Dopaminergic mechanisms in memory consolidation and antidepressant reversal of a chronic mild stress-induced cognitive impairment`

Mariusz Papp,Katarzyna Tota-Glowczyk,Piotr Gruca,Ewa Litwa,Magdalena Lason-Tyburkiewicz,Monika Niemczyk,Paul Willner

doi:10.1007/s00213-017-4651-4

Mariusz Papp, Katarzyna Tota-Glowczyk + Show 5 more

Open Access

https://doi.org/10.1007/s00213-017-4651-4

Copy DOI

Abstract

Cognitive deficits in depression can be modelled using the novel object recognition (NOR) test, performance in which is impaired by chronic mild stress (CMS). We aimed to examine the involvement of mesocorticolimbic DA terminal regions, and to establish the substrate for CMS-induced impairment of NOR and its reversal by chronic antidepressant treatment. In experiments 1 and 2, we examined the effect of infusions into medial PFC, dorsal hippocampus (HPC), and nucleus accumbens (NAc) shell of D1 and D2 antagonists and D3 agonist, which were predicted to impair NOR with a short (1 h) delay, and of D1 and D2 agonists and D3 antagonist, which were predicted to facilitate NOR with a long (24 h) delay. Using optimal doses identified in experiment 2, in experiments 3 and 4, we examined effects on drug-stimulated NOR of CMS and chronic treatment with venlafaxine (VFX) or risperidone (RSP). We found a wide involvement of DA systems in memory for NOR: D1 receptors in PFC, HPC, and NAc; D3 receptors in PFC and HPC; and D2 receptors in PFC. CMS impaired D2- and D3-mediated effects in PFC and HPC; antidepressants rescued those effects in PFC but not HPC. The involvement of DA in NOR is multifaceted, but the effects of CMS and antidepressants are more discrete, involving D2 and D3 receptors in PFC specifically. While raising many difficult questions, these results suggest that the D2 and D3 receptors in the medial PFC may be an important substrate for cognitive deficits in depression and their remediation.

Highlights

While depression is primarily a disorder of mood and motivation, people who are depressed present a range of cognitive deficits, including impairments of memory and executive functioning, which are receiving increased attention (Willner 1984; Austin et al 2001; Carvalho et al 2014; Belzung et al 2015; Malhi et al 2015)
Psychopharmacology (2017) 234:2571–2585 animals subjected to Chronic mild stress (CMS) are impaired in a variety of spatial and emotional memory tasks (e.g., Song et al 2012; Cuadrado-Tejedor et al 2011; Llorente et al 2011; Gu et al 2014; Liu et al 2014; Riaz et al 2015; Şahin et al 2015; Tran et al 2016). These cognitive deficits include impaired performance in the novel object recognition (NOR) test, which, like many other effects of CMS, is rescued by chronic antidepressant treatment (Orsetti et al 2007; Elizalde et al 2008; Llorente et al 2011; Liu et al 2014; Papp et al 2016, 2017). In this test, which exploits the animal’s natural tendency to explore novel objects and requires no training, the animal is first exposed to two identical objects: when subsequently reexposed to one of them alongside a novel object, a greater exploration of the novel object indicates that the familiar object has been remembered (Ennaceur and Delacour 1988)
All three drugs impaired NOR when injected into the prefrontal cortex (PFC)

Summary

Introduction

While depression is primarily a disorder of mood and motivation, people who are depressed present a range of cognitive deficits, including impairments of memory and executive functioning (imperfectly captured in the DSM symptom BConcentration: diminished ability to think or concentrate, or more indecisiveness^: American Psychiatric Association 2013), which are receiving increased attention (Willner 1984; Austin et al 2001; Carvalho et al 2014; Belzung et al 2015; Malhi et al 2015). Psychopharmacology (2017) 234:2571–2585 animals subjected to CMS are impaired in a variety of spatial and emotional memory tasks (e.g., Song et al 2012; Cuadrado-Tejedor et al 2011; Llorente et al 2011; Gu et al 2014; Liu et al 2014; Riaz et al 2015; Şahin et al 2015; Tran et al 2016) These cognitive deficits include impaired performance in the novel object recognition (NOR) test, which, like many other effects of CMS, is rescued by chronic antidepressant treatment (Orsetti et al 2007; Elizalde et al 2008; Llorente et al 2011; Liu et al 2014; Papp et al 2016, 2017). Drugs are administered shortly after the exposure session, to affect the consolidation stage of memory, though other procedures (pre-exposure or pre-retrieval) are sometimes used

Objectives

Methods

Results

Discussion

Conclusion