Dopamine concentrations fluctuate on a subsecond time scale in the nucleus accumbens (NAc) of awake rats. These transients occur in resting animals, are more frequent following administration of drugs of abuse, and become time-locked to cues predicting reward. Despite their importance in various behaviors, the origin of these signals has not been demonstrated. Here we show that dopamine transients are evoked by neural activity in the ventral tegmental area (VTA), a brain region containing dopaminergic cell bodies. The frequency of naturally occurring dopamine transients in a resting, awake animal was reduced by a local VTA microinfusion of either lidocaine or (Ϯ)2-amino,5-phosphopentanoic acid (AP-5), an NMDA receptor antagonist that attenuates phasic firing. When dopamine increases were pharmacologically evoked by noncontingent administration of cocaine, intra-VTA infusion of lidocaine or AP-5 significantly diminished this effect. Dopamine transients acquired in response to a cue during intracranial self-stimulation were also attenuated by intra-VTA microinfusion of AP-5, and this was accompanied by an increase in latency to lever press. The results from these three distinct experiments directly demonstrate, for the first time, how neuronal firing of dopamine neurons originating in the VTA translates into synaptic overflow in a key terminal region, the NAc shell.Key words: in vivo voltammetry; neurotransmission; carbon-fiber microelectrode; cocaine; intracranial self-stimulation; burst firing IntroductionDopaminergic neurons provide a critical modulatory influence in reward seeking (Everitt and Robbins, 2000;Phillips et al., 2003a), prediction error (Schultz et al., 1997 and reinforcement (Wise, 2004). Real-time dopamine neurotransmission in awake animals, monitored with fast-scan cyclic voltammetry at carbonfiber microelectrodes, has revealed naturally occurring, subsecond dopamine concentration fluctuations (transients) in the nucleus accumbens (NAc) (Robinson et al., 2002;Wightman et al., 2007). Under basal conditions these transients occur at highly variable frequencies with amplitudes of ϳ50 nM and durations of ϳ1 s . They are enhanced upon administration of drugs of abuse (Stuber et al., 2005), and become timelocked to cues that predict reward availability (Phillips et al., 2003a;Roitman et al., 2004;Day et al., 2007;Owesson-White et al., 2008). Despite their importance, the origin of dopamine transients in the NAc is unclear.The most likely cause of dopamine transients is phasic firing of dopaminergic neurons in the ventral tegmental area (VTA).These neurons normally fire in a tonic pattern (ϳ5 Hz) and periodically discharge in short bursts (ϳ20 Hz). Bursts are particularly apparent at presentation of primary rewards or their associated cues (Schultz et al., 1997;Hyland et al., 2002). The activity of dopaminergic neurons is regulated by multiple inputs (Floresco et al., 2003;Lodge and Grace, 2006), and in brain slices that lack these inputs, phasic activity is not observed (Overton and Clark, 1997). In t...
Dopamine in the nucleus accumbens (NAc) is an important neurotransmitter for reward-seeking behaviors such as intracranial selfstimulation (ICSS), although its precise role remains unclear. Here, dynamic fluctuations in extracellular dopamine were measured during ICSS in the rat NAc shell with fast-scan cyclic voltammetry at carbon-fiber microelectrodes. Rats were trained to press a lever to deliver electrical stimulation to the substantia nigra (SNc)/ ventral tegmental area (VTA) after the random onset of a cue that predicted reward availability. Latency to respond after cue onset significantly declined across trials, indicative of learning. Dopamine release was evoked by the stimulation but also developed across trials in a time-locked fashion to the cue. Once established, the cue-evoked dopamine transients continued to grow in amplitude, although they were variable from trial to trial. The emergence of cue-evoked dopamine correlated with a decline in electrically evoked dopamine release. Extinction of ICSS resulted in a significant decline in goal-directed behavior coupled to a significant decrease in cue-evoked phasic dopamine across trials. carbon-fiber electrode ͉ cyclic voltammetry ͉ extinction ͉ nucleus accumbens shell ͉ reward I ntracranial self-stimulation (ICSS) was discovered in 1954 (1). In this paradigm, a rat depresses a lever to deliver an electric shock to electrodes implanted within the brain. Extensive mapping studies by Olds and Olds later showed that the neuroanatomical region supporting ICSS centered in the posterior MFB region of the lateral hypothalamus (2). This finding provoked considerable interest, because it identified a brain reward pathway that could be centrally activated without the need for sensory stimulation (3, 4). Although a role for several neurotransmitters has been implicated in ICSS, dopamine appears to play a primary role (5, 6), leading to the view that dopaminergic signaling is essential during goal-directed behaviors. Indeed, it was postulated that increased dopaminergic neurotransmission was necessary for the reinforcement of reward-related behavior (7).More recently, electrophysiological studies in primates have provided new insight into the role of dopaminergic neurons in reward processing (8). In response to unexpected rewards, dopamine neurons exhibit phasic firing. However, when an animal learns that a cue predicts reward, the burst of neuronal firing switches to the onset of the cue (9-12). Responses to the cue increase with repeated trials, and these paired responses of midbrain dopamine neurons follow the expectations of models of associative learning in which dopamine signaling is a reward-prediction error (12,13). Similar responses to conditioned stimuli that predict reward have also been observed for midbrain dopaminergic neurons in rats (14).A phasic increase in dopamine neuronal firing should lead to a dopamine concentration transient in terminal areas such as the nucleus accumbens (NAc). Indeed, using fast-scan cyclic voltammetry at carbon-fiber microe...
The mesolimbic dopamine system is critically involved in modulating reward-seeking behavior and is transiently activated upon presentation of reward-predictive cues. It has previously been shown, using fast-scan cyclic voltammetry in behaving rats, that cues predicting a variety of reinforcers including food/water, cocaine or intracranial self-stimulation (ICSS) elicit time-locked transient fluctuations in dopamine concentration in the nucleus accumbens (NAc) shell. These dopamine transients have been found to correlate with reward-related learning and are believed to promote reward-seeking behavior. Here, we investigated the effects of varying reinforcer magnitude (intracranial stimulation parameters) on cue-evoked dopamine release in the NAc shell in rats performing ICSS. We found that the amplitude of cue-evoked dopamine is adaptable, tracks reinforcer magnitude and is significantly correlated with ICSS seeking behavior. Specifically, the concentration of cue-associated dopamine transients increased significantly with increasing reinforcer magnitude, while, at the same time, the latency to lever press decreased with reinforcer magnitude. These data support the proposed role of NAc dopamine in the facilitation of rewardseeking and provide unique insight into factors influencing the plasticity of dopaminergic signaling during behavior.
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