Fluoxetine Disrupts the Integration of Anxiety and Aversive Memories

Abstract

Anxiety disorders may result from an overexpression of aversive memories. Evidence suggests that the hippocampal cholinergic system could be the point of convergence of anxiety and memory. We propose that clinically effective anxiolytics may exert their effect by interfering with this integration mechanism. To assess anxiety and aversive memory, we used the shock-probe burying test. A reduction in anxiety in this test is indicated by decreased burying, whereas impaired cognition is reflected by an increased number of probe-contacts and/or reduced retention latency. Both an aversive stimulus and the memory of that stimulus significantly increased hippocampal acetylcholine (ACh) levels (Experiment 1). In fact, the memory of the event seemed to be more important than the event itself since the aversive memory induced a greater increase in hippocampal ACh. Injections (i.p.) of fluoxetine (Prozac s ) reduced burying behavior, while not affecting probe contacts or retention latency (Experiment 2). Although injections of fluoxetine did not affect basal hippocampal ACh efflux (Experiment 3), fluoxetine abolished the increase in ACh induced by the aversive stimulus and the memory of that stimulus (Experiment 4), emphasizing the significance of aversive memories in anxiety disorders. These actions may be mediated by a decrease in the event-related enhancement in cholinergic neurotransmission through M1 cholinergic receptors (Experiment 5). Therefore, anxiety disorders may stem from an unopposed formation of aversive memories and clinically effective anxiolytics hinder the association between emotional and cognitive processing. This reduces the emotional impact of aversive memories, thereby opposing consequent anxiety.

Chronic Vortioxetine Treatment Reduces Exaggerated Expression of Conditioned Fear Memory and Restores Active Coping Behavior in Chronically Stressed Rats

“…These findings are in agreement with a previous report that vortioxetine dose-dependently reduced anxiety in the marble burying test in mice (Bisulco et al, 2009). A similar effect has also been observed in previous studies in which SSRI treatment selectively decreased burying behavior (Degroot and Nomikos, 2005). The lateral septum is critical to determining coping behavior on the shock probe defensive burying test (Treit et al, 1993).…”

CB1Receptor Antagonism Increases Hippocampal Acetylcholine Release: Site and Mechanism of Action

“…Thus, even though there seems to be a compensatory response after long-term inactivation of CB 1 receptors, CB 1 R KO mice still have higher hippocampal ACh levels when the hippocampal cholinergic system is actively recruited. To the extent that an increase in hippocampal ACh efflux is associated with an enhanced coping ability and an improvement in cognitive performance (Degroot and Nomikos, 2005), this ACh hyper-responsiveness could explain why the CB 1 R KO mice perform better in learning and memory tasks and can even experience "impaired forgetting" (i.e., inability to forget a previously learned response), even if it would be beneficial to the animals to neutralize/forget this response (Reibaud et al, 1999;Varvel and Lichtman, 2002). In addition, it could explain why CB 1 R antagonism modulates anxiety levels by enhancing the ability of the animals to perceive aversive stimuli and respond accordingly through active avoidance (Degroot and Nomikos, 2004).…”

The expression level of muscarinic M1 receptor subtypes in different regions of rat brain

“…Muscarinic receptors are known to play major role in learning, storing memory and in posture control where the blockage of the muscarinic receptors leads to memory loss [20,21]. Therefore, it is really important to understand the underlying mechanism of the cholinergic muscarinic receptors in PTSD.…”