Elsevier

Neuroscience

Volume 115, Issue 4, 16 December 2002, Pages 999-1007
Neuroscience

Genetic susceptibility of mesocortical dopamine to stress determines liability to inhibition of mesoaccumbens dopamine and to behavioral ‘despair’ in a mouse model of depression

https://doi.org/10.1016/S0306-4522(02)00581-XGet rights and content

Abstract

Clinical and preclinical research suggests a major role of mesocortical dopamine (DA) in psychopathology through regulation of subcortical, especially mesoaccumbens, DA functioning. In these experiments we demonstrate that the high vulnerability to stress-induced ‘despair’ and mesoaccumbens DA inhibition, exhibited by mice of the inbred strain C57BL/6 (C57) in a common animal model of depression, depends on their being highly susceptible to stress-induced mesocortical DA activation. Thus, C57 mice but not mice of the DBA/2 strain showed an extremely high level of immobility on their first experience with the forced swimming test (FST) as well as immediate and strong activation of mesocortical DA metabolism and inhibition of mesoaccumbens DA metabolism and release. In addition, the behavioral and the mesoaccumbens DA responses to FST in C57 mice were reduced and reversed, respectively, by bilateral mesocortical DA depletion. Finally, chronic treatment with the antidepressant clomipramine reduced immobility and eliminated both mesocortical DA activation and mesoaccumbens DA inhibition in response to FST.

These results suggest that a genetically determined susceptibility to stress by the mesocortical DA system may favor the development of pathological behavioral responses through inhibition of subcortical DA transmission.

Section snippets

Animals

Male mice of the inbred C57BL/6JIco (C57) and DBA/2JIco (DBA) strains (Charles River, Como, Italy) were used for these experiments. All mice were purchased at 6 weeks of age. Upon their arrival, animals were housed in groups of four per standard breeding cage (27×21×13.5 cm) with food and water ad libitum on a 12-h dark–light cycle (light on between 7.00 and 19.00 h). Experiments started when animals reached 8 weeks of age and were carried out in a room separated from the colony room. All the

Genotype-dependent effects of FST on immobility and on brain DA metabolism and release

C57 mice displayed significantly higher levels of immobility than DBA mice over the 10-min test. Indeed, two-way ANOVA for repeated measures revealed significant main effects of the factors strain and time (strain: F(1,39)=23.2; P<0.0005; time: F(3,39)=20.9; P<0.0005) but no significant interaction between factors. However, strain comparison at each time point revealed a significant difference only for the first two points (2.5 and 5 min), which was statistically higher for the first one (2.5

Mice from the C57 and DBA inbred strains show different behavioral and opposite mesocorticolimbic DA responses to FST

The present experiments were aimed at assessing the hypothesis that genetic susceptibility to stress-induced mesocortical DA activation determines liability to experimental ‘despair’ through mesoaccumbens DA inhibition.

The results showed that C57 mice were more immobile than DBA mice during the whole 10-min test. Moreover, although both strains showed a time-dependent increase in immobility, during the first 2.5 min of the test this response was already substantial in the C57 strain of mice but

Overall conclusions

The results obtained demonstrate a genotype-dependent susceptibility to ‘despair’ in the FST that depends on mesocortical DA hyperresponsivity to stress, through inhibitory control of the mesoaccumbens DA. This conclusion is strongly supported by three lines of evidence: (1) mice of the C57 inbred strain are highly susceptible to FST-induced ‘despair’, activation of mesocortical DA metabolism and inhibition of mesoaccumbens DA release; (2) a bilateral depletion of mesocortical DA is capable of

Acknowledgements

Preliminary results were included in a review presented at the electronic symposium ‘Dopamine Hypothesis of ADHD: Hypo, Hyper or Both?’ (http://www.ucls.es/inabis2000/symposia). This research has been supported by the Ministero della Ricerca Scientifica e Tecnologica (COFIN 1999–2000), Consiglio Nazionale delle Ricerche (1999) and Ateneo 60% (1998–1999).

References (48)

  • E.F. Espejo et al.

    Prefrontocortical dopamine depletion induces antidepressant-like effects in rats and alters the profile of desipramine during Porsolt’s test

    Neuroscience

    (1999)
  • M.C. Garrett et al.

    Role of type A and B monoamine oxidase on the formation of 3,4-dihydroxyphenylacetic acid (DOPAC) in tissues from the brain of the rat

    Neuropharmacology

    (1990)
  • A. Imperato et al.

    Repeated stressful experiences differently affect the time-dependent responses of the mesolimbic dopamine system to stress

    Brain Res.

    (1993)
  • D. King et al.

    Effects of dopamine depletion in the medial prefrontal cortex on the stress-induced increase in extracellular dopamine in the nucleus accumbens core and shell

    Neuroscience

    (1997)
  • M. Kurachi et al.

    Hypofrontality does not occur with 6-hydroxydopamine lesions of the medial prefrontal cortex in rat brain

    Eur. Neuropsychopharmacol.

    (1995)
  • S. Puglisi-Allegra et al.

    Acute stress induces time-dependent responses in dopamine mesolimbic system

    Brain Res.

    (1991)
  • P.V. Rada et al.

    Dopamine release in the nucleus accumbens by hypothalamic stimulation-escape behavior

    Brain Res.

    (1998)
  • Z.L. Rossetti et al.

    Depletion of mesolimbic dopamine during behavioral despair: partial reversal by chronic imipramine

    Eur. J. Pharmacol.

    (1993)
  • B.A. Sorg et al.

    Effects of cocaine and footshock stress on extracellular dopamine levels in the medial prefrontal cortex

    Neuroscience

    (1993)
  • R. Ventura et al.

    Opposite genotype-dependent mesocorticolimbic dopamine response to stress

    Neuroscience

    (2001)
  • B.H.C. Westerink

    Sequence and significance of dopamine metabolism in the rat brain

    Neurochem. Int.

    (1985)
  • P.L. Wood et al.

    Striatal 3-methoxytyramine as an index of dopamine release: effects of electrical stimulation

    Neurosci. Lett.

    (1982)
  • R.M. Zacharko et al.

    Stressor-induced anhedonia and the mesocorticolimbic system

    Neurosci. Biobehav. Rev.

    (1991)
  • E.D. Abercrombie et al.

    Differential effects of stress on in vivo dopamine release in striatum, nucleus accumbens and medial frontal cortex

    J. Neurochem.

    (1989)
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