A distinct D1-MSN subpopulation down-regulates dopamine to promote negative emotional state

AbstractDopamine (DA) level in the nucleus accumbens (NAc) is critical for reward and aversion encoding. DA released from the ventral mesencephalon (VM) DAergic neurons increases the excitability of VM-projecting D1-dopamine receptor-expressing medium spiny neurons (D1-MSNs) in the NAc to enhance DA release and augment rewards. However, how such a DA positive feedback loop is regulated to maintain DA homeostasis and reward-aversion balance remains elusive. Here we report that the ventral pallidum (VP) projection of NAc D1-MSNs (D1NAc-VP) is inhibited by rewarding stimuli and activated by aversive stimuli. In contrast to the VM projection of D1-MSN (D1NAc-VM), activation of D1NAc-VP projection induces aversion, but not reward. D1NAc-VP MSNs are distinct from the D1NAc-VM MSNs, which exhibit conventional functions of D1-MSNs. Activation of D1NAc-VP projection stimulates VM GABAergic transmission, inhibits VM DAergic neurons, and reduces DA release into the NAc. Thus, D1NAc-VP and D1NAc-VM MSNs cooperatively control NAc dopamine balance and reward-aversion states.

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Selective D2 and D3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

10.1101/439398 ◽

2018 ◽

Author(s):

Daniel F. Manvich ◽

Alyssa K. Petko ◽

Rachel C. Branco ◽

Stephanie L. Foster ◽

Kirsten A. Porter-Stransky ◽

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Keyword(s):

Nucleus Accumbens ◽

Drugs Of Abuse ◽

Ex Vivo ◽

Medium Spiny Neurons ◽

D3 Receptor ◽

Receptor Antagonists ◽

Fast Scan Cyclic Voltammetry ◽

Spiny Neurons ◽

Cocaine Responses ◽

Da Release

AbstractBackgroundThe D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for the treatment of several diseases including schizophrenia, Parkinson’s disease, and substance use disorders. However, studies investigating the modulatory impact of D3R antagonism on dopamine neurotransmission or the effects drugs of abuse have produced mixed results, in part because D3R-targeted compounds often also interact with D2 receptors (D2R). The purpose of this study was to compare the consequences of selective D2R or D3R antagonism on the behavioral effects of cocaine in mice, and to identify the neurobiological mechanisms underlying their modulatory effects.MethodsWe characterized the effects of selective D2R or D3R antagonism in mice on 1) basal and cocaine-induced locomotor activity, 2) presynaptic dopamine release and clearance in the nucleus accumbens using ex vivo fast scan cyclic voltammetry, and 3) dopamine-mediated signaling in D1-expressing and D2-expressing medium spiny neurons using ex vivo electrophysiology.ResultsPretreatment with the selective D2R antagonist L-741,626 attenuated, while pretreatment with the selective D3R antagonist PG01037 enhanced, the locomotor-activating effects of acute and repeated cocaine administration. While both antagonists potentiated cocaine-induced increases in presynaptic DA release, D3R blockade uniquely facilitated DA-mediated excitation of D1-expressing medium spiny neurons in the nucleus accumbens.ConclusionsSelective D3R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D2R antagonism or nonselective D2-like receptor antagonists, likely by facilitating D1-mediated excitation in the nucleus accumbens. These findings provide important insights into the neuropharmacological actions of D3R antagonists on mesolimbic dopamine neurotransmission.

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Distinct role of nucleus accumbens D2-MSN projections to ventral pallidum in different phases of motivated behavior

10.1101/2020.11.27.401042 ◽

2020 ◽

Author(s):

Carina Soares-Cunha ◽

Raquel Correia ◽

Ana Verónica Domingues ◽

Bárbara Coimbra ◽

Nivaldo AP de Vasconcelos ◽

...

Keyword(s):

Nucleus Accumbens ◽

Behavioral Effect ◽

Ventral Pallidum ◽

Medium Spiny Neurons ◽

Motivated Behavior ◽

Spiny Neurons ◽

Reward Delivery ◽

Instrumental Task ◽

Motivated Behaviors

AbstractThe nucleus accumbens (NAc) is a key region in motivated behaviors. NAc medium spiny neurons (MSNs) are divided into those expressing dopamine receptor D1 or D2. Classically, D1- and D2-MSNs have been described as having opposing roles in reinforcement but recent evidence suggests a more complex role for D2-MSNs.Here we show that optogenetic modulation of D2-MSN to ventral pallidum (VP) projections during different stages of motivated behavior has contrasting effects in motivation. Activation of D2-MSN-VP projections during a reward-predicting cue results in increased motivational drive, whereas activation at reward delivery results in decreased motivation; optical inhibition has the opposite behavioral effect. In addition, in a free choice instrumental task, animals prefer the lever that originates one pellet in opposition to pellet plus D2-MSN-VP optogenetic activation, and vice versa for optogenetic inhibition.In summary, D2-MSN-VP projections play different (and even opposing) roles in distinct phases of motivated behavior.

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