The role of cannabinoid transmission in emotional memory formation : implications for addiction and schizophrenia, Huibing Tan et al., 2014

The role of cannabinoid transmission in emotional memory formation: implications for addiction and schizophrenia

Huibing Tan, Tasha Ahmad, Michael Loureiro, Jordan Zunder and Steven R. Laviolette

Frontiers in Psychiatry, 2014,Vol 5, Article 73, 1-12

doi : 10.3389/fpsyt.2014.00073


Emerging evidence from both basic and clinical research demonstrates an important role for endo-cannabinoid (ECB) signaling in the processing of emotionally salient information, learning, and memory. Cannabinoid transmission within neural circuits involved in emotional processing has been shown to modulate the acquisition, recall, and extinction of emotionally salient memories and importantly, can strongly modulate the emotional salience of incoming sensory information. Two neural regions in particular, the medial prefrontal cortex (PFC) and the basolateral nucleus of the amygdala (BLA), play important roles in emotional regulation and contain high levels of cannabinoid receptors. Furthermore, both regions show profound abnormalities in neuropsychiatric disorders such as addiction and schizophrenia. Considerable evidence has demonstrated that cannabinoid transmission functionally interacts with dopamine (DA), a neurotransmitter system that is of exceptional importance for both addictive behaviors and the neuropsychopathology of disorders like schizophrenia. Research in our laboratory has focused on how cannabinoid transmission both within and extrinsic to the mesolimbic DA system, including the BLA!mPFC circuitry, can modulate both rewarding and aversive emotional information. In this review, we will summarize clinical and basic neuroscience research demonstrating the importance of cannabinoid signaling within this neural circuitry. In particular, evidence will be reviewed emphasizing the importance of cannabinoid signaling within the BLA!mPFC circuitry
in the context of emotional salience processing, memory formation and memory-related plasticity. We propose that aberrant states of hyper or hypoactive ECB signaling within the amygdala-prefrontal cortical circuit may lead to dysregulation of mesocorticolimbic DA transmission controlling the processing of emotionally salient information. These disturbances may in turn lead to emotional processing, learning, and memory abnormalities related to various neuropsychiatric disorders, including addiction and schizophrenia-related psychoses.

Keywords : cannabinoids, emotion, schizophrenia, addiction, opiates, frontal cortex, dopamine, amygdala



The endocannabinoid (ECB) system is widely distributed in the mammalian brain and demonstrates relatively high density in neural regions implicated in the processing of emotionally salient information, such as the basolateral nucleus of the amygdala (BLA), prefrontal cortex (PFC), VTA, and NAc (1, 2). Naturally occurring ECBs include 2-arachidonoylglycerol (2-AG) and anandamide, which produce their actions via distinct neurophysiological mechanisms. Thus, while 2-AG is known to act as a fast-acting and transient retrograde messenger, anandamide can produce slower retrograde synaptic effects (3). In both cases, the canonical understanding of ECB function is that ECBs are generally released from post-synaptic neuronal elements and feedback in a retrograde manner onto pre-synaptic terminals, which may be either excitatory or inhibitory in nature (4). Retrograde synaptic modulation via the ECB system is known to be involved in short-term synaptic depression and can suppress both excitatory and inhibitory signaling within specific neuronal circuits (3, 4). As will be described presently, given this anatomical and pharmacological complexity, a wide variety of potential functional consequences can be attributed to CB1 receptor activation (via either ECBs, plant-derived or synthetic cannabinoid receptor agents). For within the BLA, CB1 receptors are localized primarily on inhibitory local GABAergic interneurons or terminals, but are absent in the adjacent central nucleus (1, 5, 6). In this case, activation of BLA CB1 receptors is known to decrease feedforward inhibition via inhibitory interneurons thereby increasing the activity of BLA projection neurons (7), leading to modulatory effects in efferent projection targets, such as the PFC (8, 9). Conversely, activation of CB1 receptors associated with excitatory pre-synaptic elements, such as glutamatergic terminals, may be capable of producing net inhibitory post-synaptic effects, depending upon the specific neuronal circuit under investigation. In both cases, emerging evidence points to the primary functional role of ECB signaling as indirectly modulating neuronal outputs via actions on pre-synaptic elements, primarily involving the inhibition of feedforward inhibitory influences on these neuronal outputs. As will be reviewed below, such mechanisms implicate the ECB system as a critical functional relay capable of controlling the output of a variety of neural emotional processing centers, including connections between the BLA and PFC, and the regulation of DAergic signaling within the mesocorticolimbic circuit.



Abnormal emotional processing, learning and memory are core features of various neuropsychiatric conditions, including schizophrenia and addiction. Disturbances in the ability to form appropriate associative memories and perform adaptive associative learning tasks, has been identified as critical neuropsychopathological features in both schizophrenia (10, 11) and addiction (12, 13).