Genetic susceptibility of mesocortical dopamine to stress determines liability to inhibition of mesoaccumbens dopamine and to behavioral ‘despair’ in a mouse model of depression
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).
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2017, Neuroscience and Biobehavioral ReviewsCitation Excerpt :The direction of this imbalance depends on complex gene by environment interactions (Cabib et al., 2002; Cabib and Puglisi-Allegra, 1996; Ventura et al., 2002, 2001). An imbalance that favours the pre-frontal dopamine release has been linked to a depressive phenotype (helplessness, anhedonia) and a decreased sensitivity to stereotypy-inducing drugs; such imbalance can be restored by anti-depressant drugs (Karler et al., 1998; McFarland and Kalivas, 2001; Prasad et al., 1999; Ventura et al., 2002). An imbalance that favours the nucleus accumbens dopamine release is related to escape attempts, an increased sensitivity to stereotypy-inducing drugs and an increase of spontaneous stereotypies in the home cage (Alcaro et al., 2002; Cabib et al., 2002; Cabib and Bonaventura, 1997; Ventura et al., 2002).