Regulation of prefrontal excitatory neurotransmission by dopamine in the nucleus accumbens core

Abstract

Key points• Dopamine's control over excitatory signals from the cortex to the nucleus accumbens is thought to underlie motor learning, behavioural reinforcement and drug dependence.• In this study, we combined optical recordings of presynaptic release with whole-cell electrophysiology in CB 1 receptor-null mice and bacterial artificial chromosome (BAC) transgenic mice with fluorescently labelled D1 and D2 receptor-expressing neurons to identify the specific interactions between dopamine and glutamate signalling at individual cortical terminals within the nucleus accumbens core.• Experiments showed that dopamine produces frequency-dependent filtering of low-probability release synapses. At low frequencies, D1 receptors excited striatal output neurons of the striatonigral and striatopallidal pathways, while D2 receptors specifically inhibited neurons of the striatopallidal pathway. At higher frequencies, the dopamine-dependent release of adenosine and endocannabinoids promoted further temporal filtering of cortical signals entering both output pathways.• These results help us understand how dopamine provides frequency and temporal filtering of cortical information by promoting activity through the striatonigral pathway, while inhibiting weak signals.Abstract Interactions between dopamine and glutamate signalling within the nucleus accumbens core are required for behavioural reinforcement and habit formation. Dopamine modulates excitatory glutamatergic signals from the prefrontal cortex, but the precise mechanism has not been identified. We combined optical and electrophysiology recordings in murine slice preparations from CB 1 receptor-null mice and green fluorescent protein hemizygotic bacterial artificial chromosome transgenic mice to show how dopamine regulates glutamatergic synapses specific to the striatonigral and striatopallidal basal ganglia pathways. At low cortical frequencies, dopamine D1 receptors promote glutamate release to both D1 and D2 receptor-expressing medium spiny neurons while D2 receptors specifically inhibit excitatory inputs to D2 receptor-expressing cells by decreasing exocytosis from cortical terminals with a low probability of release. At higher cortical stimulation frequencies, this dopaminergic modulation of presynaptic activity is occluded by adenosine and endocannabinoids. Glutamatergic inputs to both D1 and D2 receptor-bearing medium spiny neurons are inhibited by adenosine, released upon activation of NMDA and AMPA receptors and adenylyl cyclase in D1 receptor-expressing cells. Excitatory inputs to D2 receptor-expressing cells are specifically inhibited by endocannabinoids, whose release is dependent on D2 and group 1 metabotropic glutamate receptors. The convergence of excitatory and inhibitory modulation of corticoaccumbal activity by dopamine, adenosine and endocannabinoids creates subsets of corticoaccumbal inputs, selectively and temporally reinforces strong cortical signals through the striatonigral pathway while inhibiting the weak, and may provide a mechanism whereby conti...

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…The depression seems to be of presynaptic origin in both cases, because mEPSC frequency, but not amplitude, is reduced (Pennartz et al, 1992;Nicola et al, 1996; but see Ortinski et al, 2012 for effects after withdrawal from cocaine) although no changes in postsynaptic cell parameters are observed (O'Donnell and Grace, 1994). This inhibition is also produced by endogenous dopamine (Harvey and Lacey, 1996;Brady and O'Donnell, 2004) and is observed by washing cocaine or amphetamine directly on the slice (Nicola et al, 1996;Li and Kauer, 2004;Wang et al, 2012). Although evidence indicates that the D1 receptors mediating the inhibition are presynaptic (Pennartz et al, 1992;Nicola et al, 1996;Nicola and Malenka, 1997), it has been suggested that the presynaptic alterations are a consequence of the interaction between postsynaptic D1 receptors and NMDARs, which causes the release of adenosine that affects the presynaptic terminal (Harvey and Lacey, 1997;Chergui and Lacey, 1999;Wang et al, 2012).…”

“…This inhibition is also produced by endogenous dopamine (Harvey and Lacey, 1996;Brady and O'Donnell, 2004) and is observed by washing cocaine or amphetamine directly on the slice (Nicola et al, 1996;Li and Kauer, 2004;Wang et al, 2012). Although evidence indicates that the D1 receptors mediating the inhibition are presynaptic (Pennartz et al, 1992;Nicola et al, 1996;Nicola and Malenka, 1997), it has been suggested that the presynaptic alterations are a consequence of the interaction between postsynaptic D1 receptors and NMDARs, which causes the release of adenosine that affects the presynaptic terminal (Harvey and Lacey, 1997;Chergui and Lacey, 1999;Wang et al, 2012). Similarly, D2 receptor-mediated inhibition is thought to include postsynaptic release of eCBs, thereby pointing to a role for postsynaptic D2 receptors .…”

Original article Involvement of D 2 /D 2 dopamine antagonists upon open-arms exploratory behaviours induced by intra-nucleus accumbens shell administration of N-methyl-D-aspartate

“…Meanwhile, activation of glutamate receptor increases the dopamine release in the NAc [31]. We also know from the literature that NAc dopamine and glutamate signalling interactions are crucially required in behavioural reinforcement and habit formation and dopamine can modulate excitatory glutamatergic projection from the PFC [82]. The elevation of extracellular dopamine and glutamate levels in the striatum might disrupt Ca 2+ homeostasis leading to the endoplasmic reticulum (ER) stress response [4,72].…”

“…These results may suggest the involvement of the dopamine transmission through D 1 and D 2 receptors of the NAc. Several investigations have suggested the possible dopaminergic and glutamatergic systems interaction in the NAc [66,67] based on which the NAc glutamate transmission is modulated by the dopamine system [37,53,82]. With respect to the interaction of these systems, there is a study showing that the NMDA receptors are localized on the NAc shell neurons which abundantly contain dopamine D 1 receptors [81].…”

Possible contributions of a novel form of synaptic plasticity inAplysiato reward, memory, and their dysfunctions in mammalian brain

“…Presynaptic D1 or nicotinic receptors are present on glutamatergic afferents to hippocampus, entorhinal cortex (EC), prefrontal cortex (PFC), and nucleus accumbens (NAc), as well as afferents to ventral tegmental area (VTA) dopaminergic neurons themselves (Bergson et al 1995;Jones and Wonnacott 2004;Paspalas and Goldman-Rakic 2005;Dumartin et al 2007). The D1 receptors act through adenylyl cyclase and PKA to enhance spontaneous release of glutamate in hippocampus, EC, PFC, NAc, and VTA (Kalivas and Duffy 1995;Bouron and Reuter 1999;Yang 1999;Wang et al 2002Wang et al , 2012. Results in NAc are mixed, and in some cases presynaptic D1 receptors instead decrease glutamatergic transmission (Nicola and Malenka 1998).…”