The serotonin 5-HT 1A receptor (5-HT 1A R) and dopamine D 2 receptor (D 2 R) have been implicated as important sites of action in antipsychotics. Several lines of evidence indicate the key role of G protein-coupled receptors (GPCRs) heteromers in pathophysiology of schizophrenia and highlight these complexes as novel drug targets. Because heterodimers can form only on those cells co-expressing constituent receptors, they present a target of high pharmacological specificity in the context of biochemical effects induced by antipsychotic drugs. In studies conducted in the HEK 293 cell line, we demonstrated that 5-HT 1A R and D 2 R are able to form constitutive heterodimers, and antipsychotic drugs (clozapine, olanzapine, aripiprazole, and lurasidone) enhanced this process, with clozapine being most effective. Various functional tests (cAMP and IP 1 as well as ERK activation) indicated that the drugs had different effects on signal transduction by the heteromer. Interestingly, co-incubation of heterodimer-expressing HEK 293 cells with clozapine and the 5-HT 1A R agonist 8-OH DPAT potentiated post-synaptic effects, especially with respect to ERK activation. Our results indicate that the D 2 -5-HT 1A complex possesses biochemical, pharmacological, and functional properties distinct from those of mono-and homomers. This result has implications for the development of improved pharmacotherapy for schizophrenia or other disorders (activating the heteromer might be cognitive enhancing, since it is expressed in frontal cortex) through the specific targeting of heterodimers.

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RationaleThe involvement of somatostatin (SST) and its receptors in the pathophysiology of depression and stress has been evidenced by numerous studies.ObjectivesThe purpose of the present study was to find whether chronic mild stress (CMS), an animal model of depression, affects the SST receptors in the rat brain and pituitary, as well as the level of SST in plasma.MethodsIn CMS model, rats were subjected to 2 weeks of stress and behaviorally characterized using the sucrose consumption test into differently reacting groups based on their response to stress, i.e., stress-reactive (anhedonic), stress-non-reactive (resilient), and invert-reactive rats (characterized by excessive sucrose intake). We measured specific binding of [125I]Tyr3-Octreotide, expression of mRNA encoding sst2R receptors in the rat brains, expression of SST and its receptors in rat pituitary, and the level of SST in the plasma.ResultsThe obtained results show decreases in binding of [125I]Tyr3-Octreotide in most of rat brain regions upon CMS and no significant differences between three stressed groups of animals, except for significant up-regulation of sst2 receptor in medial habenula (MHb) in the stress-reactive group. In the same group of animals, significant increase in plasma SST level was observed.ConclusionsThere are two particularly sensitive sites distinguishing the response to stress in CMS model. In the brain, it is MHb, while on the periphery this predictor is SST level in plasma. These changes may broaden an understanding of the mechanisms involved in the stress response and point to the intriguing role of MHb.

The data presented in this paper support the hypothesis on the role of calcium signaling regulated by the D1-D2 heteromer which may be of relevance for schizophrenia etiology.

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