nucleus accumbens

ANOVARM:

Repeated measures ANOVA

BNST:

Bed nucleus of stria terminalis

BSA:

Bovine serum albumin

CB1r/CB2r:

Cannabinoid receptor type1/Cannabinoid receptor type2

CeA:

Central nucleus of amygdala

CNS:

Central nervous system

DBH:

Dopamine beta hydroxylase

DSAP:

Saporin conjugated with antibody against DBH

EZM:

Elevated zero maze

Ir:

Immunoreactivity

KOR:

Kappa opioid receptor

NE:

Norepinephrine

NTS:

Nucleus of the solitary tract

PB:

Phosphate buffer

PFC:

Prefrontal cortex

ROI:

Region of interest

SAP:

Saporin

TS:

Tris saline buffer

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Acknowledgments

This works was supported by PHS grant DA 020129. Ana Franky Carvalho was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/33236/2007).

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The authors have nothing to disclose.

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Authors and Affiliations

  1. Neuroscience, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Ana Franky Carvalho, Arith-Ruth S. Reyes & Elisabeth J. Van Bockstaele

  2. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

    Ana Franky Carvalho

  3. Department of Psychiatry and Human Behavior, Thomas Jefferson University, Philadelphia, PA, USA

    Robert C. Sterling

  4. Department of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA

    Ellen Unterwald

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  1. Ana Franky Carvalho
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  2. Arith-Ruth S. Reyes
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  3. Robert C. Sterling
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  4. Ellen Unterwald
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  5. Elisabeth J. Van Bockstaele
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Correspondence to Ana Franky Carvalho.

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Carvalho, A.F., Reyes, AR.S., Sterling, R.C. et al. Contribution of limbic norepinephrine to cannabinoid-induced aversion. Psychopharmacology 211, 479–491 (2010). https://doi.org/10.1007/s00213-010-1923-7

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