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The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine-hydroxylase-expressing (TH + ) neurons in the ventral tegmental area. Here we report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus coeruleus TH + neurons project more profusely than ventral tegmental area TH + neurons to the hippocampus, optogenetic activation of locus coeruleus TH + neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation. Surprisingly, two effects of locus coeruleus TH + photoactivation are sensitive to hippocampal D 1 /D 5 receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting potentiation of synaptic transmission in CA1 ex vivo . Thus, locus coeruleus TH + neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in the hippocampus. Projections from the locus coeruleus, an area typically defined by noradrenergic signalling, to the hippocampus drive novelty-based memory enhancement through possible co-release of dopamine. Memory consolidation in the locus coeruleus Memory retention can be enhanced when something novel or categorically relevant occurs shortly before or after the time of memory encoding, as in 'flashbulb memory'. Dopamine-based mechanisms originating in the ventral tegmental area have been implicated in the phenomenon. These authors suggest that projections from the locus coeruleus—typically defined by noradrenergic signalling—to the hippocampus drive this novelty-based memory enhancement through the possible local release of dopamine.

Striatal cholinergic interneurons (SCINs) exhibit pause responses conveying information about rewarding events, but the mechanisms underlying these pauses remain elusive. Thalamic inputs induce a pause mediated by intrinsic mechanisms and regulated by dopamine D2 receptors (D2Rs), though the underlying membrane currents remain unknown. Moreover, the role of D5 receptors (D5Rs) has not been addressed so far. Here, we performed ex vivo studies showing that glutamate released by thalamic inputs in the dorsolateral striatum induces a burst in SCINs, followed by a pause mediated by the activation of a Kv1-dependent delayed rectifier current. Endogenous dopamine promotes this pause through D2R stimulation, while pharmacological stimulation of D5Rs suppresses it. Remarkably, this pause is absent in parkinsonian mice rendered dyskinetic by chronic L-DOPA treatment but can be reinstated acutely by the inverse D5R agonist clozapine. Blocking the Kv1 current eliminates the pause reinstated by the D5R inverse agonist. In contrast, the D2-type receptor agonists quinpirole and sumanirole failed to reinstate a pause in dyskinetic mice. In conclusion, stimulation of thalamic inputs induces excitation followed by a pause in SCINs, which is lost in parkinsonian mice that have been rendered dyskinetic. This pause is mediated by delayed rectifier Kv1 channels, which are tonically blocked in dyskinetic mice by a mechanism depending on D5R ligand-independent activity. Targeting these alterations may have therapeutic value in Parkinson’s disease.

Long-term memory (LTM) consolidation requires the synthesis of plasticity-related proteins (PRPs). In addition, we have shown recently that LTM formation also requires the setting of a \"learning tag\" able to capture those PRPs. Weak training, which results only in short-term memory, can set a tag to use PRPs derived from a temporal-spatial closely related event to promote LTM formation. Here, we studied the involvement of glutamatergic, dopaminergic, and noradrenergic inputs on the setting of an inhibitory avoidance (IA) learning tag and the synthesis of PRPs. Rats explored an open field (PRP donor) followed by weak (tag inducer) or strong (tag inducer plus PRP donor) IA training. Throughout pharmacological interventions around open-field and/or IA sessions, we found that hippocampal dopamine D1/D5- and β-adrenergic receptors are specifically required to induce PRP synthesis. Moreover, activation of the glutamatergic NMDA receptors is required for setting the learning tags, and this machinery further required α-Ca²⁺/calmodulin-dependent protein kinase II and PKA but not ERK1/2 activity. Together, the present findings emphasize an essential role of the induction of PRPs and learning tags for LTM formation. The existence of only the PRP or the tag was insufficient for stabilization of the mnemonic trace.

Dopamine (DA), a neurotransmitter in the nervous system, has been shown to modulate immune function. We have previously reported that five subtypes of DA receptors, including D1R, D2R, D3R, D4R and D5R, are expressed in T lymphocytes and they are involved in regulation of T cells. However, roles of these DA receptor subtypes and their coupled signal-transduction pathway in modulation of natural killer (NK) cells still remain to be clarified. The spleen of mice was harvested and NK cells were isolated and purified by negative selection using magnetic activated cell sorting. After NK cells were incubated with various drugs for 4 h, flow cytometry measured cytotoxicity of NK cells against YAC-1 lymphoma cells. NK cells expressed the five subtypes of DA receptors at mRNA and protein levels. Activation of D1-like receptors (including D1R and D5R) with agonist SKF38393 enhanced NK cell cytotoxicity, but activation of D2-like receptors (including D2R, D3R and D4R) with agonist quinpirole attenuated NK cells. Simultaneously, SKF38393 elevated D1R and D5R expression, cAMP content, and phosphorylated cAMP-response element-binding (CREB) level in NK cells, while quinpirole reduced D3R and D4R expression, cAMP content, and phosphorylated CREB level in NK cells. These effects of SKF38393 were blocked by SCH23390, an antagonist of D1-like receptors, and quinpirole effects were abolished by haloperidol, an antagonist of D2-like receptors. In support these results, H89, an inhibitor of phosphokinase A (PKA), prevented the SKF38393-dependent enhancement of NK cells and forskolin, an activator of adenylyl cyclase (AC), counteracted the quinpirole-dependent suppression of NK cells. These findings show that DA receptor subtypes are involved in modulation of NK cells and suggest that D1-like receptors facilitate NK cells by stimulating D1R/D5R-cAMP-PKA-CREB signaling pathway and D2-like receptors suppress NK cells by inhibiting D3R/D4R-cAMP-PKA-CREB signaling pathway. The results may provide more targets of therapeutic strategy for neuroimmune diseases.

Abstract Background Dopamine D1 receptor signaling plays key roles in core domains of neural function, including cognition and reward processing; however, many questions remain about the functions of circuits modulated by dopamine D1 receptor, largely because clinically viable, selective agonists have yet to be tested in humans. Methods Using a novel, exploratory neurofunctional domains study design, we assessed the safety, tolerability, pharmacodynamics, and pharmacokinetics of PF-06412562, a selective D1/D5R partial agonist, in healthy male volunteers who met prespecified criteria for low working memory capacity. Functional magnetic resonance imaging, electrophysiologic endpoints, and behavioral paradigms were used to assess working memory, executive function, and motivation/reward processing following multiple-dose administration of PF-06412562. A total of 77 patients were assigned PF-06412562 (3 mg twice daily and 15 mg twice daily) or placebo administered for 5 to 7 days. Due to the exploratory nature of the study, it was neither powered for any specific treatment effect nor corrected for multiple comparisons. Results Nominally significant improvements from baseline in cognitive endpoints were observed in all 3 groups; however, improvements in PF-06412562–treated patients were less than in placebo-treated participants. Motivation/reward processing endpoints were variable. PF-06412562 was safe and well tolerated, with no serious adverse events, severe adverse events, or adverse events leading to dose reduction or temporary discontinuation except for 1 permanent discontinuation due to increased orthostatic heart rate. Conclusions PF-06412562, in the dose range and patient population explored in this study, did not improve cognitive function or motivation/reward processing more than placebo over the 5- to 7-day treatment period. ClinicalTrials.gov Identifier NCT02306876

Background:SKF83959 stimulates the phospholipase Cβ/inositol phosphate 3 pathway, resulting in the activation of Ca2+/calmodulin-dependent kinase IIα, which affects the synthesis of brain-derived neurotrophic factor, a neurotrophic factor critical for the pathophysiology of depression. Previous reports showed that SKF83959 elicited antidepressant activity in the forced swim test and tail suspension test as a novel triple reuptake inhibitor. However, there are no studies showing the effects of SKF83959 in a chronic stress model of depression and the role of phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway in SKF83959-mediated antidepressant effects.Methods:In this study, SKF83959 was firstly investigated in the chronic social defeat stress model of depression. The changes in hippocampal neurogenesis, dendrite spine density, and brain-derived neurotrophic factor signaling pathway after chronic social defeat stress and SKF83959 treatment were then investigated. Pharmacological inhibitors and small interfering RNA/short hairpin RNA methods were further used to explore the antidepressive mechanisms of SKF83959.Results:We found that SKF83959 produced antidepressant effects in the chronic social defeat stress model and also restored the chronic social defeat stress-induced decrease in hippocampal brain-derived neurotrophic factor signaling pathway, dendritic spine density, and neurogenesis. By using various inhibitors and siRNA/shRNA methods, we further demonstrated that the hippocampal dopamine D5 receptor, phospholipase C/inositol phosphate 3/ calmodulin-dependent kinase IIα pathway, and brain-derived neurotrophic factor system are all necessary for the SKF83959 effects.Conclusion:These results suggest that SKF83959 can be developed as a novel antidepressant and produces antidepressant effects via the hippocampal D5/ phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway.

Determining the individual roles of the two dopamine D1-like receptors (D1R and D5R) on sodium transport in the human renal proximal tubule has been complicated by their structural and functional similarity. Here we used a novel D5R-selective antagonist (LE-PM436) and D1R- or D5R-specific gene silencing to determine second messenger coupling pathways and heterologous receptor interaction between the two receptors. D1R and D5R colocalize in renal proximal tubule cells and physically interact, as determined by co-immunoprecipitation and fluorescent resonance energy transfer microscopy. Stimulation of renal proximal tubule cells with fenoldopam (D1R/D5R agonist) led to both adenylyl cyclase and phospholipase C (PLC) activation using real-time fluorescent resonance energy transfer biosensors ICUE3 and CYPHR, respectively. Fenoldopam increased cAMP accumulation and PLC activity and inhibited both NHE3 and NaKATPase activities. LE-PM436 and D5R siRNA blocked the fenoldopam-stimulated PLC pathway but not cAMP accumulation, whereas D1R siRNA blocked both fenoldopam-stimulated cAMP accumulation and PLC signaling. Either D1R or D5R siRNA, or LE-PM436 blocked the fenoldopam-dependent inhibition of sodium transport. Further studies using the cAMP-selective D1R/D5R agonist SKF83822 and PLC-selective D1R/D5R agonist SKF83959 confirmed the cooperative influence of the two pathways on sodium transport. Thus, D1R and D5R interact in the inhibition of NHE3 and NaKATPase activity, the D1R primarily by cAMP, whereas the D1R/D5R heteromer modulates the D1R effect through a PLC pathway.

Hippocampal sharp wave (SW)/ripple complexes are thought to contribute to memory consolidation. Previous studies suggest that behavioral rewards facilitate SW occurrence in vivo. However, little is known about the precise mechanism underlying this enhancement. Here, we examined the effect of dopaminergic neuromodulation on spontaneously occurring SWs in acute hippocampal slices. Local field potentials were recorded from the CA1 region. A brief (1 min) treatment with dopamine led to a persistent increase in the event frequency and the magnitude of SWs. This effect lasted at least for our recording period of 45 min and did not occur in the presence of a dopamine D1/D5 receptor antagonist. Functional multineuron calcium imaging revealed that dopamine-induced SW augmentation was associated with an enriched repertoire of the firing patterns in SW events, whereas the overall tendency of individual neurons to participate in SWs and the mean number of cells participating in a single SW were maintained. Therefore, dopaminergic activation is likely to reorganize cell assemblies during SWs.

Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behavioral response to methamphetamine. Interestingly, D5 dopamine receptor-deficient mice displayed increased ambulation in response to methamphetamine. Furthermore, dopamine transporter threonine phosphorylation levels, which regulate amphetamine-induced dopamine release, were elevated in D5 dopamine receptor-deficient mice. The increase in methamphetamine-induced locomotor activity was eliminated by pretreatment with the dopamine transporter blocker GBR12909. Taken together, these results suggest that dopamine transporter activity and threonine phosphorylation levels are regulated by D5 dopamine receptors.

Consolidation and reconsolidation are independent memory processes. Consolidation stabilizes new memories, whereas reconsolidation restabilizes memories destabilized when reactivated during recall. However, the biological role of the destabilization/reconsolidation cycle is still unknown. It has been hypothesized that reconsolidation links new information with reactivated memories, but some reports suggest that new and old memories are associated through consolidation mechanisms instead. Object-recognition memory (ORM) serves to judge the familiarity of items and is essential for remembering previous events. We took advantage of the fact that ORM consolidation, destabilization, and reconsolidation can be pharmacologically dissociated to demonstrate that, depending on the activation state of hippocampal dopamine D1/D5 receptors, the memory of a novel object presented during recall of the memory of a familiar one can be formed via reconsolidation or consolidation, but only reconsolidation can link them. We also found that recognition memories formed through reconsolidation can be destabilized even if indirectly reactivated. Our results indicate that dopamine couples novelty detection with memory destabilization to determine whether a new recognition trace is associated with an active network and suggest that declarative reminders should be used with caution during reconsolidation-based psychotherapeutic interventions.