Elsevier

Neuroscience

Volume 206, 29 March 2012, Pages 155-166
Neuroscience

Cognitive, Behavioral, and Systems Neuroscience
Research Paper
Corticotropin-releasing factor in the nucleus accumbens shell induces swim depression, anxiety, and anhedonia along with changes in local dopamine/acetylcholine balance

https://doi.org/10.1016/j.neuroscience.2011.12.009Get rights and content

Abstract

The nucleus accumbens shell (NAcS) has been implicated in controlling stress responses through corticotropin-releasing factor (CRF). In addition to studies indicating that CRF in the NAcS increases appetitive motivation, there is indirect evidence suggesting that NAcS CRF may also cause aversive responses and that these behaviors may be mediated through local dopamine (DA) and acetylcholine (ACh) systems. To provide a direct test of this hypothesis, we used male Sprague–Dawley rats with implanted cannulas aimed at the NAcS. Experiment 1 showed local CRF injection (10 or 50 ng/side) to increase immobility in the forced swim test and a CRF antagonist D-Phe-CRF (12-41) to attenuate this depressive-like behavior. In Experiment 2, injection of CRF (250 ng/side) also decreased the rats' preference for sucrose, while in Experiment 3, CRF (50 or 250 ng/side) induced anxiety-like behaviors in an elevated plus maze and open field. These same doses of CRF in Experiment 4 failed to alter the rats' locomotor activity, indicating that these behavioral changes were not caused by deficits in activity. In Experiment 5, results from in vivo microdialysis revealed that CRF in the NAcS markedly increased local extracellular ACh, while also producing a small increase in DA. These results show that NAcS CRF can generate a variety of aversive behaviors, including swim depression, anhedonia, and anxiety, in addition to approach behavior. They suggest that these behaviors may occur, in part, through enhanced activation of ACh and DA in the NAcS, respectively, supporting a role for this brain area in mediating the dual effects of stress.

Highlights

▶CRF in the NAcS produces swim depression, anhedonia, and anxiety-like behaviors. ▶NAcS CRF markedly increases ACh, which may contribute to these aversive behaviors. ▶NAcS CRF induces an increase in DA that may be related to appetitive behaviors. ▶NAcS CRF may therefore mediate the dual effects of stress through local ACh and DA.

Section snippets

Subjects and surgery

Male Sprague–Dawley rats (225–350 g, Taconic Farms, Germantown, NY, USA) were individually housed on a reversed 12:12-h light–dark cycle and had ad libitum access to food and water. All tests were conducted between 9:00 and 15:30. Subjects were anesthetized using ketamine (Fort Dodge Animal Health; Overland Park, KS, USA) (80 mg/kg, i.p.) and xylazine (LLOYD Incorporated; Shenandoah, IA, USA) (10 mg/kg, i.p.), supplemented with ketamine when necessary. Stainless steel 21-gauge guide shafts (10

Experiment 1: CRF in the NAcS increases immobility in the forced swim test, while a CRF antagonist blocks CRF-induced swim depression

Histological examination revealed that the injections in each of the experiments were made directly into the shell of the NAc, as illustrated in Fig. 1A. To test the hypothesis that CRF acts in this area to induce depressive-like immobility, rats (n=7–11/group) were given an injection of CRF (10 or 50 ng/side) or vehicle, and their performance in the forced swim test was assessed. As compared with vehicle injection, CRF at both doses in the NAcS significantly increased immobility and decreased

Discussion

The current study assessed the role of extracellular CRF activation in the NAcS, with emphasis placed first on characterizing various behavioral responses induced by CRF and then on determining local neurochemical changes induced by this peptide. Our major findings were that CRF activation in the NAcS: (1) induces depressive-like behaviors such as swim depression and an anhedonic state; (2) elicits anxiety-like behaviors in an elevated plus maze and an open field; and (3) produces a marked and

Conclusions

The results of this study show that activation of the NAcS CRF system produces a variety of aversive emotional responses that occur in association with changes in the local ACh and DA balance. Although a causal relationship has yet to be established, these findings raise the possibility that the aversive behaviors induced by NAcS CRF may be mediated, in part, by changes in ACh and DA, with the ACh aversion system more significantly and persistently activated. They also suggest that the NAcS

Acknowledgments

This research is supported by the E. H. Lane Foundation. We thank Dr. Jean Rivier (The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, San Diego, CA) for kindly providing the D-Phe-CRF (12–41). We also thank Dr. Jessica Barson (The Rockefeller University, NY) for her assistance in preparing this manuscript.

References (77)

  • G.F. Koob

    The role of CRF and CRF-related peptides in the dark side of addiction

    Brain Res

    (2010)
  • M.M. Lim et al.

    CRF receptors in the nucleus accumbens modulate partner preference in prairie voles

    Horm Behav

    (2007)
  • G.P. Mark et al.

    Extracellular acetylcholine is increased in the nucleus accumbens following the presentation of an aversively conditioned taste stimulus

    Brain Res

    (1995)
  • G. Martinez et al.

    Effects of selective NMDA and non-NMDA blockade in the nucleus accumbens on the plus-maze test

    Physiol Behav

    (2002)
  • I. Merchenthaler

    Corticotropin releasing factor (CRF)-like immunoreactivity in the rat central nervous systemExtrahypothalamic distribution

    Peptides

    (1984)
  • J.C. Mifsud et al.

    Nicotine infused into the nucleus accumbens increases synaptic dopamine as measured by in vivo microdialysis

    Brain Res

    (1989)
  • G.J. Mogenson et al.

    From motivation to action: functional interface between the limbic system and the motor system

    Prog Neurobiol

    (1980)
  • C.M. Pennartz et al.

    The nucleus accumbens as a complex of functionally distinct neuronal ensembles: an integration of behavioural, electrophysiological and anatomical data

    Prog Neurobiol

    (1994)
  • R.J. Primus et al.

    Autoradiographic localization of CRF1 and CRF2 binding sites in adult rat brain

    Neuropsychopharmacology

    (1997)
  • P. Rada et al.

    Microdialysis evidence that acetylcholine in the nucleus accumbens is involved in morphine withdrawal and its treatment with clonidine

    Brain Res

    (1991)
  • P.V. Rada et al.

    Morphine and naloxone, i.p. or locally, affect extracellular acetylcholine in the accumbens and prefrontal cortex

    Pharmacol Biochem Behav

    (1996)
  • A.C. Riegel et al.

    CRF facilitates calcium release from intracellular stores in midbrain dopamine neurons

    Neuron

    (2008)
  • M. Sauvage et al.

    Detection of corticotropin-releasing hormone receptor 1 immunoreactivity in cholinergic, dopaminergic and noradrenergic neurons of the murine basal forebrain and brainstem nuclei—potential implication for arousal and attention

    Neuroscience

    (2001)
  • Y. Shaham et al.

    Stress-induced relapse to heroin and cocaine seeking in rats: a review

    Brain Res Brain Res Rev

    (2000)
  • J.D. Shepard et al.

    Strain differences in anxiety-like behavior: association with corticotropin-releasing factor

    Behav Brain Res

    (2008)
  • A. Skorzewska et al.

    The effect of CRF and alpha-helical CRF(9–41) on rat fear responses and amino acids release in the central nucleus of the amygdala

    Neuropharmacology

    (2009)
  • M.G. Spina et al.

    Behavioral effects of central administration of the novel CRF antagonist astressin in rats

    Neuropsychopharmacology

    (2000)
  • T. Steckler et al.

    Corticotropin-releasing hormone receptor subtypes and emotion

    Biol Psychiatry

    (1999)
  • V. Sturm et al.

    The nucleus accumbens: a target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders

    J Chem Neuroanat

    (2003)
  • A.H. Swiergiel et al.

    Effects of chronic footshock, restraint and corticotropin-releasing factor on freezing, ultrasonic vocalization and forced swim behavior in rats

    Behav Brain Res

    (2007)
  • L.K. Takahashi

    Role of CRF(1) and CRF(2) receptors in fear and anxiety

    Neurosci Biobehav Rev

    (2001)
  • K.M. Taylor et al.

    Conditioned taste aversion from neostigmine or methyl-naloxonium in the nucleus accumbens

    Physiol Behav

    (2011)
  • R.J. Valentino et al.

    Corticotropin-releasing factor in the dorsal raphe nucleus: linking stress coping and addiction

    Brain Res

    (2010)
  • X.M. Yang et al.

    Central beta 1-adrenergic receptors are involved in CRF-induced defensive withdrawal

    Pharmacol Biochem Behav

    (1990)
  • M.R. Zarrindast et al.

    Involvement of opioidergic system of the ventral hippocampus, the nucleus accumbens or the central amygdala in anxiety-related behavior

    Life Sci

    (2008)
  • M. Amargos-Bosch et al.

    Stimulation of alpha1-adrenoceptors in the rat medial prefrontal cortex increases the local in vivo 5-hydroxytryptamine release: reversal by antipsychotic drugs

    J Neurochem

    (2003)
  • Diagnostic and statistical manual of mental disorders: DSM-IV-TR

    (2000)
  • M. Barrot et al.

    CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli

    Proc Natl Acad Sci U S A

    (2002)
  • Cited by (0)

    View full text