Studies on neurochemical mechanisms underlying non-response to antidepressants in a rat Chronic Mild Stress model of treatment-resistant depression

In a series of our earlier studies we found that resistance to antidepressant treatment may result from structural and functional abnormalities within ventral hippocampus (vHPC), medial prefrontal cortex (mPFC) and nucleus accumbens (NA), and their connections with other structures forming so-called neuronal depression circuit [1]. Moreover, we demonstrated that resistance to antidepressant treatment in Wistar-Kyoto (WKY) rats exposed to the Chronic Mild Stress (CMS, animal model of treatment-resistant depression, TRD) may be overcome by repeated optogenetic stimulation (OGS) of afferents from vHPC to mPFC [2]. One of the structures which may also be involved in these mechanisms is habenula (Hb), which plays an important role in the regulation of mood and motivation, and in mechanisms of coping with stress and other aversive events.

In this study WKY rats were subjected to CMS and treated with chronic (4 weeks) venlafaxine (VEN, 10 mg/kg, IP) and/or repeated (once weekly) OGS of vHPC to mPFC and of mPFC to Hb pathways.

As in our previous studies, CMS was found to reduce sucrose consumption, an effect related to anhedonia. Neither venlafaxine nor OGS administered alone was effective in normalization of the behavioural deficit induced by CMS. However, the CMS-induced decrease in sucrose consumption was fully reversed when both treatments were applied together.

After completion of treatments, the animals were decapitated and brain tissue samples were collected to analyze transcripts of markers specific to the glutamatergic (Glu) and γ-aminobutyric acid (GABA) systems in the vHPC, mPFC, and Hb. In addition, synaptic density in these structures was examined by immunohistochemical determination of synapsin-1 levels. The most pronounced changes were observed in the Hb and vHPC. Regarding GABAergic function, both OGS and VEN affected Gad

1 and Gad2 transcripts in the Hb. OGS increased the levels of these mRNAs in stressed animals, whereas VEN normalized this effect to control values. In Glu transmission, an increase in vGlut2 mRNA was observed in stressed animals in the vHPC, and both OGS and VEN treatment normalized this effect to the control level. In Hb, OGS increased Gria1 mRNA that was blocked by VEN. Moreover, OGS altered synaptic density in Hb. These effects in the Hb were normalized by VEN. Thus, both OGS and VEN have an impact on GABA and Glu neurotransmissions in different brain structures, potentially restoring the stress-induced imbalance between inhibitory and excitatory signaling, especially in the Hb.

Present data support the hypothesis that resistance to antidepressant treatment may be related not only to impairment within the vHPC-PFC-NAc pathway but also to disruption in glutamatergic and GABA-ergic transmission of the LHb that could be effectively reversed by concurrent use of pharmacological and optogenetic interventions.

The study was funded by the NCN grant no. 2023/51/B/NZ7/00657.

The authors declare no direct or indirect financial interests or potential conflicts of interest.

References

1. Papp M, Gruca P, Lason M, Litwa E, Solecki W, Willner P (2021) Insufficiency of ventral hippocampus to medial prefrontal cortex transmission explains antidepressant non-response, J Psychopharm. 35, 1253-1264.
2. Papp M, Gruca P, Litwa E, Lason M, Willner P. (2023) Optogenetic stimulation of transmission from prelimbic cortex to nucleus accumbens core overcomes resistance to venlafaxine in an animal model of treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry. 123:110715.