Elsevier

Biological Psychiatry

Volume 61, Issue 8, 15 April 2007, Pages 979-989
Biological Psychiatry

Original article
Distinct Patterns of Neural Activation Associated with Ethanol Seeking: Effects of Naltrexone

https://doi.org/10.1016/j.biopsych.2006.07.034Get rights and content

Background

Alcoholism, like other substance abuse disorders, is a chronically relapsing condition. Compared with other abused drugs, however, little is known about the neural mechanisms mediating ethanol (EtOH)-craving and -seeking behavior leading to relapse. This study, therefore, was conducted to identify candidate brain regions that are recruited by an EtOH-associated contextual stimulus (S+). A secondary objective was to determine whether EtOH S+-elicited neural recruitment patterns are modified by the opiate antagonist naltrexone (NTX), a compound that reduces cue-induced craving in alcoholics and attenuates ethanol seeking in animal models of relapse.

Methods

Rats were tested in a conditioned reinstatement model of relapse with subsequent examination of brain c-fos expression patterns elicited by an EtOH S+ versus a cue associated with nonreward (S). In addition, modification of these expression patterns by NTX was examined.

Results

The EtOH S+ reinstated extinguished responding and increased c-fos expression within the prefrontal cortex, hippocampus, nucleus accumbens, and hypothalamic paraventricular nucleus (PVN). Naltrexone suppressed the S+-induced reinstatement and attenuated hippocampal CA3 c-fos expression, while increasing neural activity in the extended amygdala and PVN.

Conclusions

Ethanol-associated contextual stimuli recruit key brain regions that regulate associative learning, goal-directed behavior, and Pavlovian conditioning of emotional significance to previously neutral stimuli. In addition, the data implicate the hippocampus, amygdala, and PVN as potential substrates for the inhibitory effects of NTX on conditioned reinstatement.

Section snippets

Subjects

Male Wistar rats (Charles River, Raleigh, North Carolina) weighing 180 to 200 g on arrival were housed three per cage in a temperature and humidity controlled vivarium on a reversed 12-hour light/dark cycle (lights off 8:00 am). Training and testing were conducted daily from 12:00 pm to 3:00 pm. All procedures were carried out in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by The Scripps Research Institute Institutional Animal Care and Use

Ethanol Self-Administration, Conditioning, and Extinction

All rats acquired responding reinforced by 10% ethanol and developed stable ethanol self-administration during the conditioning phase. The mean (± SEM) number of responses averaged across the three final sessions was 26 ± 3 during ethanol and 7 ± 1 during nonreward sessions (Figure 2A). Rats emitted 16 ± 2 responses during the first extinction session. All rats reached the extinction criterion within 10 days.

Behavioral Effects of Ethanol Cue Exposure and Modification by Naltrexone

Rats exposed to the ethanol S+ and pretreated with vehicle or NTX (S+/VEH) showed

Discussion

Confirming earlier findings (Ciccocioppo et al 2002, Ciccocioppo et al 2003, Katner and Weiss 1999, Liu and Weiss 2002), an olfactory stimulus (S+) conditioned to ethanol reward, but not a cue associated with nonreward (S), elicited recovery of responding at a previously ethanol-paired lever. Exposure to the ethanol S+ and ensuing ethanol-seeking behavior was associated with activation of the Pre-L, Infra-L, and AC mPFC divisions; the NAC; and dorsal HIPPO, indicating that major components of

Conclusions

Ethanol-associated contextual stimuli elicit specific recruitment patterns within the mPFC, NAC, and HIPPO in rats similar to those produced by other abused drugs, as well as brain activation patterns evoked by ethanol cues in alcoholics (Grusser et al 2004, Maas et al 1998, Myrick et al 2004). The findings also reveal that the effects of the “anticraving” agent NTX on this recruitment profile are complex. While it must be taken into account that c-fos expression is not a comprehensive marker

References (90)

  • H.C. Fox et al.

    Frequency of recent cocaine and alcohol use affects drug craving and associated responses to stress and drug-related cues

    Psychoneuroendocrinology

    (2005)
  • R.J. Frysztak et al.

    The effect of medial frontal cortex lesions on cardiovascular conditioned emotional responses in the rat

    Brain Res

    (1994)
  • R.A. Fuchs et al.

    Effects of excitotoxic lesions of the basolateral amygdala on cocaine-seeking behavior and cocaine conditioned place preference in rats

    Brain Res

    (2002)
  • P.C. Holland et al.

    Hippocampus and context in classical conditioning

    Curr Opin Neurobiol

    (1999)
  • R.C. Honey et al.

    Associative components of recognition memory

    Curr Opin Neurobiol

    (2000)
  • C.G. Jang et al.

    Impaired water maze learning performance in mu-opioid receptor knockout mice

    Brain Res Mol Brain Res

    (2003)
  • J.N. Kew et al.

    Differential regulation of synaptic transmission by mGlu2 and mGlu3 at the perforant path inputs to the dentate gyrus and CA1 revealed in mGlu2 -/- mice

    Neuropharmacology

    (2002)
  • F. Kiefer et al.

    Hypothalamic-pituitary-adrenocortical axis activity: A target of pharmacological anticraving treatment?

    Biol Psychiatry

    (2006)
  • J. Kilbride et al.

    Presynaptic inhibitory action of the group II metabotropic glutamate receptor agonists, LY354740 and DCG-IV

    Eur J Pharmacol

    (1998)
  • K.J. Kovacs

    c-Fos as a transcription factor: A stressful (re)view from a functional map

    Neurochem Int

    (1998)
  • P.A. Lipton et al.

    Crossmodal associative memory representations in rodent orbitofrontal cortex

    Neuron

    (1999)
  • M.E. McCaul et al.

    Naltrexone dampens ethanol-induced cardiovascular and hypothalamic-pituitary-adrenal axis activation

    Neuropsychopharmacology

    (2001)
  • L.M. Oswald et al.

    Opioids and alcoholism

    Physiol Behav

    (2004)
  • T.H. Park et al.

    Neuroanatomical patterns of fos-like immunoreactivity induced by a palatable meal and meal-paired environment in saline- and naltrexone-treated rats

    Brain Res

    (1998)
  • W.E. Pratt et al.

    Neurons in rat medial prefrontal cortex show anticipatory rate changes to predictable differential rewards in a spatial memory task

    Behav Brain Res

    (2001)
  • B.E. Schroeder et al.

    A common profile of prefrontal cortical activation following exposure to nicotine- or chocolate-associated contextual cues

    Neuroscience

    (2001)
  • R.E. See et al.

    Muscarinic receptor antagonism in the basolateral amygdala blocks acquisition of cocaine-stimulus association in a model of relapse to cocaine-seeking behavior in rats

    Neuroscience

    (2003)
  • M.L. Simmons et al.

    Endogenous opioid regulation of hippocampal function

    Int Rev Neurobiol

    (1996)
  • K.M. Stormark et al.

    Autonomic cued reactivity in alcoholics: The effect of olfactory stimuli

    Addict Behav

    (1995)
  • A.N. Topple et al.

    Possible neural substrates of beer-craving in rats

    Neurosci Lett

    (1998)
  • F. Weiss

    Neurobiology of craving conditioned reward and relapse

    Curr Opin Pharmacol

    (2005)
  • B. Adinoff et al.

    Suppression of the HPA axis stress-response: Implications for relapse

    Alcohol Clin Exp Res

    (2005)
  • B. Adinoff et al.

    Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-month-abstinent alcohol-dependent men, part 1: Adrenocortical and pituitary glucocorticoid responsiveness

    Alcohol Clin Exp Res

    (2005)
  • B. Adinoff et al.

    Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-month-abstinent alcohol-dependent men, part 2: Response to ovine corticotropin-releasing factor and naloxone

    Alcohol Clin Exp Res

    (2005)
  • C.R. Bramham et al.

    Endogenous activation of mu and delta-1 opioid receptors is required for long-term potentiation induction in the lateral perforant path: Dependence on GABAergic inhibition

    J Neurosci

    (1996)
  • E.E. Brown et al.

    Evidence for conditional neuronal activation following exposure to a cocaine-paired environment: Role of forebrain limbic structures

    J Neurosci

    (1992)
  • K.M. Buller et al.

    Indomethacin attenuates oxytocin and hypothalamic-pituitary-adrenal axis responses to systemic interleukin-1 beta

    J Neuroendocrinol

    (1998)
  • A.R. Childress et al.

    Limbic activation during cue-induced cocaine craving

    Am J Psychiatry

    (1999)
  • R. Ciccocioppo et al.

    Reinstatement of ethanol-seeking behavior by drug cues following single versus multiple ethanol intoxication in the rat: Effects of naltrexone

    Psychopharmacology (Berl)

    (2003)
  • R. Ciccocioppo et al.

    Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: Reversal by D(1) antagonists

    Proc Natl Acad Sci U S A

    (2001)
  • C.V. Dayas et al.

    Neuroendocrine responses to an emotional stressor: Evidence for involvement of the medial but not the central amygdala

    Eur J Neurosci

    (1999)
  • C.V. Dayas et al.

    Chronic footshock, but not a physiological stressor, suppresses the alcohol deprivation effect in dependent rats

    Alcohol Alcohol

    (2004)
  • P. Di Ciano et al.

    Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats

    J Neurosci

    (2004)
  • B.J. Everitt et al.

    Psychomotor stimulant addiction: A neural systems perspective

    J Neurosci

    (2002)
  • K.L. Foster et al.

    GABA(A) and opioid receptors of the central nucleus of the amygdala selectively regulate ethanol-maintained behaviors

    Neuropsychopharmacology

    (2004)
  • Cited by (125)

    • Prefrontal Cortical (PFC) circuits

      2022, Neurocircuitry of Addiction
    • Hippocampal circuits

      2022, Neurocircuitry of Addiction
    • Motivational competition and the paraventricular thalamus

      2021, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      PVT neurons express a variety of receptors including for corticotropin-releasing hormone, opioids, dopamine, neuropeptide S, VIP, and cannabinoid, among others (Colavito et al., 2015; Kirouac, 2015). PVT has been implicated in a diverse range of functions including arousal (Colavito et al., 2015), stress (Bhatnagar, 2003; Bhatnagar and Dallman, 1999; Bhatnagar et al., 2002; Hsu et al., 2014), fear (Beas et al., 2018; Do-Monte et al., 2015; Penzo et al., 2015; Zhu et al., 2018), appetitive learning (Otis et al., 2017, 2019; Zhu et al., 2018), incentive salience (Campus et al., 2019; Haight and Flagel, 2014; Haight et al., 2015, 2017), relapse to drug seeking (Dayas et al., 2007, 2008; Hamlin et al., 2009; James et al., 2011, 2010; James and Dayas, 2013; Marchant et al., 2010; Martin-Fardon and Boutrel, 2012; Matzeu et al., 2017, 2015), opiate withdrawal (Zhu et al., 2016), drinking and feeding (Barson et al., 2015; Ong et al., 2017). We suggest that PVT is implicated in these diverse functions because they each have in common the need for bistable selection as they involve competing motivational demands on the animal and PVT is a key component of the circuitry for this selection.

    View all citing articles on Scopus
    View full text