Background: Mania seems to be associated with an increased dopamine (DA) transmission.
Antidepressant treatments can induce mania in humans and potentiated DA transmission in animals, by
sensitizing DA D2 receptors in the mesolimbic system. We have suggested that the sensitization of D2
receptors may be responsible of antidepressant-induced mania. This review aims to report the
experimental evidence that led to the hypothesis that antidepressant-induced DA receptors dysregulation
can be considered an animal model of bipolar disorder.
Methods: We reviewed papers reporting preclinical and clinical studies on the role of DA in the
mechanism of action of antidepressant treatments and in the patho-physiology of mood disorders.
Results: A number of preclinical and clinical evidence suggests that mania could be associated with an
increased DA activity, while a reduced function of this neurotransmission might underlie depression.
Chronic treatment with imipramine induces a sensitization of DA D2 receptors in the mesolimbic system,
followed, after drug discontinuation, by a reduced sensitivity associated with an increased immobility
time in forced swimming test of depression (FST). Blockade of glutamate NMDA receptors by
memantine administration prevents the imipramine effect on DA receptors sensitivity and on the FST.
Conclusion: We suggest that chronic treatment with antidepressants induces a behavioural syndrome that
mimics mania (the sensitization of DA receptors), followed by depression (desensitization of DA
receptors and increased immobility time in the FST), i.e. an animal model of bipolar disorder. Moreover
the observation that memantine prevents the “bipolar-like” behavior, suggests that the drug may have an
antimanic and mood stabilizing effect. Preliminary clinical observations support this hypothesis.