The Y2 receptor agonist PYY(3-36) increases the behavioural response to novelty and acute dopaminergic drug challenge in mice.

The gastrointestinal hormone PYY(3-36) is a preferential Y2 neuropeptide Y (NPY) receptor agonist. Recent evidence indicates that PYY(3-36) acts on central dopaminergic pathways, but its influence on dopamine-dependent behaviours remains largely unknown. We therefore explored the effects of peripheral PYY(3-36) treatment on the behavioural responses to novelty and to dopamine-activating drugs in mice. In addition, we examined whether PYY(3-36) administration may activate distinct dopamine and γ-aminobutyric acid (GABA) cell populations in the mesoaccumbal and nigrostriatal pathways. We found that i.p. PYY(3-36) injection led to a dose-dependent increase in novel object exploration. The effective dose of PYY(3-36) (1 μg/100 g body weight) also potentiated the locomotor reaction to the indirect dopamine receptor agonist amphetamine and increased stereotyped climbing/leaning responses following administration of the direct dopamine receptor agonist apomorphine. PYY(3-36) administration did not affect activity of midbrain dopaminergic cells as evaluated by double immuno-enzyme staining of the neuronal early gene product c-Fos with tyrosine hydroxylase. PYY(3-36) did, however, lead to a marked increase in the number of cells co-expressing c-Fos with glutamic acid decarboxylase in the nucleus accumbens and caudate putamen, indicating activation of GABAergic cells in dorsal and ventral striatal areas. Our results support the hypothesis that acute administration of the preferential Y2 receptor agonist PYY(3-36) modulates dopamine-dependent behaviours. These effects do not seem to involve direct activation of midbrain dopamine cells but instead are associated with neuronal activation in the major input areas of the mesoaccumbal and nigrostriatal pathways.