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Endocannabinoid-dependent modulation of phasic dopamine signaling encodes external and internal reward-predictive cues.

Wenzel JM, Cheer JF - Front Psychiatry (2014)

Bottom Line: Indeed, administration of exogenous cannabinoids results in burst firing of DA neurons of the ventral tegmental area and increases extracellular DA in the nucleus accumbens (NAcc).That is, as the interval progresses, NAcc DA levels decline leading to accelerated food seeking and the resulting characteristic FI scallop pattern of responding.The current review will explore the striatal beat frequency model of interval timing as it pertains to cannabinoid signaling and propose a neurocircuitry through which this system modulates interoceptive time cues.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine , Baltimore, MD , USA.

ABSTRACT
The mesolimbic dopamine (DA) system plays an integral role in incentive motivation and reward seeking and a growing body of evidence identifies signal transduction at cannabinoid receptors as a critical modulator of this system. Indeed, administration of exogenous cannabinoids results in burst firing of DA neurons of the ventral tegmental area and increases extracellular DA in the nucleus accumbens (NAcc). Implementation of fast-scan cyclic voltammetry (FSCV) confirms the ability of cannabinoids to augment DA within the NAcc on a subsecond timescale. The use of FSCV along with newly developed highly selective pharmacological compounds advances our understanding of how cannabinoids influence DA transmission and highlights a role for endocannabinoid-modulated subsecond DAergic activation in the incentive motivational properties of not only external, but also internal reward-predictive cues. For example, our laboratory has recently demonstrated that in mice responding under a fixed-interval (FI) schedule for food reinforcement, fluctuations in NAcc DA signal the principal cue predictive of reinforcer availability - time. That is, as the interval progresses, NAcc DA levels decline leading to accelerated food seeking and the resulting characteristic FI scallop pattern of responding. Importantly, administration of WIN 55,212-2, a synthetic cannabinoid agonist, or JZL184, an indirect cannabinoid agonist, increases DA levels during the interval and disrupts this pattern of responding. Along with a wealth of other reports, these results illustrate the role of cannabinoid receptor activation in the regulation of DA transmission and the control of temporally guided reward seeking. The current review will explore the striatal beat frequency model of interval timing as it pertains to cannabinoid signaling and propose a neurocircuitry through which this system modulates interoceptive time cues.

No MeSH data available.


Related in: MedlinePlus

Illustration of 2-arachidonylglycerol (2-AG) synthesis. (A) Depolarization-induced Ca2+ influx within dopamine (DA) neurons of the ventral tegmental area (VTA) results in the hydrolysis of 1,2-diacylglycerol (DAG) by DGL-α and DGL-β lipases to form 2-AG (98, 100). (B) Alternatively, activation of Gq/11 protein-coupled receptors (e.g., group 1 metabotropic glutamate receptors) directly stimulate phospholipase-Cβ (PLC), resulting in the hydrolysis of membrane phosphate phosphatidylinositol 4,5-bisphosphate (PIP2) to DAG, allowing for subsequent hydrolysis of DAG to 2-AG (101–103). In addition, Ca2+-dependent and GPCR-dependent 2-AG synthesis can co-occur to synergistically produce high concentrations of 2-AG (104, 105). (C) Following on-demand synthesis, 2-AG then diffuses from the postsynaptic DA neurons and binds with CB1 receptors on presynaptic gamma- aminobutyric acid (GABA) cells, inhibiting GABA release and thereby disinhibiting DAergic cell activity.
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Figure 1: Illustration of 2-arachidonylglycerol (2-AG) synthesis. (A) Depolarization-induced Ca2+ influx within dopamine (DA) neurons of the ventral tegmental area (VTA) results in the hydrolysis of 1,2-diacylglycerol (DAG) by DGL-α and DGL-β lipases to form 2-AG (98, 100). (B) Alternatively, activation of Gq/11 protein-coupled receptors (e.g., group 1 metabotropic glutamate receptors) directly stimulate phospholipase-Cβ (PLC), resulting in the hydrolysis of membrane phosphate phosphatidylinositol 4,5-bisphosphate (PIP2) to DAG, allowing for subsequent hydrolysis of DAG to 2-AG (101–103). In addition, Ca2+-dependent and GPCR-dependent 2-AG synthesis can co-occur to synergistically produce high concentrations of 2-AG (104, 105). (C) Following on-demand synthesis, 2-AG then diffuses from the postsynaptic DA neurons and binds with CB1 receptors on presynaptic gamma- aminobutyric acid (GABA) cells, inhibiting GABA release and thereby disinhibiting DAergic cell activity.

Mentions: The discovery of cannabinoid receptors was followed shortly after by the identification of their primary endogenous ligands – N-arachidonylethanolamine (anandamide; AEA), a partial agonist at CB1 receptors, and 2-arachidonylglycerol (2-AG), a full agonist at both CB1 and CB2 receptors (94–96). The biosynthesis of AEA is not fully understood, although it is generally agreed that AEA is synthesized from N-arachidonoyl phosphatidylethanolamine (NAPE) in a Ca2+-dependent manner via one of the several possible enzymatic pathways (97, 98). Conversely, both Ca2+-dependent and Ca2+-independent synthesis pathways for 2-AG have been outlined (illustrated in Figure 1). Following synthesis and release, AEA and 2-AG signaling is quickly terminated through cellular reuptake and hydrolysis primarily by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively [FAAH can also hydrolyze 2-AG (99)]. While several additional endocannabinoids have since been discovered, AEA and 2-AG remain the best characterized.


Endocannabinoid-dependent modulation of phasic dopamine signaling encodes external and internal reward-predictive cues.

Wenzel JM, Cheer JF - Front Psychiatry (2014)

Illustration of 2-arachidonylglycerol (2-AG) synthesis. (A) Depolarization-induced Ca2+ influx within dopamine (DA) neurons of the ventral tegmental area (VTA) results in the hydrolysis of 1,2-diacylglycerol (DAG) by DGL-α and DGL-β lipases to form 2-AG (98, 100). (B) Alternatively, activation of Gq/11 protein-coupled receptors (e.g., group 1 metabotropic glutamate receptors) directly stimulate phospholipase-Cβ (PLC), resulting in the hydrolysis of membrane phosphate phosphatidylinositol 4,5-bisphosphate (PIP2) to DAG, allowing for subsequent hydrolysis of DAG to 2-AG (101–103). In addition, Ca2+-dependent and GPCR-dependent 2-AG synthesis can co-occur to synergistically produce high concentrations of 2-AG (104, 105). (C) Following on-demand synthesis, 2-AG then diffuses from the postsynaptic DA neurons and binds with CB1 receptors on presynaptic gamma- aminobutyric acid (GABA) cells, inhibiting GABA release and thereby disinhibiting DAergic cell activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150350&req=5

Figure 1: Illustration of 2-arachidonylglycerol (2-AG) synthesis. (A) Depolarization-induced Ca2+ influx within dopamine (DA) neurons of the ventral tegmental area (VTA) results in the hydrolysis of 1,2-diacylglycerol (DAG) by DGL-α and DGL-β lipases to form 2-AG (98, 100). (B) Alternatively, activation of Gq/11 protein-coupled receptors (e.g., group 1 metabotropic glutamate receptors) directly stimulate phospholipase-Cβ (PLC), resulting in the hydrolysis of membrane phosphate phosphatidylinositol 4,5-bisphosphate (PIP2) to DAG, allowing for subsequent hydrolysis of DAG to 2-AG (101–103). In addition, Ca2+-dependent and GPCR-dependent 2-AG synthesis can co-occur to synergistically produce high concentrations of 2-AG (104, 105). (C) Following on-demand synthesis, 2-AG then diffuses from the postsynaptic DA neurons and binds with CB1 receptors on presynaptic gamma- aminobutyric acid (GABA) cells, inhibiting GABA release and thereby disinhibiting DAergic cell activity.
Mentions: The discovery of cannabinoid receptors was followed shortly after by the identification of their primary endogenous ligands – N-arachidonylethanolamine (anandamide; AEA), a partial agonist at CB1 receptors, and 2-arachidonylglycerol (2-AG), a full agonist at both CB1 and CB2 receptors (94–96). The biosynthesis of AEA is not fully understood, although it is generally agreed that AEA is synthesized from N-arachidonoyl phosphatidylethanolamine (NAPE) in a Ca2+-dependent manner via one of the several possible enzymatic pathways (97, 98). Conversely, both Ca2+-dependent and Ca2+-independent synthesis pathways for 2-AG have been outlined (illustrated in Figure 1). Following synthesis and release, AEA and 2-AG signaling is quickly terminated through cellular reuptake and hydrolysis primarily by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively [FAAH can also hydrolyze 2-AG (99)]. While several additional endocannabinoids have since been discovered, AEA and 2-AG remain the best characterized.

Bottom Line: Indeed, administration of exogenous cannabinoids results in burst firing of DA neurons of the ventral tegmental area and increases extracellular DA in the nucleus accumbens (NAcc).That is, as the interval progresses, NAcc DA levels decline leading to accelerated food seeking and the resulting characteristic FI scallop pattern of responding.The current review will explore the striatal beat frequency model of interval timing as it pertains to cannabinoid signaling and propose a neurocircuitry through which this system modulates interoceptive time cues.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine , Baltimore, MD , USA.

ABSTRACT
The mesolimbic dopamine (DA) system plays an integral role in incentive motivation and reward seeking and a growing body of evidence identifies signal transduction at cannabinoid receptors as a critical modulator of this system. Indeed, administration of exogenous cannabinoids results in burst firing of DA neurons of the ventral tegmental area and increases extracellular DA in the nucleus accumbens (NAcc). Implementation of fast-scan cyclic voltammetry (FSCV) confirms the ability of cannabinoids to augment DA within the NAcc on a subsecond timescale. The use of FSCV along with newly developed highly selective pharmacological compounds advances our understanding of how cannabinoids influence DA transmission and highlights a role for endocannabinoid-modulated subsecond DAergic activation in the incentive motivational properties of not only external, but also internal reward-predictive cues. For example, our laboratory has recently demonstrated that in mice responding under a fixed-interval (FI) schedule for food reinforcement, fluctuations in NAcc DA signal the principal cue predictive of reinforcer availability - time. That is, as the interval progresses, NAcc DA levels decline leading to accelerated food seeking and the resulting characteristic FI scallop pattern of responding. Importantly, administration of WIN 55,212-2, a synthetic cannabinoid agonist, or JZL184, an indirect cannabinoid agonist, increases DA levels during the interval and disrupts this pattern of responding. Along with a wealth of other reports, these results illustrate the role of cannabinoid receptor activation in the regulation of DA transmission and the control of temporally guided reward seeking. The current review will explore the striatal beat frequency model of interval timing as it pertains to cannabinoid signaling and propose a neurocircuitry through which this system modulates interoceptive time cues.

No MeSH data available.


Related in: MedlinePlus