Cannabinoid Modulation of Dopamine Release During Motivation, Periodic Reinforcement, Exploratory Behavior, Habit Formation, and Attention

Motivational and attentional processes energize action sequences to facilitate evolutionary competition and promote behavioral fitness. Decades of neuropharmacology, electrophysiology and electrochemistry research indicate that the mesocorticolimbic DA pathway modulates both motivation and attention. More recently, it was realized that mesocorticolimbic DA function is tightly regulated by the brain’s endocannabinoid system and greatly influenced by exogenous cannabinoids—which have been harnessed by humanity for medicinal, ritualistic, and recreational uses for 12,000 years. Exogenous cannabinoids, like the primary psychoactive component of cannabis, delta-9-tetrahydrocannabinol, produce their effects by acting at binding sites for naturally occurring endocannabinoids. The brain’s endocannabinoid system consists of two G-protein coupled receptors, endogenous lipid ligands for these receptor targets, and several synthetic and metabolic enzymes involved in their production and degradation. Emerging evidence indicates that the endocannabinoid 2-arachidonoylglycerol is necessary to observe concurrent increases in DA release and motivated behavior. And the historical pharmacology literature indicates a role for cannabinoid signaling in both motivational and attentional processes. While both types of behaviors have been scrutinized under manipulation by either DA or cannabinoid agents, there is considerably less insight into prospective interactions between these two important signaling systems. This review attempts to summate the relevance of cannabinoid modulation of DA release during operant tasks designed to investigate either motivational or attentional control of behavior. We first describe how cannabinoids influence DA release and goal-directed action under a variety of reinforcement contingencies. Then we consider the role that endocannabinoids might play in switching an animal’s motivation from a goal-directed action to the search for an alternative outcome, in addition to the formation of long-term habits. Finally, dissociable features of attentional behavior using both the 5-choice serial reaction time task and the attentional set-shifting task are discussed along with their distinct influences by DA and cannabinoids. We end with discussing potential targets for further research regarding DA-cannabinoid interactions within key substrates involved in motivation and attention

Characterization of skeletal muscle effects associated with daptomycin in rats

Daptomycin is a lipopeptide antibiotic with strong bactericidal effects against Gram-positive bacteria and minor side effects on skeletal muscles. The type and magnitude of the early effect of daptomycin on skeletal muscles of rats was quantified by histopathology, examination of contractile properties, Evans Blue Dye uptake, and effect on the patch repair process. A single dose of daptomycin of up to 200 mg/kg had no effect on muscle fibers. A dose of 150 mg/kg of daptomycin, twice per day for 3 days, produced a small number of myofibers (≤0.22%) with loss of plasma membrane integrity and/or infiltration by neutrophils and/or macrophages. Multiple doses of daptomycin are required for a quantifiable effect on skeletal muscles of rats. Some fibers were Evans Blue Dye–positive but were not yet infiltrated by neutrophils. This suggests that the sarcolemma may be the primary target for the observed effects. Muscle Nerve, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77978/1/21691_ftp.pd

Simulating the Biogeochemical and Biogeophysical Impacts of Transient Land Cover Change and Wood Harvest in the Community Climate System Model (CCSM4) from 1850 to 2100

This is the publisher's version, also available electronically from http://journals.ametsoc.org/doi/abs/10.1175/JCLI-D-11-00256.1.To assess the climate impacts of historical and projected land cover change in the Community Climate System Model, version 4 (CCSM4), new time series of transient Community Land Model, version 4 (CLM4) plant functional type (PFT) and wood harvest parameters have been developed. The new parameters capture the dynamics of the Coupled Model Intercomparison Project phase 5 (CMIP5) land cover change and wood harvest trajectories for the historical period from 1850 to 2005 and for the four representative concentration pathway (RCP) scenarios from 2006 to 2100. Analysis of the biogeochemical impacts of land cover change in CCSM4 reveals that the model produced a historical cumulative land use flux of 127.7 PgC from 1850 to 2005, which is in general agreement with other global estimates of 156 PgC for the same period. The biogeophysical impacts of the transient land cover change parameters were cooling of the near-surface atmosphere over land by −0.1°C, through increased surface albedo and reduced shortwave radiation absorption. When combined with other transient climate forcings, the higher albedo from land cover change was counteracted by decreasing snow albedo from black carbon deposition and high-latitude warming. The future CCSM4 RCP simulations showed that the CLM4 transient PFT parameters can be used to represent a wide range of land cover change scenarios. In the reforestation scenario of RCP 4.5, CCSM4 simulated a drawdown of 67.3 PgC from the atmosphere into the terrestrial ecosystem and product pools. By contrast the RCP 8.5 scenario with deforestation and high wood harvest resulted in the release of 30.3 PgC currently stored in the ecosystem

The Community Land Model version 5 : description of new features, benchmarking, and impact of forcing uncertainty

The Community Land Model (CLM) is the land component of the Community Earth System Model (CESM) and is used in several global and regional modeling systems. In this paper, we introduce model developments included in CLM version 5 (CLM5), which is the default land component for CESM2. We assess an ensemble of simulations, including prescribed and prognostic vegetation state, multiple forcing data sets, and CLM4, CLM4.5, and CLM5, against a range of metrics including from the International Land Model Benchmarking (ILAMBv2) package. CLM5 includes new and updated processes and parameterizations: (1) dynamic land units, (2) updated parameterizations and structure for hydrology and snow (spatially explicit soil depth, dry surface layer, revised groundwater scheme, revised canopy interception and canopy snow processes, updated fresh snow density, simple firn model, and Model for Scale Adaptive River Transport), (3) plant hydraulics and hydraulic redistribution, (4) revised nitrogen cycling (flexible leaf stoichiometry, leaf N optimization for photosynthesis, and carbon costs for plant nitrogen uptake), (5) global crop model with six crop types and time‐evolving irrigated areas and fertilization rates, (6) updated urban building energy, (7) carbon isotopes, and (8) updated stomatal physiology. New optional features include demographically structured dynamic vegetation model (Functionally Assembled Terrestrial Ecosystem Simulator), ozone damage to plants, and fire trace gas emissions coupling to the atmosphere. Conclusive establishment of improvement or degradation of individual variables or metrics is challenged by forcing uncertainty, parametric uncertainty, and model structural complexity, but the multivariate metrics presented here suggest a general broad improvement from CLM4 to CLM5

On the role of subsecond dopamine release in conditioned avoidance

Using shock avoidance procedures to study conditioned behavioral responses has a rich history within the field of experimental psychology. Such experiments led to the formulation of the general concept of negative reinforcement and specific theories attempting to explain escape and avoidance behavior, or why animals choose to either terminate or prevent the presentation of an aversive event. For example, the two-factor theory of avoidance holds that cues preceding an aversive event begin to evoke conditioned fear responses, and these conditioned fear responses reinforce the instrumental avoidance response. Current neuroscientific advances are providing new perspectives into this historical literature. Due to its well-established role in reinforcement processes and behavioral control, the mesolimbic dopamine system presented itself as a logical starting point in the search for neural correlates of avoidance and escape behavior. We recently demonstrated that phasic dopamine release events are inhibited by stimuli associated with aversive events but increased by stimuli preceding the successful avoidance of the aversive event. The latter observation is inconsistent with the second component of the two-factor theory of avoidance and; therefore, led us propose a new theoretical explanation of conditioned avoidance: 1) fear is initially conditioned to the warning signal and dopamine computes this fear association as a decrease in release, 2) the warning signal, now capable of producing a negative emotional state, suppresses dopamine release and behavior, 3) over repeated trials the warning signal becomes associated with safety rather than fear; dopaminergic neurons already compute safety as an increase in release and begin to encode the warning signal as the earliest predictor of safety 4) the warning signal now promotes conditioned avoidance via dopaminergic modulation of the brain’s incentive-motivational circuitry