Activation Of D1-like Receptors Research Articles

Amphetamine Promotes Cortical Up State in Part Via Dopamine Receptors.

Cortical neurons oscillate between Up and Down states during slow wave sleep and general anesthesia. Recent studies show that Up/Down oscillations also occur during quiet wakefulness. Arousal eliminates Down states and transforms Up/Down oscillations to a persistent Up state. Further evidence suggests that Up/Down oscillations are crucial to memory consolidation, whereas their transition to a persistent Up state is essential for arousal and attention. We have shown that D-amphetamine promotes cortical Up state, and the effect depends on activation of central α1A adrenergic receptors. Here, we report that dopamine also plays a role in D-amphetamine’s effect. Thus, using local-field-potential recording in the prefrontal cortex in chloral hydrate-anesthetized rats, we showed that the Up-state promoting effect of D-amphetamine was attenuated by antagonists at either D1 or D2-like dopamine receptors. The effect was also partially mimicked by co-activation of D1 and D2-like receptors. These results are consistent with the fact that D-amphetamine increases the release of both norepinephrine and dopamine. They are also in agreement with studies showing that dopamine promotes wakefulness and mediates D-amphetamine-induced emergence from general anesthesia. The effect of D-amphetamine was not mimicked, however, by activation of either D1 or D2-like receptors alone, indicating an interdependence between D1 and D2-like receptors. The dopamine/norepinephrine precursor L-DOPA also failed to promote the Up state. While more studies are needed to understand the difference between L-DOPA and D-amphetamine, our finding may provide an explanation for why L-DOPA lacks significant psychostimulant properties and is ineffective in treating attention-deficit/hyperactivity disorder.

Inhibitory Effect of Apomorphine on Focal and Nonfocal Plasticity in the Human Motor Cortex

Dopamine is crucial for neuroplasticity, which is considered to be the neurophysiological foundation of learning and memory. The specific effect of dopamine on plasticity such as long-term potentiation (LTP) and long-term depression (LTD) is determined by receptor subtype specificity, concentration level, and the kind of plasticity induction technique. In healthy human subjects, the dopamine precursor levodopa (L-DOPA) exerts a dosage-dependent non-linear effect on motor cortex plasticity. Low and high dosage L-DOPA impaired or abolished plasticity, while medium-dose preserved and reversed plasticity in previous studies. Similar dosage-dependent effects were also observed for selective D1-like and D2-like receptor activation that favor excitatory and inhibitory plasticity, respectively. However, such a dosage-dependent effect has not been explored for a nonselective dopamine agonist such as apomorphine in humans. To this aim, nonfocal and focal motor cortex plasticity induction using paired associative stimulation (PAS) and transcranial direct current stimulation (tDCS) were performed respectively in healthy participants under 0.1, 0.2, 0.3 mg apomorphine or placebo drug. Transcranial magnetic stimulation-elicited motor-evoked potentials were used to monitor motor cortical excitability alterations. We hypothesized that, similar to L-DOPA, apomorphine will affect motor cortex plasticity. The results showed that apomorphine with the applied dosages has an inhibitory effect for focal and nonfocal LTP-like and LTD-like plasticity, which was either abolished, diminished or reversed. The detrimental effect on plasticity induction under all dosages of apomorphine suggests a predominantly presynaptic mechanism of action of these dosages.

Ethanol inhibition of lateral orbitofrontal cortex neuron excitability is mediated via dopamine D1/D5 receptor-induced release of astrocytic glycine

Recent findings from this laboratory demonstrate that ethanol reduces the intrinsic excitability of orbitofrontal cortex (OFC) neurons via activation of strychnine-sensitive glycine receptors. Although the mechanism linking ethanol to the release of glycine is currently unknown, astrocytes are a source of neurotransmitters including glycine and activation of dopamine D1-like receptors has been reported to enhance extracellular levels of glycine via a functional reversal of the astrocytic glycine transporter GlyT1. We recently reported that like ethanol, dopamine or a D1/D5 receptor agonist increases a tonic current in lateral OFC (lOFC) neurons. Therefore, in this study, we used whole-cell patch-clamp electrophysiology to examine whether ethanol inhibition of OFC spiking involves the release of glycine from astrocytes and whether this release is dopamine receptor dependent. Ethanol, applied acutely, decreased spiking of lOFC neurons and this effect was blocked by antagonists of GlyT1, the norepinephrine transporter or D1-like but not D2-like receptors. Ethanol enhanced the tonic current of OFC neurons and occluded the effect of dopamine suggesting that ethanol and dopamine may share a common pathway. Altering astrocyte function by suppressing intracellular astrocytic calcium signaling or blocking the astrocyte-specific Kir4.1 potassium channels reduced but did not completely abolish ethanol inhibition of OFC neuron firing. However, when both astrocytic calcium signaling and Kir4.1 channels were inhibited, ethanol had no effect on firing. Ethanol inhibition was also prevented by inhibitors of phospholipase C and conventional isoforms of protein kinase C (cPKC) previously shown to block D1R-induced GlyT1 reversal and PKC inhibition of Kir4.1 channels. Finally, the membrane potential of OFC astrocytes was depolarized by bath application of a Kir4.1 blocker, a D1 agonist or ethanol and ethanol effect was blocked by a D1 antagonist. Together, these findings suggest that acute ethanol inhibits OFC neuron excitability via a D1 receptor-mediated dysregulation of astrocytic glycine transport.

Blockade of D1-like dopaminergic receptors suppresses Th17-cell function in multiple sclerosis

To investigate the direct effect of D1-like dopaminergic receptors antagonist on Th17-cells function in multiple sclerosis (MS) in vitro. Forty-one relapsing-remitting MS patients and twenty-five healthy subjects were examined. The functional activity of Th17-cells was assessed by the ability to produce IL-17 and IFN-γ by peripheral blood mononuclear cells (PBMCs) and CD4+ T cells, stimulated with microbeads coated with anti-CD3/anti-CD28-antibodies. To study the involvement of D1-like dopaminergic receptors in modulation of Th17-cell function, the samples of PBMCs or CD4+ T-cells were cultured in the presence of dopamine and/or specific D1-like dopaminergic receptors antagonist (SCH23390). Cytokine levels in cell culture supernatants were measured by ELISA. The production of IL-17 and IFN-γ by stimulated PBMCs were higher in MS patients during relapse than in MS patients during clinical remission or in healthy subjects. The production of cytokines by stimulated PBMCs or CD4+ T-cells in MS patients during clinical remission and healthy subjects was comparable. Dopamine reduced the production of cytokines by PBMCs and CD4+ T-cells in all groups. Blockade of D1-like dopaminergic receptors did not affect the dopamine-mediated cytokine suppression in MS patients and healthy subjects. Blockade of D1-like dopaminergic receptors directly suppressed cytokine production by PBMCs and CD4+ T-cells in MS patients and healthy subjects. Dopamine and blockade of D1-like dopaminergic receptors have an inhibitory effect on Th17-cell function in MS. The activation of D2-like dopaminergic receptors could mediate the inhibitory effect of dopamine on Th17-cells.

Central Mechanisms of Apomorphine and m-Chlorophenylpiperazine on Synergistic Action for Ejaculation in Rats

BackgroundWe previously reported that the combination of the dopamine (DA) receptor agonist apomorphine and the 5-hydroxytryptamine (5-HT2) receptor agonist m-chlorophenylpiperazine (m-CPP) in rats potently and selectively facilitates the ejaculatory response through activation of D2-like and 5-HT2C receptors, respectively. AimThe aim of this study was to clarify the target level of the proejaculatory effects induced by combination of these agonists. MethodsFor in vivo behavioral studies, apomorphine and m-CPP were given intracerebroventricularly and intrathecally alone or in combination with either drug administered systemically. Male rats were acclimated to observational cages bedded in paper towels, and the occurrence of ex copula ejaculation was assessed by evaluating the presence and weight of ejaculatory plugs dropped from the tip of the penis to the paper towels or adhered to the tip of the penis at 30 min after drug administration. For in vitro contraction studies, seminal vesicles isolated from rats were suspended in an organ bath to test contractile responses to drug combinations, and the effects of the combined drugs on the contractile response of noradrenaline were also tested. Main Outcome MeasuresThe presence and weight of ejaculatory plugs produced by drug-induced ejaculation and the contractile responses of the seminal vesicle were evaluated. ResultsIntrathecal m-CPP (10 μg), but not intracerebroventricular m-CPP, evoked the synergistic effects on ejaculation when used in combination with systemically administered apomorphine (0.1 mg/kg, subcutaneous). Moreover, the synergy between m-CPP and apomorphine was completely abolished by the intrathecal 5-HT2C receptor antagonist SB242084 (10 μg). Intrathecal or intracerebroventricular apomorphine (1–10 μg) evoked proejaculatory effects in combination with systemically administered m-CPP (0.3 mg/kg, intraperitoneal). The selective peripherally acting D2-like receptor agonist carmoxirole did not evoke ejaculation when used in combination with m-CPP. Furthermore, isolated rat seminal vesicles were completely insensitive to the combination of apomorphine and m-CPP. ConclusionThese results indicated that the synergistic effects of the drugs on ejaculation were induced at the central level but not at peripheral sites. Our findings also suggested that the 5-HT2C receptor mediated the stimulation of the spinal ejaculatory pattern generator and was synergistically potentiated by the spinal DA receptor and that activation of the supraspinal DA receptor was also involved in mediating these synergistic effects.Yoshizumi M, Yonezawa A, Kimura Y, et al. Central Mechanisms of Apomorphine and m-Chlorophenylpiperazine on Synergistic Action for Ejaculation in Rats. J Sex Med 2021;18:231–239.

Norepinephrine transporter antagonism prevents dopamine-dependent synaptic plasticity in the mouse dorsal hippocampus

The rodent dorsal hippocampus is essential for episodic memory consolidation, a process heavily modulated by dopamine D1-like receptor (D1/5R) activation. It was previously thought that the ventral tegmental area provided the only supply of dopamine release to dorsal hippocampus, but several recent studies have established the locus coeruleus (LC) as the major source for CA1. Here we show that selective blockade of the norepinephrine transporter (NET) prevents dopamine-dependent, late long-term synaptic potentiation (LTP) in dorsal CA1, a neural correlate of memory formation that relies on LC-mediated activation of D1/5Rs. Since dopamine activation of D1/5Rs by vesicular release is expected to be enhanced by NET antagonism, our data identify NET reversal as a plausible mechanism for LC-mediated DA release. We also show that genetic deletion of LC NMDA receptors (NMDARs) blocks D1R-mediated LTP, suggesting the requirement of both a functional NET and presynaptic NMDARs for this release. As LC activity is highly correlated with attentional processes and memory, these experiments provide insight into how selective attention influences memory formation at the synaptic and circuit levels.

Activation of ventrolateral orbital cortex improves mouse neuropathic pain–induced anxiodepression

Depression and anxiety are frequently observed in patients suffering from neuropathic pain. The underlying mechanisms remained unclear. The ventrolateral orbital cortex (VLO) has attracted considerable interest in its role in antidepressive effect in rodents. In the present study, we further investigated the role of the VLO in the anxiodepressive consequences of neuropathic pain in a chronic constriction injury of infraorbital nerve–induced trigeminal neuralgia (TN) mouse model. Elevated plus maze, open field, forced swimming, tail suspension, and sucrose preference tests were used to evaluate anxiodepressive-like behaviors. The results show that chemogenetic activation of bilateral VLO neurons, especially CaMK2A+ pyramidal neurons, blocked the TN-induced anxiodepressive-like behaviors. Chemogenetic and optogenetic activation of VGLUT2+ or inhibition of VGAT+ VLO neurons was sufficient to produce an antianxiodepressive effect in TN mice. Pharmacological activation of D1-like receptors (D1Rs) but not D2Rs in the VLO significantly alleviated TN-induced depressive-like behaviors. Electrophysiological recordings revealed a decreased excitability of VLO excitatory neurons following neuropathic pain. Furthermore, activation of submedius thalamic nucleus–VLO (Sm-VLO) projection mimicked the antianxiodepressive effect of VLO excitation. Conversely, activation of VLO-periaqueductal gray matter (PAG) projection had no effect on TN-induced anxiodepressive behaviors. This study provides a potentially novel mechanism–based therapeutic strategy for the anxiodepressive consequences of neuropathic pain.

Dopamine D4 receptor subtype activation reduces the rat cardiac parasympathetic discharge.

The dopaminergic system influences the heart rhythm by inhibiting the rat cardiac sympathetic and parasympathetic neurotransmissions through activation of D2-like receptors (encompassing the D2, D3, and D4 subtypes). Whereas D2 receptor subtype activation results in cardiac sympatho-inhibition, the dopamine receptor subtypes involved in rat cardiac vago-inhibition remain unknown. Hence, this study investigated the specific functional role of the D2-like receptor subtypes (D2, D3, and/or D4) inhibiting the rat heart cholinergic drive. For this purpose, male Wistar rats were pithed and prepared for cardiac vagal stimulation. Bradycardic responses were obtained by electrical stimulation of vagal fibres (3, 6, 9 Hz; n = 100) or i.v. acetylcholine (ACh; 1, 5, 10 μg/kg; n = 15). Expression of D2, D3, and D4 receptors was studied in left and right atrium samples by PCR (n = 4). Intravenous injections of quinpirole (D2-like agonist; 1-30 μg/kg), but not of SFK-38393 (D1-like agonist; 1-30 μg/kg), dose-dependently inhibited the vagally induced bradycardia. The vago-inhibition induced by quinpirole (which failed to affect the bradycardia to i.v. ACh) was unchanged after i.v. injections of the antagonists L-741,626 (D2; 100 μg/kg) or SB-277011-A (D3; 100 μg/kg), but it was abolished by L-745,870 (D4; 100 μg/kg). mRNA levels of D2, D3, and D4 receptor subtype were detected in the left and right rat atria. Our results suggest that the quinpirole-induced vagolytic effect involves prejunctional D4 receptor subtypes, located in the left and right atria. This provides new evidence on the relevance of D4 receptor modulating the heart parasympathetic control.

Dopamine D2-Like Receptors Modulate Intrinsic Properties and Synaptic Transmission of Parvalbumin Interneurons in the Mouse Primary Motor Cortex.

Dopamine (DA) plays a crucial role in the control of motor and higher cognitive functions such as learning, working memory, and decision making. The primary motor cortex (M1), which is essential for motor control and the acquisition of motor skills, receives dopaminergic inputs in its superficial and deep layers from the midbrain. However, the precise action of DA and DA receptor subtypes on the cortical microcircuits of M1 remains poorly understood. The aim of this work was to investigate in mice how DA, through the activation of D2-like receptors (D2Rs), modulates the cellular and synaptic activity of M1 parvalbumin-expressing interneurons (PVINs) which are crucial to regulate the spike output of pyramidal neurons (PNs). By combining immunofluorescence, ex vivo electrophysiology, pharmacology and optogenetics approaches, we show that D2R activation increases neuronal excitability of PVINs and GABAergic synaptic transmission between PVINs and PNs in Layer V of M1. Our data reveal how cortical DA modulates M1 microcircuitry, which could be important in the acquisition of motor skills.

D2-Like Receptors Mediate Dopamine-Inhibited Insulin Secretion via Ion Channels in Rat Pancreatic β-Cells.

Dopamine (DA) has a vital role in the central nervous system and also modulates lipid and glucose metabolism. The present study aimed to investigate the effect of dopamine on insulin secretion and the underlying mechanisms in rat pancreatic β-cells. Data from the radioimmunoassay indicated that dopamine inhibited insulin secretion in a glucose- and dose-dependent manner. This inhibitory effect of dopamine was mediated mainly by D2-like receptors, but not D1-like receptors. Whole-cell patch-clamp recordings showed that dopamine decreased voltage-dependent Ca2+ channel currents, which could be reversed by inhibition of the D2-like receptor. Dopamine increased voltage-dependent potassium (KV) channel currents and shortened action potential duration, which was antagonized by inhibition of D2-like receptors. Further experiments showed that D2-like receptor activation by quinpirole increased KV channel currents. In addition, using calcium imaging techniques, we found that dopamine reduced intracellular Ca2+ concentration, which was also reversed by D2-like receptor antagonists. Similarly, quinpirole was found to decrease intracellular Ca2+ levels. Taken together, these findings demonstrate that dopamine inhibits insulin secretion mainly by acting on D2-like receptors, inhibiting Ca2+ channels, and activating Kv channels. This process results in shortened action potential duration and decreased intracellular Ca2+ levels in β-cells. This work offers new insights into a glucose-dependent mechanism whereby dopamine regulates insulin secretion.

Neuromodulatory Selection of Motor Neuron Recruitment Patterns in a Visuomotor Behavior Increases Speed.

Animals generate locomotion at different speeds to suit their behavioral needs. Spinal circuits generate locomotion at these varying speeds by sequential activation of different spinal interneurons and motor neurons. Larval zebrafish can generate slow swims for prey capture and exploration by activation of secondary motor neurons and much faster and vigorous swims during escape and struggle via additional activation of primary motor neurons. Neuromodulators are known to alter the motor output of spinal circuits, but their precise role in speed regulation is not wellunderstood. Here, in the context of optomotor response (OMR), an innate evoked locomotor behavior, we show that dopamine (DA) provides an additional layer to regulation of swim speed in larval zebrafish. Activation of D1-like receptors increases swim speed during OMR in free-swimming larvae. By analyzing tail bend kinematics in head-restrained larvae, we show that the increase in speed is actuated by larger tail bends. Whole-cell patch-clamp recordings from motor neurons reveal that, during OMR, typically only secondary motor neurons are active, whereas primary motor neurons are quiescent. Activation of D1-like receptors increases intrinsic excitability and excitatory synaptic drive in primary and secondary motor neurons. These actions result in greater recruitment of motor neurons during OMR. Our findings provide an example of neuromodulatory reconfiguration of spinal motor neuron speed modules where members are selectively recruited and motor drive is increased to effect changes in locomotor speed. VIDEO ABSTRACT.

Opposite effects of dopamine on the mechanical activity of circular and longitudinal muscle of human colon.

Because dopamine (DA) has gained increasing evidence as modulator of gut motility, we aimed to characterize dopaminergic response in human colon, evaluating function and distribution of dopamine receptors in circular vs longitudinal muscle strips. Mechanical responses to DA and dopaminergic agonists on slow phasic contractions and on basal tone were examined in vitro as changes in isometric tension. RT-PCR was used to reveal the distribution of dopaminergic receptors. In spontaneous active circular muscle, DA induced an increase in the amplitude of slow phasic contractions and of the basal tone, via activation of D1-like receptors. DA contractile responses were insensitive to neural blockers or to atropine and inhibited by phospholipase C (PLC) pathway inhibitors. In precontracted circular muscle strips, DA, at the higher concentrations tested, caused a relaxant response via activation of D2-like receptors. In the longitudinal muscle, DA caused only muscular relaxation due to activation of D2-like receptors. DA relaxant responses were insensitive to neural blockers or to nitric oxide synthase inhibitor and reduced by a wide-spectrum K+ channel blockers. Transcripts encoding for all the dopaminergic receptor subtypes was observed in both circular and longitudinal preparations. Dopamine is able to modulate contractile activity of the human colon. In the circular muscle layer, DA induces mainly muscular contraction activating non-neural D1-like receptors, coupled to PLC/IP3 pathway. In the longitudinal muscle layer, DA induces muscular relaxation acting on non-neural D2-like receptors leading to the increase in K+ conductance.

Dopaminergic Inhibition of Pyramidal Cells in Anterior Cingulate Cortex is Defective in Chronic Neuropathic Pain

Pyramidal neurons in the anterior cingulate cortex (ACC), a prefrontal region involved in processing the affective components of pain, display hyperexcitability in chronic neuropathic pain conditions and their silencing abolishes hyperalgesia. We show here that dopamine, through D1-like receptor signaling, inhibits layer 2/3 pyramidal neurons of mouse ACC through modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Activation of Gs-coupled D1-like receptors by dopamine induces the opening of HCN channels at physiological membrane potentials, driving a significant decrease in input resistance and excitability. Systemic L-DOPA in chronic neuropathic mice rescues HCN channel activity, normalizes pyramidal excitability in ACC, and has anti-allodynic effects on mechanical and thermal responses. Moreover, microinjection of a selective D1-like agonist in ACC induces relief of ongoing pain in neuropathic animals. We conclude that dopaminergic inhibition in ACC plays an analgesic role in physiological conditions and is defective in chronic pain.

Activation of D1-like dopamine receptors is involved in the impairment of spatial memory in the offspring of morphine-abstinent rats

Accumulating evidence suggests that epigenetic mechanisms play an essential role in the formation and maintenance of memory as well as addiction. In this study, we examined the role of D1-like dopamine receptor (D1 DR) on spatial memory in the offspring of morphine-abstinent rats. Adult male and female rats received morphine orally for 21 days and were drug-free for ten days. The rats were prepared to mate and the offspring were divided into four groups: offspring of drug-naïve parents, offspring of maternal morphine-exposed, offspring of paternal morphine-exposed, and PME + MME group. Saline or SCH23390 was injected into the hippocampus and prefrontal (PFC), and the Morris Water Maze task was performed. Afterward, the rats were sacrificed, and phosphorylated-CREB (p-CREB) was assessed using Western blotting. The data obtained from saline-treated offspring indicated that spatial memory was deteriorated in the offspring of morphine-abstinent parents compared with the control which improved when they received SCH23390. The level of p-CREB also decreased in the hippocampus, while it increased in the PFC and hippocampus after SCH23390 administration. Our results suggested that morphine exposure before conception could induce impairment in spatial memory in the offspring. Since D1 DR was up-regulated in the PFC of the offspring, blocking D1 DR led to improved memory deficit in the offspring of morphine-abstinent rats. Improvement of memory is correlated to p-CREB level in the hippocampus and PFC.

Roles of the noradrenergic nucleus locus coeruleus and dopaminergic nucleus A11 region as supraspinal defecation centers in rats.

We previously demonstrated that administration of norepinephrine, dopamine, and serotonin into the lumbosacral defecation center caused propulsive contractions of the colorectum. It is known that the monoamines in the spinal cord are released mainly from descending neurons in the brainstem. In fact, stimulation of the medullary raphe nuclei, the origin of descending serotonergic neurons, enhances colorectal motility via the lumbosacral defecation center. Therefore, the purpose of this study was to examine the roles of the noradrenergic nucleus locus coeruleus (LC) and dopaminergic nucleus A11 region in the defecation reflex. Colorectal motility was measured with a balloon in anesthetized rats. Electrical stimulation of the LC and A11 region increased colorectal pressure only when a GABAA receptor antagonist was injected into the lumbosacral spinal cord. The effects of the LC stimulation and A11 region stimulation on colorectal motility were inhibited by antagonists of α1-adrenoceptors and D2-like dopamine receptors injected into the lumbosacral spinal cord, respectively. Spinal injection of a norepinephrine-dopamine reuptake inhibitor augmented the colokinetic effect of LC stimulation. The effect of stimulation of each nucleus was abolished by surgical severing of the parasympathetic pelvic nerves. Our findings demonstrate that activation of descending noradrenergic neurons from the LC and descending dopaminergic neurons from the A11 region causes enhancement of colorectal motility via the lumbosacral defecation center. The present study provides a novel concept that the brainstem monoaminergic nuclei play a role as supraspinal defecation centers.NEW & NOTEWORTHY The present study demonstrates that electrical and chemical stimulations of the locus coeruleus or A11 region augment contractions of the colorectum. The effects of locus coeruleus and A11 stimulations on colorectal motility are due to activation of α1-adrenoceptors and D2-like dopamine receptors in the lumbosacral defecation center, respectively. The present study provides a novel concept that the brainstem monoaminergic nuclei play a role as supraspinal defecation centers.

Cellular Mechanism for Specific Mechanical Antinociception by D2-like Receptor at the Spinal Cord Level

Intrathecal (i.t.) administration of quinpirole, a dopamine (DA) D2-like receptor agonist, produces antinociception to mechanonociceptive stimuli but not to thermonociceptive stimuli. To determine a cellular mechanism for the specific antinociceptive effect of D2-like receptor activation on mechanonociception, we evaluated the effect of quinpirole on voltage-gated Ca2+ influx in cultured dorsal root ganglion (DRG) neurons and the D2 DA receptor distribution in subpopulations of rat nociceptive DRG neurons.Small-diameter DRG neurons were classified into IB4+ (nonpeptidergic) and IB4- (peptidergic). Intracellular [Ca2+] microfluorometry and voltage-clamp experiments showed that quinpirole reduced Ca2+ influx and inhibited the high voltage-activated Ca2+ current (HVA-ICa) in half of IB4+ neurons, leaving Ca2+ entry and HVA-ICa in IB4- neurons nearly unaffected. Pretreatment with ω-conotoxin MVIIA prevented the effect of quinpirole on HVA-ICa from IB4+ neurons, indicating that quinpirole mainly inhibits CaV2.2 channels. Immunofluorescence experiments showed that D2 DA receptor was present mainly in IB4+ small DRG neurons. Finally, in behavioral experiments in rats, the clinically approved D2-like receptor agonist pramipexole produced spinal antinociception in a similar fashion to quinpirole, with a significant effect only in the mechanonociceptive test. Our results explain, at least in part, why D2-like receptor agonists produce antinociception on mechanonociceptors.

Methamphetamine exacerbates neuroinflammatory response to lipopolysaccharide by activating dopamine D1-like receptors

Methamphetamine (METH) is a highly addictive and widely abused drug worldwide. Although much research is on the drug's direct effects, METH may also alter host immunity. The mechanism by which METH influences immunity remains elusive. Here, C57BL6/J mice were intraperitoneally injected with 5 mg/kg METH four times at two-hour intervals. The microglial inhibitor minocycline or dopamine D1-like receptor antagonist SCH-23390 was also applied prior to METH injection. Twenty-four hours following the first METH injection, mice were challenged by lipopolysaccharide (LPS) at a dose of 330 μg/kg, and the hippocampus (Hip), caudate putamen (CPU), nucleus accumbens (NAc) and prefrontal cortex (PFC) were collected 4 h after LPS administration. IL-6 and TNF-α levels were detected by ELISA. The activation of D1-like receptors and microglial marker Iba1 were examined by immunohistochemical staining and Western blot. Finally, we examined the phosphorylation of ERK1/2 and CREB. We found that METH exposure increased LPS-induced IL-6 and TNF-α production in the Hip, CPU and NAc regions. METH also augmented microglia activation and D1/5DR expression in response to LPS. Moreover, administering SCH-23390 significantly reduced IL-6 and TNF-α production and Iba1 expression following LPS challenge. Similar inhibitory effects were also observed by minocycline administration. Moreover, phosphorylation of ERK1/2 and CREB was increased after METH and LPS exposure but decreased by SCH-23390. These data illustrate that METH exacerbates neuroinflammation response in LPS-stimulated mouse brains through dopamine D1-like receptors, microglia, and relevant signaling proteins, which may have therapeutic implications.

Dopamine induces release of calcium from internal stores in layer II lateral entorhinal cortex fan cells.

The entorhinal cortex plays an important role in temporal lobe processes including learning and memory, object recognition, and contextual information processing. The alteration of the strength of synaptic inputs to the lateral entorhinal cortex may therefore contribute substantially to sensory and mnemonic functions. The neuromodulatory transmitter dopamine exerts powerful effects on excitatory glutamatergic synaptic transmission in the entorhinal cortex. Interestingly, inputs from midbrain dopamine neurons appear to specifically target clusters of excitatory cells located in the superficial layers of the entorhinal cortex. We have previously demonstrated that dopamine facilitates synaptic transmission through the activation of D1-like receptors. This facilitation of synaptic transmission is dependent on both activation of classical D1-like-receptors, and upon activation of dopamine receptors linked to increases in phospholipase C, inositol triphosphate (IP3), and intracellular calcium. In the present study we combined electrophysiological recordings of evoked excitatory postsynaptic currents with imaging of intracellular calcium using the fluorescent indicator fluo-4 to monitor calcium transients evoked by dopamine in electrophysiologically identified putative fan and pyramidal cells of the lateral entorhinal cortex. Bath application of dopamine (1 μM), or the phosphatidylinositol (PI)-linked D1-like-receptor agonist SKF83959 (5 μM), induced reliable and reversible increases in fluo-4 fluorescence and excitatory postsynaptic currents in fan cells, but not in pyramidal cells. In contrast, application of the classical D1-like-receptor agonist SKF38393 (10 μM) did not result in significant increases in fluorescence. Blocking release of calcium from internal stores by loading cells with the IP3 receptor blocker heparin (1 mM) or the ryanodine receptor blocker dantrolene (20 μM) abolished both the calcium transients and the facilitation of evoked synaptic currents induced by dopamine. Dopamine also induced calcium transients in fan cells when calcium was excluded from the extracellular medium, further indicating that the calcium transients are linked to release from internal stores. These results indicate that following D1-like-receptor binding, dopamine selectively induces transient elevations in intracellular calcium via activation of IP3 and ryanodine receptors, and that these elevations are linked to the facilitation of synaptic responses in putative layer II entorhinal cortex fan cells.

Dissociative effects of dorsomedial striatum D1 and D2 receptor antagonism in the regulation of anxiety and learned approach-avoidance conflict decision-making

The dorsal striatum is traditionally known for its role in sensorimotor integration. However, the dorsomedial striatum (DMS) has also been implicated in cost-benefit conflict processing, a role more readily attributed to the ventral striatum (VS), as a site of limbic-motor integration. We recently showed that dopaminergic D1 (D1R) and D2 receptors (D2R) in the VS exert dissociable control over cue-elicited approach-avoidance decision-making, in the presence of conflicting motivational stimuli. We therefore sought to investigate the contribution of DMS dopaminergic receptors in the regulation of cue-elicited and innate approach-avoidance decision-making. Using a conditioned mixed-valence conflict paradigm, we trained rats in a three-arm radial maze to associate visuotactile cues with appetitive, aversive, and neutral outcomes. Rats then received an intra-DMS or intra-dorsolateral striatum (DLS) microinfusion of D1-like antagonist (SCH23390) or D2-like antagonist (sulpiride), and were then tested for the expression of approach-avoidance behavior in a conflict scenario, wherein the appetitive and aversive cues were superimposed within a single maze arm. The results revealed that DMS (but not DLS) D1R antagonism, suppressed approach towards the conflict arm while DMS (but not DLS) D2R antagonism enhanced approach. All rats were subsequently administered an elevated plus maze test as a measure of innate approach-avoidance conflict (anxiety). DMS D1R antagonism decreased anxiety, while DMS D2R and both DLS D1R and D2R antagonism increased anxiety. Our findings suggest that under motivational conflict, activation of DMS D1-like receptors facilitates approach, while activation of D2-like receptors suppress approach behavior. Furthermore, anxiety is regulated by dorsal striatal-mediated dopaminergic mechanisms.

Dopamine in the hippocampal dentate gyrus modulates spatial learning via D1-like receptors

Increasing evidence supports that dopamine (DA) plays an important role in the hippocampal function via activation of D1-like receptors (D1Rs). As the entry structure of the hippocampal formation, the hippocampal dentate gyrus (DG) is critically involved in spatial learning and memory. Despite a number of studies investigated how DA influences CA1 plasticity and learning, there are fewer studies examining the influence of DA signaling to the DG. To investigate the roles of DA and D1Rs of the DG in modulation of spatial learning and memory, the spatial learning and memory abilities of rats were measured by Morris water maze (MWM), and then the concentration of DA in the DG region was determined by in vivo brain microdialysis and HPLC. Next, the effects of local microinjection of SCH23390 (an antagonist of D1Rs) on extracellular levels of excitatory amino acids (EAAs), including glutamate (Glu) and aspartate (Asp), were measured in the DG region during MWM test in freely-moving conscious rats. During the place navigation trial of MWM test, the escape latency was decreased with the increase in training days, and DA concentration in the DG was significantly increased. In SCH23390 group rats, the escape latency was increased in place navigation trial and the percentage of time spent in target quadrant and the number of platform crossings were decreased in spatial probe trial during MWM test, compared with vehicle group. Furthermore, in vehicle group rats, the extracellular levels of Glu and Asp in the DG were significantly increased during place navigation trial of MWM test, and these responses were partly inhibited by microinjection of SCH23390. Our results suggest that DA activation of D1Rs in the hippocampal DG promotes spatial learning and memory, in part by modulating the responses of EAAs during spatial learning.