Conditioned anti-immobility by ketamine: A comparison to escitalopram and bupropion.

This study was designed to explore the clinical belief that "set and setting" play an important role in favorable responses to psychedelic agents such as ketamine (KET). In fact, there is evidence in animals that the antidepressant effect of this drug may involve drug-environment interactions in which a context paired with its effects acquires the ability to influence behavior. Therefore, it was investigated in male Sprague-Dawley rats whether exposure to a context paired with the effects of KET, or with the effects of the common antidepressant medications bupropion (BUP) and escitalopram (ESC), could produce an antidepressant-like conditioned response. In Experiment 1, subjects received saline in a vehicle-paired context (denoted as CS-), and 0, 10, or 20 mg/kg KET, 10 mg/kg ESC, or 10 mg/kg BUP in a drug-paired context (denoted as CS +), on 10 alternating days (5 pairings with each context). The rats were then exposed drug free to the CS- and CS + prior to the assessment of immobility in the forced-swimming test. Experiment 2 assessed approach/avoidance responses induced by the CS- and CS + in a place-conditioning test. It was found that exposure to the KET CS + significantly reduced immobility without affecting general locomotor activity in comparison to the SAL CS + and the BUP CS +, but not the ESC CS+. Moreover, no group differences were observed in the place-conditioning test, indicating that the anti-immobility effect of the KET CS + was likely not influenced by a conditioned incentive or aversive state. Together, these data suggest that a KET-paired context can elicit a conditioned antidepressant-like response, which may be a mechanism involved in its sustained antidepressant clinical action. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Effect of ketamine on the physiological responses to combined hypoglycemic and psychophysical stress.

There is evidence that hypoglycemic stress can interact with other stressors, and that ketamine can mitigate the impact of these stressors on behavior and physiology. The current study in male Sprague-Dawley rats investigated whether pre-treatment with 0, 10, or 20 mg/kg ketamine could modulate the interaction between hypoglycemia induced by 0 or 300 mg/kg 2-deoxy-D-glucose (2-DG) and the psychophysical stress of forced swimming (FSS; 6 sessions, 10 min/session) on serum concentrations of corticosterone (CORT) and the pro-inflammatory cytokine, tumor necrosis factor (TNF)-α. It was found that 2-DG enhanced the CORT response to an initial session of FSS, and this effect dissipated after multiple sessions. More importantly, animals displayed significantly higher levels of CORT and lower levels of TNF-α in response to a drug-free test swim conducted 1 week after exposure to the combined stressors, and these responses were not observed in rats that were pre-treated with ketamine. Overall, these findings indicate that ketamine has the potential to reduce the negative impact of interacting stressors on the biological reactivity of the hypothalamic-pituitary-adrenal axis and the immune system.

Memory enhancing effects of nicotine, cocaine, and their conditioned stimuli; effects of beta-adrenergic and dopamine D2 receptor antagonists.

BACKGROUND: There is evidence that post-training exposure to nicotine, cocaine, and their conditioned stimuli (CS), enhance memory consolidation in rats. The present study assessed the effects of blocking noradrenergic and dopaminergic receptors on nicotine and cocaine unconditioned and conditioned memory modulation. METHODS: Males Sprague-Dawley rats tested on the spontaneous object recognition task received post-sample exposure to 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs, in combination with 5-10 mg/kg propranolol (PRO; beta-adrenergic antagonist) or 0.2-0.6 mg/kg pimozide (PIM; dopamine D2 receptor antagonist). The CSs were established by confining rats in a chamber (the CS +) after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, for 2 h and in another chamber (the CS -) after injections of vehicle, repeated over 10 days (5 drug/CS + and 5 vehicle/CS - pairings in total). Object memory was tested 72 h post sample in drug-free animals. RESULTS: Co-administration of PRO or PIM blocked the memory-enhancing effects of post-training injections of nicotine, cocaine, and, importantly, exposure to their CSs. CONCLUSIONS: These data suggest that nicotine, cocaine as well as their conditioned stimuli share actions on overlapping noradrenergic and dopaminergic systems to modulate memory consolidation.

Impact of impaired glucose metabolism on responses to a psychophysical stressor: modulation by ketamine.

RATIONALE: There is evidence that hypoglycemia, a metabolic stressor, can negatively impact mood and motivation, and can interact with other stressors to potentiate their effects on behavior and physiology. OBJECTIVES/METHODS: The current study in male Sprague-Dawley rats explored the interaction between impaired glucose metabolism induced by 0, 200, or 300 mg/kg 2-deoxy-D-glucose (2-DG) and a psychophysical stressor induced by forced swimming stress (FSS; 6 sessions, 10 min/session). The endpoints of interest were blood glucose levels, progressive behavioral immobility, and saccharin preference (2-bottle choice test). Furthermore, it was investigated whether pre-treatment with 0, 10, or 20 mg/kg ketamine could modify the interaction between 2-DG and FSS on these endpoints. RESULTS: It was found that 2-DG increased blood glucose levels equally in all experimental groups, accelerated the immobile response to FSS, and suppressed saccharin preference 1 week following termination of stress exposure. As well, pre-treatment with ketamine blocked the effects of combined 2-DG and FSS on immobility and saccharin preference without affecting blood glucose levels and produced an anti-immobility effect that was observed during a drug-free test swim 1 week following administration. CONCLUSIONS: Overall, these findings demonstrate that impaired glucose metabolism can potentiate the effects of a psychophysical stressor, and that this interaction can be modulated pharmacologically by ketamine.

Reverse translation of major depressive disorder symptoms: A framework for the behavioural phenotyping of putative biomarkers.

BACKGROUND: Reverse translating putative biomarkers of depression from patients to animals is complex because Major Depressive Disorder (MDD) is a highly heterogenous condition. This review proposes an approach to reverse translation based on relating relevant bio-behavioural functions in laboratory rodents to MDD symptoms. METHODS: This systematic review outlines symptom clusters assessed by psychometric tests of MDD and antidepressant treatment response including the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. Symptoms were related to relevant behavioural assays in laboratory rodents. RESULTS: The resulting battery of tests includes passive coping, anxiety-like behaviours, sleep, caloric intake, cognition, psychomotor functions, hedonic reactivity and aversive learning. These assays are discussed alongside relevant clinical symptoms of MDD, providing a framework through which reverse translation of a biomarker can be interpreted. LIMITATIONS: Certain aspects of MDD may not be quantified by tests in laboratory rodents, and their biological significance may not always be of clinical relevance. CONCLUSIONS: Using this reverse translation approach, it is possible to clarify the functional significance of a putative biomarker in rodents and hence translate its contribution to specific clinical symptoms, or clusters of symptoms.

Correction to: Effects of combined escitalopram and aripiprazole in rats: role of the 5-HT1a receptor.

After publication of this paper, the authors determined an error in Fig. 3. Below is the correct Fig. 3.

Effects of combined escitalopram and aripiprazole in rats: role of the 5-HT1a receptor.

RATIONALE: Pre-clinical and clinical studies have suggested that the antidepressant efficacy of escitalopram (ESC) can be augmented by co-administration of aripiprazole (ARI). OBJECTIVE: To establish if the effects of ESC + ARI can be altered by modulating the 5-HT1a receptor. METHODS: Sprague-Dawley male rats received ESC + ARI (10 and 2 mg/kg/day, respectively, via osmotic or by cumulative injections), as well as the 5-HT1a antagonist WAY-100635 (WAY; 0.01-1 mg/kg) and the 5-HT1a agonist 8-OH-DPAT (DPAT; 0.3-1 mg/kg) prior to testing in locomotion chambers and in the forced swim test (FST). Expression of the 5-HT1a receptor mRNA in the dorsal raphe nucleus, hippocampus, septum, and entorhinal cortex was also assessed. RESULTS: WAY generally synergized, while DPAT antagonized, the effect of ESC + ARI on motor activity. All groups showed significantly lower 5-HT1a mRNA in the dorsal raphe nucleus. In the hippocampus, ESC + ARI and WAY + ESC + ARI groups displayed equivalent elevations of 5-HT1a mRNA, but this was not observed in groups that received DPAT + ESC + ARI. Finally, the addition of ARI to ESC augmented the effect that ESC alone had on reducing immobility in the FST. Importantly, WAY antagonized this effect, while DPAT had no consequences. CONCLUSIONS: Taken together, these results in rats indicate that the 5-HT1a receptor is involved in the behavioral and brain region-specific mRNA effects of ESC + ARI.

Programming Effects of Pubertal Lipopolysaccharide Treatment in Male and Female CD-1 Mice.

Puberty is a critical period of development marked by sexual, immune, and neural maturation. Exposure to stress during this period can lead to enduring changes in brain functioning and in behavior; however, the underlying mechanisms and the programming effects of stress during puberty remain unknown. Therefore, the objective of this study was to investigate the programming effects of pubertal immune challenge in response to a homotypic stressor later in life in CD-1 mice. Age and sex differences in the peripheral and central cytokine levels, along with sickness behavior and telemetry data, were analyzed following the secondary treatment. The results showed that pretreatment with LPS attenuated the immune response to a second homotypic challenge. Males pretreated with LPS during puberty and in early adulthood displayed an attenuated hypothermic response following the second LPS treatment compared with saline-pretreated controls, which is consistent with the attenuated peripheral IL-6 and IFN-γ concentrations. Females pretreated with LPS during puberty displayed lower IL-1ß, TNF-α, and IL-6 mRNA expression in the prefrontal cortex following the secondary immune challenge compared with saline controls. The results of this study show that exposure to LPS during puberty programs the peripheral and central immune responses, resulting in an attenuated immune response following a subsequent homotypic stressor. Thus, exposure to an immune challenge during puberty affects immune function later in life, which could permanently affect brain function and have implications on mental health.

Sex differences in the peripheral and central immune responses following lipopolysaccharide treatment in pubertal and adult CD-1 mice.

Puberty is a critical developmental period that is characterized by significant brain development. Exposure to stress during this time can alter brain functioning setting the stage for long-lasting behavioural outcomes. The objective of this study was to investigate age and sex differences in the peripheral and central immune responses, along with sickness behaviour, following immune stress. The results showed that LPS treatment increased serum cytokine levels and sickness symptoms in all mice. Pubertal males displayed increased IL-1ß concentrations at 2 h and increased IL-6 concentrations at 8 h post-treatment whereas increased concentrations of TNFα, IL-10, IL-12, IL-1ß, IFNγ, and IL-6 persisted at 8 and 24 h in adult females. Consistent with peripheral cytokines, pubertal males displayed greater IL-1ß, TNFα, and IL-6 mRNA expression in the prefrontal cortex at 2 h, whereas adult males expressed more of the aforementioned cytokines at 8 h compared to saline controls. Adult males also displayed greater IL-1ß mRNA expression compared to their female counterparts, and adult females displayed greater TNFα mRNA expression compared to their male counterparts. These results not only provide a better understanding of the age and sex differences in acute immune response, but also show important region- and time-specific differences in the response to an immune challenge, and that the peripheral immune response differs from the central response. This highlights the need to examine immune markers in both the periphery and the central nervous system for an accurate depiction of acute immune response following an immune challenge.