Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use

Departments of Psychiatry and Behavioral Sciences and Pharmacology, University of Washington, Seattle, WA 98195.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2012; 109(50). DOI: 10.1073/pnas.1213460109
Source: PubMed


Drug addiction is a neuropsychiatric disorder that marks the end stage of a progression beginning with recreational drug taking but culminating in habitual and compulsive drug use. This progression is considered to reflect transitions among multiple neural loci. Dopamine neurotransmission in the ventromedial striatum (VMS) is pivotal in the control of initial drug use, but emerging evidence indicates that once drug use is well established, its control is dominated by the dorsolateral striatum (DLS). In the current work, we conducted longitudinal neurochemical recordings to ascertain the spatiotemporal profile of striatal dopamine release and to investigate how it changes during the period from initial to established drug use. Dopamine release was detected using fast-scan cyclic voltammetry simultaneously in the VMS and DLS of rats bearing indwelling i.v. catheters over the course of 3 wk of cocaine self-administration. We found that phasic dopamine release in DLS emerged progressively during drug taking over the course of weeks, a period during which VMS dopamine signaling declined. This emergent dopamine signaling in the DLS mediated discriminated behavior to obtain drug but did not promote escalated or compulsive drug use. We also demonstrate that this recruitment of dopamine signaling in the DLS is dependent on antecedent activity in VMS circuitry. Thus, the current findings identify a striatal hierarchy that is instantiated during the expression of established responses to obtain cocaine.

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    • "Rats will also emit 50-kHz calls in anticipation of electrical stimulation of the medial forebrain bundle (MFB) that would be expected to increase phasic DA release in terminal areas such as the NAcc (Burgdorf et al., 2000). If phasic DA transmission promotes USV emission, this could also reconcile several pharmacological findings: (1) AMPH and cocaine reliably induced 50-kHz calling and increased phasic DA release (Cheer et al., 2007; Wright et al., 2010, 2013; Willuhn et al., 2012; Daberkow et al., 2013; Covey et al., 2014), (2) tonic activation of postsynaptic receptors by selective DA receptor agonists inhibited spontaneous calling (Scardochio and Clarke, 2013), and (3) the DAT blocker GBR 12909, which did not increase USV emission (Wright et al., 2013), is expected to increase both tonic and phasic DA signaling (Reith et al., 1997; Budygin et al., 2000; Owesson-White et al., 2012), the former effect potentially masking the latter. The aim of the present study was therefore to test whether phasic DA release events drive 50-kHz calls in adult rats. "
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    ABSTRACT: Rationale: Adult rats emit ultrasonic vocalizations (USVs) at around 50-kHz; these commonly occur in contexts that putatively engender positive affect. While several reports indicate that dopaminergic (DAergic) transmission plays a role in the emission of 50-kHz calls, the pharmacological evidence is mixed. Different modes of dopamine (DA) release (i.e., tonic and phasic) could potentially explain this discrepancy. Objective: To investigate the potential role of phasic DA release in 50-kHz call emission. Methods: In Experiment 1, USVs were recorded in adult male rats following unexpected electrical stimulation of the medial forebrain bundle (MFB). In parallel, phasic DA release in the nucleus accumbens (NAcc) was recorded using fast-scan cyclic voltammetry. In Experiment 2, USVs were recorded following response-contingent or non-contingent optogenetic stimulation of midbrain DAergic neurons. Four 20-s schedules of optogenetic stimulation were used: fixed-interval, fixed-time, variable-interval, and variable-time. Results: Brief electrical stimulation of the MFB increased both 50-kHz call rate and phasic DA release in the NAcc. During optogenetic stimulation sessions, rats initially called at a high rate comparable to that observed following reinforcers such as psychostimulants. Although optogenetic stimulation maintained reinforced responding throughout the 2-h session, the call rate declined to near zero within the first 30 min. The trill call subtype predominated following both electrical and optical stimulation. Conclusion: The occurrence of electrically-evoked 50-kHz calls, time-locked to phasic DA (Experiment 1), provides correlational evidence supporting a role for phasic DA in USV production. However, in Experiment 2, the temporal dissociation between calling and optogenetic stimulation of midbrain DAergic neurons suggests that phasic mesolimbic DA release is not sufficient to produce 50-kHz calls. The emission of the trill subtype of 50-kHz calls potentially provides a marker distinguishing positive affect from positive reinforcement.
    Full-text · Article · Dec 2015 · Frontiers in Behavioral Neuroscience
    • "In the last three decades, research on addiction has found significant evidence regarding the ability of cocaine to induce short-and long-lasting molecular and structural plasticity in the corticostriatal-limbic circuitry (Corbit et al. 2012; Everitt and Robbins 2005; Murray et al. 2013; Willuhn et al. 2012). Despite increasing evidence for the involvement of the cerebellum in drug-related behavioural alterations, however, this structure has been traditionally overlooked in addiction research (Carbo-Gas et al. 2014a, b; Moulton et al. 2014; Vazquez-Sanroman et al. 2015). "
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    ABSTRACT: Rationale Prior research has accumulated a substantial amount of evidence on the ability of cocaine to produce short- and long-lasting molecular and structural plasticity in the corticostriatal-limbic circuitry. However, traditionally, the cerebellum has not been included in the addiction circuitry, even though growing evidence supports its involvement in the behavioural changes observed after repeated drug experiences. Objectives In the present study, we explored the ability of seven cocaine administrations to alter plasticity in the cerebellar vermis. Methods After six cocaine injections, one injection every 48 h, mice remained undisturbed for 1 month in their home cages. Following this withdrawal period, they received a new cocaine injection of a lower dose. Locomotion, behavioural stereotypes and several molecular and structural cerebellar parameters were evaluated. Results Cerebellar proBDNF and mature BDNF levels were both enhanced by cocaine. The high BDNF expression was associated with dendritic sprouting and increased terminal size in Purkinje neurons. Additionally, we found a reduction in extracellular matrix components that might facilitate the subsequent remodelling of Purkinje-nuclear neuron synapses. Conclusions Although speculative, it is possible that these cocaine-dependent cerebellar changes were incubated during withdrawal and manifested by the last drug injection. Importantly, the present findings indicate that cocaine is able to promote plasticity modifications in the cerebellum of sensitised animals similar to those in the basal ganglia.
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    No preview · Article · Aug 2015 · Annual Review of Psychology
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