Monoacylglycerol Lipase Inhibition Using ABX-1431 Attenuates Cerebral Ischaemia Early After Traumatic Brain Injury.

An early event in the pathology of traumatic brain injury (TBI) is a reduction in cerebral blood flow (CBF), which exacerbates secondary injury development and inhibits brain recovery. The endogenous cannabinoid system signalling (eCBs) might be critical in TBI recovery due to modulating synaptic activity and exerting neuroprotective and anti-inflammatory effects. In the brain, eCBs predominantly occur at cannabinoid receptor type 1 via the eCB 2-arachidonoylglycerol (2-AG).

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.

Evaluating Potential Anxiolytic Effects of Minor Cannabinoids and Terpenes After Acute and Chronic Oral Administration in Rats.

Cannabis and its primary psychoactive constituent delta-9-tetrahydrocannabinol (D9-THC) produce biphasic, dose-dependent effects on anxiety. In addition to D9-THC, cannabis contains other "minor" cannabinoids and terpenes with purported therapeutic potential for the treatment of anxiety. Empirical data on potential therapeutic effects of these compounds is limited.

Endocannabinoid Modulation of Nucleus Accumbens Microcircuitry and Terminal Dopamine Release.

The nucleus accumbens (NAc) is located in the ventromedial portion of the striatum and is vital to valence-based predictions and motivated action. The neural architecture of the NAc allows for complex interactions between various cell types that filter incoming and outgoing information. Dopamine (DA) input serves a crucial role in modulating NAc function, but the mechanisms that control terminal DA release and its effect on NAc neurons continues to be elucidated.

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.

Evolution of in vivo dopamine monitoring techniques.

The brain dopamine system is central to numerous behavioral processes, including movement, learning, and motivation. Accordingly, disruptions of this neural system underlie numerous neurological and psychiatric disorders. Current understanding of how dopamine neurotransmission contributes to behavior and its dysfunction has been driven by technological advancements that permit spatiotemporally-defined measurements of dopaminergic signaling in behaving animals.

Use of Medical Cannabis to Treat Traumatic Brain Injury.

There is not a single pharmacological agent with demonstrated therapeutic efficacy for traumatic brain injury (TBI). With recent legalization efforts and the growing popularity of medical cannabis, patients with TBI will inevitably consider medical cannabis as a treatment option. Pre-clinical TBI research suggests that cannabinoids have neuroprotective and psychotherapeutic properties.

Accumbal Dopamine Release Tracks the Expectation of Dopamine Neuron-Mediated Reinforcement.

Dopamine (DA) transmission in the nucleus accumbens (NAc) facilitates cue-reward associations and appetitive action. Reward-related accumbal DA release dynamics are traditionally ascribed to ventral tegmental area (VTA) DA neurons. Activation of VTA to NAc DA signaling is thought to reinforce action and transfer reward-related information to predictive cues, allowing cues to guide behavior and elicit dopaminergic activity.

Contributions of nucleus accumbens dopamine to cognitive flexibility.

There is a compelling evidence that midbrain dopamine (DA) neurons and their projections to the ventral striatum provide a mechanism for motivating reward-seeking behavior, and for utilizing information about unexpected reward prediction errors (RPEs) to guide behavior based on current, rather than historical, outcomes. When this mechanism is compromised in addictions, it may produce patterns of maladaptive behavior that remain obdurate in the face of contrary information and even adverse consequences. Nonetheless, DAergic contributions to performance on behavioral tasks that rely on the ability to flexibly update stimulus-reward relationships remains incompletly understood.

Activation of the mGlu metabotropic glutamate receptor has antipsychotic-like effects and is required for efficacy of M muscarinic receptor allosteric modulators.

Recent clinical and preclinical studies suggest that selective activators of the M muscarinic acetylcholine receptor have potential as a novel treatment for schizophrenia. M activation inhibits striatal dopamine release by mobilizing endocannabinoids, providing a mechanism for local effects on dopamine signaling in the striatum but not in extrastriatal areas. G protein-coupled receptors (GPCRs) typically induce endocannabinoid release through activation of Gα-type G proteins whereas M transduction occurs through Gα-type G proteins.

Endocannabinoid Actions on Cortical Terminals Orchestrate Local Modulation of Dopamine Release in the Nucleus Accumbens.

Dopamine (DA) transmission mediates numerous aspects of behavior. Although DA release is strongly linked to firing of DA neurons, recent developments indicate the importance of presynaptic modulation at striatal dopaminergic terminals. The endocannabinoid (eCB) system regulates DA release and is a canonical gatekeeper of goal-directed behavior.

Endocannabinoid modulation of dopamine neurotransmission.

Dopamine (DA) is a major catecholamine neurotransmitter in the mammalian brain that controls neural circuits involved in the cognitive, emotional, and motor aspects of goal-directed behavior. Accordingly, perturbations in DA neurotransmission play a central role in several neuropsychiatric disorders. Somewhat surprisingly given its prominent role in numerous behaviors, DA is released by a relatively small number of densely packed neurons originating in the midbrain.

Compromised Dopaminergic Encoding of Reward Accompanying Suppressed Willingness to Overcome High Effort Costs Is a Prominent Prodromal Characteristic of the Q175 Mouse Model of Huntington's Disease.

Unlabelled: Huntington's disease (HD) is a heritable neurodegenerative disorder caused by expansion of CAG (glutamine) repeats in the HTT gene. A prodromal stage characterized by psychiatric disturbances normally precedes primary motor symptoms and suppressed motivation represents one of the earliest and most common psychiatric symptoms. Although dopamine in the nucleus accumbens (NAc) critically regulates motivation and altered dopamine signaling is implicated in HD, the nature of dopaminergic deficits and contribution to symptoms in HD is poorly understood.

Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism.

Cannabinoid modulation of drug reward and the implications of marijuana legalization.

Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana's illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana's psychoactive and reinforcing properties.

Illicit dopamine transients: reconciling actions of abused drugs.

Phasic increases in brain dopamine are required for cue-directed reward seeking. Although compelling within the framework of appetitive behavior, the view that illicit drugs hijack reward circuits by hyperactivating these dopamine transients is inconsistent with established psychostimulant pharmacology. However, recent work reclassifying amphetamine (AMPH), cocaine, and other addictive dopamine-transporter inhibitors (DAT-Is) supports transient hyperactivation as a unifying hypothesis of abused drugs.

Characterization of ultrananocrystalline diamond microsensors for dopamine detection.

We show the technical feasibility of coating and micro patterning boron-doped ultrananocrystalline diamond (UNCD) on metal microwires and of applying them as microsensors for the detection of dopamine using fast-scan cyclic voltammetry. UNCD electrode surface consistently generated electrochemical signals with high signal-to-noise ratio of >800 using potassium ferrocyanide-ferricyanide redox couple. Parylene patterned UNCD microelectrodes were effectively applied to detect dopamine reliably using flow injection analysis with a detection limit of 27 nM and in the striatum of the anesthetized rat during electrical stimulation of dopamine neurons.

Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine.

Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool.

High doses of amphetamine augment, rather than disrupt, exocytotic dopamine release in the dorsal and ventral striatum of the anesthetized rat.

High doses of amphetamine (AMPH) are thought to disrupt normal patterns of action potential-dependent dopaminergic neurotransmission by depleting vesicular stores of dopamine (DA) and inducing robust non-exocytotic DA release or efflux via dopamine transporter (DAT) reversal. However, these cardinal AMPH actions have been difficult to establish definitively in vivo. Here, we use fast-scan cyclic voltammetry (FSCV) in the urethane-anesthetized rat to evaluate the effects of 10 and 20 mg/kg AMPH on vesicular DA release and DAT function in dorsal and ventral striata.

Using fast-scan cyclic voltammetry to evaluate striatal dopamine release elicited by subthalamic nucleus stimulation.

Deep brain stimulation (DBS), an effective neurosurgical therapy for Parkinson's disease (PD), may act via eliciting neurotransmitter release. However, the precise relationships between DBS and neurotransmitter release are not established. One issue in these studies may be analytical limitations of microdialysis and positron emission tomography, the primary measurement technologies employed.