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

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.

Keywords: cannabinoids; cues; dopamine; endocannabinoids; fixed interval; reward-seeking behavior.

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 G_q/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 (–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.

Figure 2

Based on the striatal beat frequency model of interval timing – a schematic representation of the neurobiology underlying interval timing during a typical 30 s fixed interval (A,B) and during a 30 s fixed interval following administration of the synthetic cannabinoid WIN 55,212-2 (WIN) (C,D). (A) At interval onset, phasic dopamine (DA) transmission resets the internal clock through synchronization of frontal cortical oscillators [depicted in (A) as simultaneously firing cells and illustrated as red cell bodies] and clears out the coincidence detector (ventral striatum). These phasic signals arise through burst firing of ventral tegmental area (VTA) DA cells, which is facilitated by endocannabinoid (2-AG)-mediated suppression of GABA release onto VTA DA neurons. As the 30 s interval progresses (illustrated in the three panels to the right depicting time points at 10, 20, and 30 s), the once synchronized cortical oscillators fall out of phase with one another at a reliable rate. Reward delivery at interval terminus results in phasic DA transmission within the ventral striatum that enhances LTP at active cortico-striatal synapses. (B) Later when the same (in this case auditory) stimulus signals interval onset, cortical oscillators exhibit characteristic periodicities and when the previously strengthened synaptic pattern active at interval terminus is encountered again (30 s after interval onset) its activation will promote reward seeking. (C) WIN administration results in phasic activation of VTA DA neurons through binding to CB1 receptors on VTA GABAergic neurons and thereby disinhibiting VTA DA transmission. Drug-induced aberrant DAergic activation throughout the interval induces LTP at cortico-striatal synapses active prior to reward delivery (illustrated in the three panels to the right depicting time points at 10, 20, and 30 s). (D) This Hebbian strengthening of synaptic activity characteristic of earlier time points within the interval promotes premature reward seeking following subsequent cue presentation.