Cannabinoid-based Pharmacology for the Management of Substance Use Disorders.

In the last two decades, the endocannabinoid system has emerged as a crucial modulator of motivation and emotional processing. Due to its widespread neuroanatomical distribution and characteristic retrograde signaling nature, cannabinoid type I receptors and their endogenous ligands finely orchestrate somatic and axon terminal activity of dopamine neurons. Owing to these unique features, this signaling system is a promising pharmacological target to ameliorate dopamine-mediated drug-seeking behaviors while circumventing the adverse side effects of, for instance, dopaminergic antagonists.

Dorsomedial Striatum (DMS) CB1R Signaling Promotes Pavlovian Devaluation Sensitivity in Male Long Evans Rats and Reduces DMS Inhibitory Synaptic Transmission in Both Sexes.

Cannabinoid receptor-1 (CB1R) signaling in the dorsal striatum regulates the shift from flexible to habitual behavior in instrumental outcome devaluation. Based on prior work establishing individual-, sex-, and experience-dependent differences in pavlovian behaviors, we predicted a role for dorsomedial striatum (DMS) CB1R signaling in driving rigid responding in pavlovian autoshaping and outcome devaluation. We trained male and female Long Evans rats in pavlovian lever autoshaping (PLA).

Dynamic overrepresentation of accumbal cues in food- and opioid-seeking rats after prenatal THC exposure.

The increasing prevalence of cannabis use during pregnancy has raised medical concerns, primarily related to Δ9-tetrahydrocannabinol (THC), which readily crosses the placenta and affects fetal brain development. Previous research has identified dopaminergic alterations related to maternal THC consumption. However, the consequences that prenatal cannabis exposure (PCE) has on striatum-based processing during reward pursuit have not been determined.

Realisation of broadband two-dimensional nonreciprocal acoustics using an active acoustic metasurface.

Nonreciprocal acoustic devices have been shown to be able to control incident waves propagating in one direction whilst allowing incident waves propagating in the opposite direction to be transmitted without modification. Nonreciprocal sound transmission, typically, has been achieved by introducing nonlinearities or directional biasing through fluid motion or spatiotemporal modulation of resonant cavities. However, the spatial arrangement of these approaches creates preferential characteristics in one direction such that the direction of the nonreciprocal behaviour is fixed and, thus, they are not straightforwardly reconfigurable.

Dynamic Overrepresentation of Accumbal Cues in Food- and Opioid-Seeking Rats after Prenatal THC Exposure.

The increasing prevalence of cannabis use during pregnancy has raised significant medical concerns, primarily related to the presence of Δ9-tetrahydrocannabinol (THC), which readily crosses the placenta and impacts fetal brain development. Previous research has identified midbrain dopaminergic neuronal alterations related to maternal THC consumption. However, the enduring consequences that prenatal cannabis exposure (PCE) has on striatum-based processing during voluntary reward pursuit have not been specifically determined.

Dorsomedial Striatum CB1R signaling is required for Pavlovian outcome devaluation in male Long Evans rats and reduces inhibitory synaptic transmission in both sexes.

Cannabinoid-1 receptor (CB1R) signaling in the dorsal striatum regulates the shift from flexible to habitual behavior in instrumental outcome devaluation. Based on prior work establishing individual, sex, and experience-dependent differences in Pavlovian behaviors, we predicted a role for dorsomedial striatum CB1R signaling in driving rigid responding in Pavlovian autoshaping and outcome devaluation. We trained male and female Long Evans rats in Pavlovian Lever Autoshaping (PLA).

Mobilization of endocannabinoids by midbrain dopamine neurons is required for the encoding of reward prediction.

Brain levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) shape motivated behavior and nucleus accumbens (NAc) dopamine release. However, it is not clear whether mobilization of 2-AG specifically from midbrain dopamine neurons is necessary for dopaminergic responses to external stimuli predicting forthcoming reward. Here, we use a viral-genetic strategy to prevent the expression of the 2-AG-synthesizing enzyme diacylglycerol lipase α (DGLα) from ventral tegmental area (VTA) dopamine cells in adult mice.

A multivariate regressor of patterned dopamine release predicts relapse to cocaine.

Understanding mesolimbic dopamine adaptations underlying vulnerability to drug relapse is essential to inform prognostic tools for effective treatment strategies. However, technical limitations have hindered the direct measurement of sub-second dopamine release in vivo for prolonged periods of time, making it difficult to gauge the weight that these dopamine abnormalities have in determining future relapse incidence. Here, we use the fluorescent sensor GrabDA to record, with millisecond resolution, every single cocaine-evoked dopamine transient in the nucleus accumbens (NAc) of freely moving mice during self-administration.

Selective chemogenetic inactivation of corticoaccumbal projections disrupts trait choice impulsivity.

Impulsive choice has enduring trait-like characteristics and is defined by preference for small immediate rewards over larger delayed ones. Importantly, it is a determining factor in the development and persistence of substance use disorder (SUD). Emerging evidence from human and animal studies suggests frontal cortical regions exert influence over striatal reward processing areas during decision-making in impulsive choice or delay discounting (DD) tasks.

Decreased Ventral Tegmental Area CB1R Signaling Reduces Sign Tracking and Shifts Cue-Outcome Dynamics in Rat Nucleus Accumbens.

Sign-tracking (ST) rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug seeking compared with goal-tracking or intermediate rats. Cue-evoked dopamine in the nucleus accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system, endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the ventral tegmental area (VTA) to control cue-evoked striatal dopamine levels.

Endocannabinoid regulation of hippocampus-dependent memory.

Over the past few decades, tremendous work has been dedicated to understanding how cannabinoids, both endogenous and exogenous, impact the process of learning and memory. Here we attempt to summarize the breadth of this research investigating the role of cannabinoid signaling on episodic or hippocampus-dependent memory. This review will focus primarily on studies using pharmacological approaches, allowing us to discuss the impact of cannabinoids at different phases of the memory formation process.

Controlling the effective surface mass density of membrane-type acoustic metamaterials using dynamic actuators.

Membrane-type acoustic metamaterials (MAM) are thin and lightweight structures that offer exceptional low-frequency sound transmission loss (STL) values, which can exceed the corresponding mass-law significantly. Typically, the high STL of MAM is confined to a narrow frequency band, which is associated with the so-called anti-resonance. This narrow bandwidth reduces the range of potential noise control applications for MAM.

Regulation of glutamate homeostasis in the nucleus accumbens by astrocytic CB1 receptors and its role in cocaine-motivated behaviors.

Cannabinoid type 1 receptors (CB1Rs) orchestrate brain reward circuitry and are prevalent neurobiological targets for endocannabinoids and cannabis in the mammalian brain. Decades of histological and electrophysiological studies have established CB1R as presynaptic G-protein coupled receptors (GPCRs) that inhibit neurotransmitter release through retrograde signaling mechanisms. Recent seminal work demonstrates CB1R expression on astrocytes and the pivotal function of glial cells in endocannabinoid-mediated modulation of neuron-astrocyte signaling.

An experimental investigation into a dual taper acoustic black hole termination.

Acoustic black holes (ABHs) can provide effective damping of the reflected wave component when used to terminate a beam. The behaviour of an ABH is characterised by its local modes, which produce narrow frequency bands of high absorption. To enhance the performance of ABH terminations, a multi-taper ABH has previously been proposed and analytical results demonstrate that the use of two or more tapers produces a compound effect on the reflection coefficient, resulting in more bands of low reflection.

Realisation of nonreciprocal transmission and absorption using wave-based active noise control.

Nonreciprocal acoustic devices typically break reciprocity by introducing nonlinearities or directional biasing. However, these devices are generally not fully adaptable and often use resonant cavities, which only exhibit nonreciprocal behaviour over a narrow bandwidth. Therefore, to overcome these challenges, this paper investigates how wave-based active control can be used to achieve broadband nonreciprocal behaviour in a one-dimensional environment.

Local modulation by presynaptic receptors controls neuronal communication and behaviour.

Central nervous system neurons communicate via fast synaptic transmission mediated by ligand-gated ion channel (LGIC) receptors and slower neuromodulation mediated by G protein-coupled receptors (GPCRs). These receptors influence many neuronal functions, including presynaptic neurotransmitter release. Presynaptic LGIC and GPCR activation by locally released neurotransmitters influences neuronal communication in ways that modify effects of somatic action potentials.

Weighted pressure matching with windowed targets for personal sound zones.

Personal sound zones (PSZ) systems use an array of loudspeakers to render independent audio signals to multiple listeners within a room. The performance of a PSZ system, designed using weighted pressure matching, depends on the selected target responses for the bright zone. In reverberant environments, the target responses are generally chosen to be the room impulse responses from one of the loudspeakers to the control points in the selected bright zone.

Cannabis exposure during adolescence: A uniquely sensitive period for neurobiological effects.

Adolescence is a crucial developmental period where neural circuits are refined and the brain is especially vulnerable to external insults. The endocannabinoid (eCB) system undergoes changes during adolescence which affect the way in which it modulates the development of other systems, in particular dopamine circuits, which show protracted development into adolescence. Given the rise of cannabis use by adolescents and young people, as well as variants containing increasingly higher concentrations of THC, it is now crucial to understand the unique effects of adolescent exposure to cannabis on the developing brain and it might shape future adult vulnerabilities to conditions such as psychosis, schizophrenia, addiction and more.

Chronic Augmentation of Endocannabinoid Levels Persistently Increases Dopaminergic Encoding of Reward Cost and Motivation.

Motivational deficits characterized by an unwillingness to overcome effortful costs are a common feature of neuropsychiatric and neurologic disorders that are insufficiently understood and treated. Dopamine (DA) signaling in the nucleus accumbens (NAc) facilitates goal-seeking, but how NAc DA release encodes motivationally salient stimuli to influence effortful investment is not clear. Using fast-scan cyclic voltammetry in male and female mice, we find that NAc DA release diametrically responds to cues signaling increasing cost of reward, while DA release to the reward itself is unaffected by its cost.

Cocaine-induced increases in motivation require 2-arachidonoylglycerol mobilization and CB1 receptor activation in the ventral tegmental area.

A wide body of evidence supports an integral role for mesolimbic dopamine (DA) in motivated behavior. In brief, drugs that increase DA in mesolimbic terminal regions, like cocaine, enhance motivation, while drugs that decrease DA concentration reduce motivation. Data from our laboratory and others shows that phasic activation of mesolimbic DA requires signaling at cannabinoid type-1 (CB1) receptors in the ventral tegmental area (VTA), and systemic delivery of CB1 receptor antagonists reduces DA cell activity and attenuates motivated behaviors.

Repeated binge ethanol drinking enhances electrical activity of central amygdala corticotropin releasing factor neurons in vivo.

Binge ethanol drinking is an increasingly problematic component of alcohol use disorder costing the United States approximately over $150 billion every year and causes progressive neuroplasticity alterations in numerous brain regions. However, the precise nature or machinery that underlies binge drinking has not yet been elucidated. Corticotropin releasing factor (CRF) neurons in the central amygdala (CeA) are thought to modulate binge drinking, but the specific circuit mechanisms remain poorly understood.

Modulating the Neuromodulators: Dopamine, Serotonin, and the Endocannabinoid System.

Dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT), and endocannabinoids (ECs) are key neuromodulators involved in many aspects of motivated behavior, including reward processing, reinforcement learning, and behavioral flexibility. Among the longstanding views about possible relationships between these neuromodulators is the idea of DA and 5-HT acting as opponents. This view has been challenged by emerging evidence that 5-HT supports reward seeking via activation of DA neurons in the ventral tegmental area.

Prenatal THC Does Not Affect Female Mesolimbic Dopaminergic System in Preadolescent Rats.

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype.

Chronic cannabinoid exposure produces tolerance to the dopamine releasing effects of WIN 55,212-2 and heroin in adult male rats.

Synthetic cannabinoids were introduced into recreational drug culture in 2008 and quickly became one of the most commonly abused drugs in the United States. The neurobiological consequences resulting from synthetic cannabinoid repeated exposure remain poorly understood. It is possible that a blunted dopamine (DA) response may lead drug users to consume larger quantities to compensate for this form of neurochemical tolerance.

Choosing the right drug: status and future of endocannabinoid research for the prevention of drug-seeking reinstatement.

Prolonged exposure to drugs of abuse leads to severe alterations in mesocorticolimbic dopamine circuitry deeply implicated in substance use disorders. Despite considerable efforts, few medications to reduce relapse rates are currently available. To solve this issue, researchers are uncovering therapeutic opportunities offered by the endocannabinoid system.