Heterosynaptic Dopamine Neurotransmission Selects Sets of Corticostriatal Terminals

Bamford, Nigel S.; Zhang, Hui; Schmitz, Yvonne; Wu, Nan; Cepeda, Carlos; Levine, Michael S.; Schmauss, Claudia; Zakharenko, Stanislav S.; Zablow, Leonard; Sulzer, David

doi:10.1016/s0896-6273(04)00265-x

Cited by 337 publications

(356 citation statements)

References 39 publications

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“…1A). The existence of neurons that express multiple transmitters has been described in other brain circuits and may represent the neural basis for filtering mechanisms by which release of coexpressed neurotransmitters occurs at differential firing rates (19). Using EM, we found, however, that orexin and dynorphin are colocalized within the same synaptic vesicles.…”

Section: Resultsmentioning

confidence: 63%

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Muschamp

Hollander

Thompson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

216

213

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Hypocretin (orexin) and dynorphin are neuropeptides with opposing actions on motivated behavior. Orexin is implicated in states of arousal and reward, whereas dynorphin is implicated in depressive-like states. We show that, despite their opposing actions, these peptides are packaged in the same synaptic vesicles within the hypothalamus. Disruption of orexin function blunts the rewarding effects of lateral hypothalamic (LH) stimulation, eliminates cocaine-induced impulsivity, and reduces cocaine selfadministration. Concomitant disruption of dynorphin function reverses these behavioral changes. We also show that orexin and dynorphin have opposing actions on excitability of ventral tegmental area (VTA) dopamine neurons, a prominent target of orexin-containing neurons, and that intra-VTA orexin antagonism causes decreases in cocaine self-administration and LH self-stimulation that are reversed by dynorphin antagonism. Our findings identify a unique cellular process by which orexin can occlude the reward threshold-elevating effects of coreleased dynorphin and thereby act in a permissive fashion to facilitate reward.O rexin promotes arousal (1) and has been implicated in the rewarding effects of food (2, 3), sexual behavior (4), and drugs of abuse (5, 6). It is produced primarily within the hypothalamus (7), and acts at orexin 1 receptor (OX 1 R) and OX 2 R (also known as Hcrt-R1 and Hcrt-R2), which are expressed in many brain areas, including the ventral tegmental area (VTA) of the midbrain (8). Dynorphin, in contrast, is expressed widely, promotes depressive-like behaviors, and plays a key role in mediating the aversive effects of stress (9, 10). Activation of kappaopioid receptor (KORs), the receptors at which dynorphin acts (11), can attenuate the rewarding effects of drugs of abuse (12, 13) via actions that are mediated, at least in part, within midbrain dopamine (DA) systems (14, 15). Despite their seemingly opposing effects on motivation, there is evidence that these peptides may act in tandem; for example, both orexin and dynorphin are released during electrical stimulation of the hypothalamus (16). Like DA neurons, orexin and dynorphin neurons increase their activity in response to arousing stimuli like rewards and stressors (17). The functional effects of this pattern of neuropeptide coexpression on brain reward systems, and, in turn, on motivated behavior, are poorly understood because orexin and dynorphin are not traditionally studied together. Given their opposing effects on behavior and neuronal physiology when studied alone, it can be hypothesized that dominance in the effects of one peptide over the other could cause widely divergent behavioral phenotypes in reward sensitivity. For example, dominant orexin signaling may enhance reward sensitivity and reward seeking, whereas dominant dynorphin signaling may result in decreased reward sensitivity and anergia. Because these states have major relevance to psychiatric illnesses like addiction and depression, where reward processing is disordered, we sought ...

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Section: Resultsmentioning

confidence: 63%

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Muschamp

Hollander

Thompson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

216

213

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“…However, these experiments did not use trains of stimuli. A recent study using the fluorescent dye FM1-43 (N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide) to monitor synaptic activity did observe a D 2 -dependent inhibition of release (Bamford et al, 2004). Importantly, this inhibition was frequency dependent, being greater at higher frequencies.…”

Section: Discussionmentioning

confidence: 99%

Dopamine Excites Nucleus Accumbens Neurons through the Differential Modulation of Glutamate and GABA Release

Hjelmstad¹

2004

J. Neurosci.

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Afferent activity into the nucleus accumbens (NAc) occurs in bursts of action potentials. However, it is unclear how synapses in this nucleus respond to such bursts, or how these responses are altered by dopamine (DA). I examined the effects of DA on excitatory and inhibitory responses to trains of stimuli in rat NAc slices. Both EPSCs and IPSCs showed use-dependent depression during trains. Although DA inhibited both glutamate and GABA release in the NAc, it differentially inhibited release during trains. The inhibition of IPSCs persisted throughout the train of stimuli, whereas the inhibition of EPSCs progressively diminished. This differential modulation may be explained by a calcium-dependent change in the recovery from depression at the GABA synapses, where DA acts by decreasing Ca 2ϩ entry. Thus, at later stages of sustained stimulation, DA preferentially inhibits GABA release, producing a net excitatory effect during bursts suggesting a mechanism for enhancing the contrast between competing inputs into the NAc, as well as for affecting long-term plasticity in this structure.

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“…The missing subcortical activity can be attributed to the tight regulation among neurotransmitters. In the striatum, Glu, GABA, acetylcholine, and DA modulate each other and the excitatory and inhibitory activities can be quickly nullified [1,8]. Therefore, a short stimulation paradigm may not be sufficient to arouse activity observable by fMRI.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of stimulated dopamine release and hemodynamic response in the brain through electrical stimulation of rat forepaw

Chen

Ren

Wang

et al. 2008

Neuroscience Letters

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The subcortical response to peripheral somatosensory stimulation is not well studied. Prior literature suggests that somatosensory stimulation can affect dopaminergic tone. We studied the effects of electrical stimulation near the median nerve on the response to an amphetamine induced increase in synaptic dopamine. We applied the electrical stimulation close to the median nerve 20 minutes after administration of 3mg/kg amphetamine. We used fMRI and microdialysis to measure markers of DA release, together with the release of associated neurotransmitters of striatal Glutamate (Glu) and GABA.Result-1) Changes in cerebral blood volume (CBV), a marker used in fMRI, indicate that electrical stimulation significantly attenuated increased DA release (due to AMPH) in the striatum, thalamus, medial prefrontal and cingulate cortices. 2) Microdialysis showed that electrical stimulation increased Glu and GABA release and attenuated the AMPH-enhanced DA release. The striatal DA dynamics correlated with the CBV response.Conclusion-These results demonstrate that electrical stimulation near the median nerve activates Glu/GABA release which subsequently attenuate excess striatal DA release. These data provide evidence for physiologic modulation caused by electroacupuncture at points near the median nerve.

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Heterosynaptic Dopamine Neurotransmission Selects Sets of Corticostriatal Terminals

Cited by 337 publications

References 39 publications

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Dopamine Excites Nucleus Accumbens Neurons through the Differential Modulation of Glutamate and GABA Release

Inhibition of stimulated dopamine release and hemodynamic response in the brain through electrical stimulation of rat forepaw

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