Differential role of GABAergic and cholinergic ventral pallidal neurons in behavioral despair, conditioned fear memory and active coping.

The ventral pallidum (VP), a major component of the reward circuit, is well-associated with appetitive behaviors. Recent evidence suggests that this basal forebrain nucleus may have an overarching role in affective processing, including behavioral responses to aversive stimuli. We investigated this by utilizing selective immunotoxin lesions and a series of behavioral tests in adult male Wistar rats. We made bilateral GAT1-Saporin, 192-IgG-Saporin or PBS (vehicle) injections into the VP to respectively eliminate GABAergic and cholinergic neurons, and tested the animals in the forced swim test (FST), open field test (OFT), elevated plus maze (EPM), Morris water maze (MWM) and cued fear conditioning. Both GAT1-Saporin and 192-IgG-Saporin injections reduced behavioral despair without altering general locomotor activity. During the acquisition phase of cued fear conditioning, this antidepressant effect was accompanied by reduced freezing and increased darting in the 192-IgG-Saporin group, and increased jumping in the GAT1-Saporin group. In the extinction phase, cholinergic lesions impaired fear memory irrespective of the context, while GABAergic lesions reduced memory durability only during the early phases of extinction in a novel context. In line with this, selective cholinergic, but not GABAergic, lesions impaired spatial memory in the MWM. We observed no consistent effect in anxiety-like behavior assessed in the OFT and EPM. These findings indicate that both the GABAergic and cholinergic neuronal groups of the VP may contribute to emotion regulation through modulation of behavioral despair and acquired fear by suppressing active coping and promoting species-specific passive behaviors.

Chronic oral ketamine prevents anhedonia and alters neuronal activation in the lateral habenula and nucleus accumbens in rats under chronic unpredictable mild stress.

Acute injections of ketamine lead to rapid but transient antidepressant effects. Chronic oral treatment at low doses, a promising non-invasive alternative, may prolong this therapeutic effect. Here, we examine the antidepressant effects of chronic oral ketamine in rats under chronic unpredictable mild stress (CUMS), and reveal their neuronal correlates. Male Wistar rats were divided into control, ketamine, CUMS, and CUMS-ketamine groups. The CUMS protocol was applied to the latter two groups for 9 weeks, and ketamine (0.013 mg/ml) was provided ad libitum to the ketamine and CUMS-ketamine groups for 5 weeks. The sucrose consumption test, forced swim test, open field test, elevated plus maze, and Morris water maze were respectively used to assess anhedonia, behavioral despair, general locomotor activity, anxiety-like behavior and spatial reference memory. CUMS caused a reduction of sucrose consumption and impaired spatial memory, accompanied by increased neuronal activation in the lateral habenula (LHb) and paraventricular thalamic nucleus (PVT). Oral ketamine prevented behavioral despair and CUMS-induced anhedonia. Reward-triggered c-Fos immunoreactivity was decreased in the LHb and increased in the nucleus accumbens shell (NAcSh) in the CUMS-ketamine group compared to the CUMS group. Ketamine did not produce a differential effect in the OFT, EPM and MWM. These results show that chronic oral ketamine at low doses prevents anhedonia without impairing spatial reference memory. The observed neuronal activation changes in the LHb and NAcSh may be involved in the preventive effects of ketamine on anhedonia. This article is part of the Special Issue on "Ketamine and its Metabolites".