Welcome!
“Our Goal is to elucidate the mechanisms by which stress affects brain structure and function, leading to susceptibility to mental illnesses, with a focus on endocannabinoid signaling systems. By understanding these mechanisms, we hope to uncover new molecular targets for development of novel therapeutics.”
—
Sachin Patel, MD, PhD
Lizzie Gilman Professor of Psychiatry and Behavioral Sciences
Endocannabinoid Signaling and Therapeutics
The Patel Lab’s research program focuses on the role of endocannabinoids in stress-induced neuroadaptation. Psychosocial stress is a key trigger for the development and exacerbation of a variety of psychiatric disorders including depression, addiction, schizophrenia, and post-traumatic stress disorder. By understanding the molecular, structural, and physiological adaptations in endocannabinoid signaling that occur in response to stress, we hope to uncover novel targets for drug development. In addition, we hope these investigations will provide insight into the pathophysiology of stress-related neuropsychiatric disorders. We use a variety of techniques including electrophysiology, mass spectrometry, in vivo calcium imaging, protein biochemistry, genetic models, behavioral analysis and functional anatomical studies to understand the role of endocannabinoids in the brain's response to stress.
Cannabinoids
Cannabinoids, such as tetrahydrocannabinol (THC), are a class of psychoactive organic molecules produced by the plants cannabis sativa and cannabis indica (below). Within animal tissues, these compounds activate cannabinoid receptors to exert physiological and behavioral effects.
Cannabinoid receptors (CB1 and CB1) are members of the GPCR superfamily and often couple to Gi/o signaling pathways. Cannabinoid receptors and their endogenous ligands are located throughout the limbic, or "emotional," brain, where they modulate synaptic neurotransmission. Converging preclinical and clinical data suggest a role for endogenous cannabinoid signaling in the modulation of anxiety and depression. CB1 is predominantly expressed in the mammalian CNS and exhibits a widespread distribution in brain regions that control movement, cognition, and motivation. Thus, the subjective effects of cannabis range from euphoria, reduced anxiety, sedation, impaired memory, judgment, and in some cases paranoia and hallucinations. Augmentation of endocannabinoid signaling (ECS) has anxiolytic effects, whereas blockade or genetic deletion of CB₁ receptors has anxiogenic properties.
Recent epidemiological studies indicate that cannabis use, especially early in life, can predispose genetically susceptible individuals to develop mental illnesses such as schizophrenia. One aim of our research is to understand how cannabinoids interact with neurodevelopmental processes to increase vulnerability to mental illness.
Endocannabinoids
Over the past decade a novel class of neuromodulatory lipids, including N-arachidonylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), that activates neuronal cannabinoid receptors has been the focus of intense research in neuroscience. These molecules are arachidonic acid derivatives produced by neurons and glia. These compounds act at the same site as the active constituent of cannabis sativa, Δ9-tetrahydrocannabinol (THC), and are termed endogenous cannabinoids (endocannabinoids; eCBs). Production of eCBs is driven by calcium influx secondary to strong neuronal depolarization or burst firing, and activation of some Gq-coupled neurotransmitter receptors and glucocorticoid receptors. eCBs are important retrograde modulators of synaptic signaling at central synapses.
Endocannabinoid (eCB) signaling has been well established to regulate the sensitivity and magnitude of the stress response. Under acute conditions, dynamic changes in eCB signaling contribute to both the activation and termination of the stress response, and impairments in eCB signaling can enhance or prolong the normative stress response. The ability of eCB signaling to regulate the stress response largely relates to its ability to modulate presynaptic glutamate release and modulate the activation of stress-responsive neural circuits in the brain. Under conditions of repeated stress, the eCB system appears to play a role in normative adaptive responses to stress. Given this role to contribute to stress adaptation, it is not surprising then that eCB signaling could influence an individual organism's ability to exhibit resilience or susceptibility to chronic stress. Although limited in nature, there is a growing body of literature that indeed does suggest that dynamic engagement of eCB signaling in response to stress contributes to stress resilience, while deficient recruitment of eCB signaling may favor the development of stress susceptibility.
Endocannabinoid-mediated Synaptic Suppression
The primary role of endocannabinoids such as 2-AG is retrograde synaptic suppression. Upon neuronal depolarization or Gq-coupled receptor activation, 2-AG is synthesized and released. It diffuses to presynaptic axon terminals where it activates CB1 receptors. Activation of CB1 receptors causes a decrease in neurotransmitter release. CB1 receptors are located on both GABAergic and glutamatergic axon terminals synapsing onto principle neurons. CB1-mediated synaptic suppression can be transient or long-lasting depending on specific pre- and post- synaptic activity levels.