Major depressive disorder is a significant and costly cause of global disability. Until the discovery of the rapid acting antidepressant (RAAD) effects of ketamine, treatments were limited to drugs that have delayed clinical benefits. The mechanism of action of ketamine is currently unclear but one hypothesis is that it may involve neuropsychological effects mediated through modulation of affective biases (where cognitive processes such as learning and memory and decision-making are modified by emotional state). Previous work has shown that affective biases in a rodent decision-making task are differentially altered by ketamine, compared to conventional, delayed onset antidepressants. This study sought to further investigate these effects by comparing ketamine with other NMDA antagonists using this decision-making task. We also investigated the subtype selective GluN2B antagonist, CP-101,606 and muscarinic antagonist scopolamine which have both been shown to have RAAD effects. Both CP-101,606 and scopolamine induced similar positive biases in decision-making to ketamine, but the same effects were not seen with other NMDA antagonists. Using targeted medial prefrontal cortex (mPFC) infusions, these effects were localised to the mPFC. In contrast, the GABA agonist, muscimol, induced general disruptions to behaviour. These data suggest that ketamine and other RAADs mediate a specific effect on affective bias which involves the mPFC. Non-ketamine NMDA antagonists lacked efficacy and we also found that temporary inactivation of the mPFC did not fully recapitulate the effects of ketamine, suggesting a specific mechanism. Fig. 1 SCHEMATIC OF THE JUDGEMENT BIAS TASK AND TRIAL STRUCTURE.: In the judgement bias task (JBT), rats are trained to associate one tone frequency (2 kHz) with a high value reward: i.e. if the rat presses the correct lever (shown as the left lever in (a), but counterbalanced across rats in a cohort) they receive a high value reward (four reward pellets). They also learn to associate a second tone frequency (8 kHz) with receiving a low value reward (one reward pellet; shown in (a) as pressing the right lever during the tone). Judgement bias, or decision making about an ambiguous cue, which is known to be influenced by affective state, can be probed by presenting an ambiguous tone that has a mipdoint frequency between the two reference cues (5 kHz), and recording which lever the rat presses. If the rat is expecting the more positive outcome (indicative of an optimistic judgement bias), then they will more often choose the large reward lever, but if the rat is in a more negative affective state, they will expect the less positive outcome and more often choose the low reward lever, a pessimistic judgement bias. During the task, tones are presented within discrete trials, the format of which is depicted as a flow chart in (b). The task is self-initiated, and so each trial begins only once the rat makes a nosepoke entry into the magazine port. This is followed by a 5 s intertrial interval (ITI), during which time the rat has to wait and refrain from making a lever press response. If the rat does press a lever, they are punished with a 10 second timeout (TO). The tone cue is presented for a maximum of 20 seconds following the ITI, or until the rat makes a lever press response. The outcome following each lever press depends on which tone was played, and which lever was pressed. Correct lever presses to either reference tone (high or low tones) results in the corresponding reward being delivered to the magazine, whilst incorrect lever presses results in a 10 s TO. This TO also occurs if the rat fails to make any lever press during the 20 s tone presentation (an omission). During TOs, lever presses and magazine entries are recorded but have no consequences, meaning the rat has to wait to be able to begin the next trial. When the midpoint tone is presented, 50% of the time this tone is “classified” by the software as having the same response properties as the high reward tone. I.e., if the rat makes a high reward lever press during a midpoint tone presentation classified in this way, then they will receive a four pellet reward, but will experience the 10 s TO if they make a low reward lever press. Similarly, if the midpoint tone is “classified” as having the same response properties as the low reward tone, then a high reward lever press would result in a TO, whilst a low reward lever press would result in delivery of the small reward. In this way, each lever is only every associated with the same reward outcome (i.e. four pellets for the high reward lever), but the midpoint tone becomes randomly reinforced, and so rats will maintain responding for this tone across multiple trials within a session, whilst being unable to learn a specific reward contingency to associate with the midpoint tone. Fig. 2 THE EFFECT OF ACUTE TREATMENT WITH RAPID ACTING ANTIDEPRESSANT DRUGS AND NMDA RECEPTOR ANTAGONISTS ON JUDGEMENT BIAS OF THE MIDPOINT AMBIGUOUS TONE.: Ketamine (0.0, 1.0 mg/kg; n = 13), scopolamine (0.0, 0.03, 0.1 mg/kg; n = 16), CP-101,606 (Expt 1: 0.0, 0.3, 1.0, 3.0 mg/kg, n = 15; Expt 2: 0.0, 6.0 mg/kg, n = 15), lanicemine (0.0, 0.3, 1.0, 3.0 mg/kg; n = 16), memantine (0.0, 0.1, 0.3, 1.0 mg/kg; n = 16) and MK-801 (0.0, 0.01, 0.03 mg/kg; n = 16 were administered acutely by intraperitoneal injection prior to testing on the judgement bias task. (a) Replicating previous studies, ketamine (1.0 mg/kg) positively changed CBI. (b) Scopolamine (0.1 mg/kg) also caused a positive change from baseline in CBI. (c) In experiment 1, there was no overall effect of CP-101,606 on change in CBI. A positive change was seen in experiment 2 with a higher 6.0 mg/kg dose. d-g Lanicemine, memantine, MK-801 and low doses of PCP did not induce a change in CBI for the midpoint tone at the doses tested. Data shown and represent mean ± SEM (bars and error bars) overlaid with individual data points for each rat. Dashed line (panel c) indicates separate, counterbalanced experiments. *p < 0.05; p < 0.05 for a one-sample t test for 3.0 mg/kg CP-101,6060 only (comparison to a test value of zero representing a change in CBI for that drug only from baseline). CP-101,606, ketamine, lanicemine, memantine, PCP: 60 min pre-treatment; scopolamine, MK-801: 30 min pre-treatment. Fig. 3 BEHAVIOURAL DATA FROM THE JUDGEMENT BIAS TASK FOLLOWING ACUTE TREATMENT WITH HIGH DOSES OF KETAMINE.: Acute doses of ketamine (Expt 1: 0.0, 10.0 mg/kg, n = 16; Expt 2: 0.0, 25.0 mg/kg, n = 16) were administered by intraperitoneal injection to measure their effect on judgement bias. (a) Neither high dose of ketamine caused a change in interpretation of the midpoint tone. b Both doses of ketamine increased accuracy for the low tone. (c) Both doses of ketamine increased response latencies across all three tones. d Omissions were increased across all three tones following both ketamine doses. (e) High doses of ketamine (10.0, 25.0 mg/kg) decreased premature responding. ***p < 0.001, **p < 0.01, *p < 0.05. Data represent mean ± SEM (panels b-e) with individual data points overlaid for each rat (panel a). Dashed lines indicate separate, counterbalanced experiments. 60 min pre-treatment. HT high reward tone, MT midpoint tone, LT low reward tone. Fig. 4 DATA FROM MPFC CANNULATED RATS ON THE JUDGEMENT BIAS TASK.: Probe tests with no experimental manipulation were conducted before and after mPFC cannulation surgery to ensure that the surgery itself did not effect performance in the judgement bias task. a Cognitive bias index became more negative in the probe tests conducted after surgery. b The location of the injector placement was confirmed post-mortem and black dots represent the location of the cannula tip as assessed from Cresyl violet-stained brain sections. Coronal sections are +3.7 mm to +2.5 mm relative to bregma (Paxinos and Watson, 1998). c-g In the first infusion experiment, ketamine (Ket; 1.0 μg/μl) muscimol (Mus; 0.1 μg/μl), scopolamine (Sco; 0.1 μg/μl) or vehicle (Veh; 0.0 μg/μl; n = 13), were administered by intracerebral infusion into the mPFC to measure the effect on judgement bias. c Ketamine, muscimol and scopolamine all caused a positive change in cognitive bias index (CBI) for the midpoint tone. d Muscimol decreased accuracy for both reference tones. e Muscimol increased response latencies for the high and midpoint tones. f For the high and low tones, muscimol increased omissions. g Muscimol also increased premature responding. Data represent mean ± SEM (panels a, c-g) with individual data points overlaid for each rat (panel a, c). Black dashed line (panel f) represents 50% accuracy depicting performance at chance. 5 min pre-treatment. ***p < 0.001, *p < 0.05. HT high reward tone; MT midpoint tone; LT low reward tone. Fig. 5 BEHAVIOURAL DATA FROM THE JUDGEMENT BIAS TASK FOLLOWING MPFC INFUSIONS OF CP-101,606.: CP-101,606 (Expt 1: 00.0, 1.0 μg/μl, n = 13; Expt 2: 0.0, 3.0 μg/μl, n = 12) was administered by intracerebral infusion in the mPFC to measure the effect on judgement bias. a The higher dose of CP-101,606 (3.0 μg/μl) caused a positive change from baseline in CBI. b Accuracy was not altered by either dose of CP-101,606. c In experiment 1, CP-101,606 (1.0 μg/μl) increased response latency for the midpoint tone. d, e There was no effect of either dose on omissions or premature responding, *p < 0.05. Data represent mean ± SEM (panels b-e) with individual data points overlaid for each rat (panel a). Dashed lines indicate separate, counterbalanced experiments. 5 min pre-treatment. HT high reward tone, MT midpoint tone, LT low reward tone.

References

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