Cannabinoid Receptor Activation Shifts Temporally Engendered Patterns of Dopamine Release

Abstract

The ability to discern temporally pertinent environmental events is essential for the generation of adaptive behavior in conventional tasks, and our overall survival. Cannabinoids are thought to disrupt temporally controlled behaviors by interfering with dedicated brain timing networks. Cannabinoids also increase dopamine release within the mesolimbic system, a neural pathway generally implicated in timing behavior. Timing can be assessed using fixed-interval (FI) schedules, which reinforce behavior on the basis of time. To date, it remains unknown how cannabinoids modulate dopamine release when responding under FI conditions, and for that matter, how subsecond dopamine release is related to time in these tasks. In the present study, we hypothesized that cannabinoids would accelerate timing behavior in an FI task while concurrently augmenting a temporally relevant pattern of dopamine release. To assess this possibility, we measured subsecond dopamine concentrations in the nucleus accumbens while mice responded for food under the influence of the cannabinoid agonist WIN 55 212-2 in an FI task. Our data reveal that accumbal dopamine concentrations decrease proportionally to interval duration-suggesting that dopamine encodes time in FI tasks. We further demonstrate that WIN 55 212-2 dose-dependently increases dopamine release and accelerates a temporal behavioral response pattern in a CB1 receptor-dependent manner-suggesting that cannabinoid receptor activation modifies timing behavior, in part, by augmenting time-engendered patterns of dopamine release. Additional investigation uncovered a specific role for endogenous cannabinoid tone in timing behavior, as elevations in 2-arachidonoylglycerol, but not anandamide, significantly accelerated the temporal response pattern in a manner akin to WIN 55 212-2.

Dopamine Encodes Retrospective Temporal Information in a Context-Independent Manner

“…Wait time dopamine levels decayed according to an exponential function for the first 15 s (prior to the first possible CS presentation) and by a linear function thereafter in Long Wait trials (Figure 1C, Figure S1). This reduction in wait time dopamine levels is consistent with the time-dependent decrease in dopamine neuron firing prior to the presentation of a CS (Bromberg-Martin et al, 2010; Pasquereau and Turner, 2015), as well as with the cumulative decrease in NAc dopamine levels observed across trials and throughout behavioral sessions (Bassareo et al, 2015; Oleson et al, 2014). Inhibiting dopamine neuron activity accelerates the subjective estimate of elapsed time (Soares et al, 2016), which suggests the decrease in wait time dopamine levels could signal the passage of time.…”

Dynamic Nigrostriatal Dopamine Biases Action Selection

“…The optogenetic results are inconsistent with predicted changes in the psychometric curve under pure manipulation of time (Figure S8). Therefore, while the dopamine system has been linked to timing behaviors under certain experimental settings (Buhusi and Meck, 2005; Oleson et al, 2014), neither our physiological measurements nor our behavioral manipulations can be fully explained as dopamine signaling the time intervals alone.…”

“…In order to directly assess the role of dopamine in implementation of this behavior, fast-scan cyclic voltammetry (FSCV) with chronically implanted carbon fiber microelectrodes (Clark et al, 2010; Oleson et al, 2014) was employed to monitor subsecond dopamine changes in the dorsal striatum during behavior (Figure 1E; Figure S1A–S1C). Dorsal striatal dopamine concentration increased after trial onset, and remained elevated during 2 s trials (Figure 1F and 1H; paired t-test, t 10 = 2.210, P < 0.05).…”

“…Previously, dopamine has been implicated in timing behaviors (Buhusi and Meck, 2005;Oleson et al, 2014), mostly based on results of pharmacological experiments with global manipulation, though it remains unclear whether these effects resulted from altering time perception or because of disrupted action selection. A recent study by Soares et al (2016) utilized a temporal discrimination task to determine the contribution of midbrain dopamine to interval duration judgment.…”

NMDA receptors are involved in the antidepressant-like effects of capsaicin following amphetamine withdrawal in male mice

“…(Renoir et al, 2012;Che et al, 2013). With-35 drawal from stimulants is accompanied by dysphoric state 36 which contributes to drug-seeking behavior and relapse, 37 and causes treatment failure in individuals with stimulant 38 dependence (Koob et al, 1998;Oleson et al, 2014). 39 2005).…”