Dopamine D1-like Receptor Activation Research Articles

Acute Ongoing Nociception Delays Recovery of Consciousness from Sevoflurane Anesthesia via a Midbrain Circuit.

Although anesthesia provides favorable conditions for surgical procedures, recent studies have revealed that the brain remains active in processing noxious signals even during anesthesia. However, whether and how these responses affect the anesthesia effect remains unclear. The ventrolateral periaqueductal gray (vlPAG), a crucial hub for pain regulation, also plays an essential role in controlling general anesthesia. Hence, it was hypothesized that the vlPAG may be involved in the regulation of general anesthesia by noxious stimuli. Here, we found that acute noxious stimuli, including capsaicin-induced inflammatory pain, acetic acid-induced visceral pain, and incision-induced surgical pain, significantly delayed recovery from sevoflurane anesthesia in male mice, whereas this effect was absent in the spared nerve injury-induced chronic pain. Pre-treatment with peripheral analgesics could prevent the delayed recovery induced by acute nociception. Furthermore, we found that acute noxious stimuli, induced by the injection of capsaicin under sevoflurane anesthesia, increased c-Fos expression and activity in the GABAergic neurons of the ventrolateral periaqueductal gray (vlPAGGABA). Specific re-activation of capsaicin-activated vlPAGGABA neurons mimicked the effect of capsaicin and its chemogenetic inhibition prevented the delayed recovery from anesthesia induced by capsaicin. Finally, we revealed that the vlPAGGABA neurons regulated the recovery from anesthesia through the inhibition of ventral tegmental area dopaminergic neuronal activity, thus decreasing dopamine release and activation of dopamine D1-like receptors in the brain. These findings reveal a novel, cell- and circuit-based mechanism for regulating anesthesia recovery by nociception and it is important to provide new insights for guiding the management of the anesthesia recovery period.Significance Statement There is evidence that the brain still processes pain signals during anesthesia. However, the significance and mechanisms of this phenomenon are poorly understood. Here, utilizing various pain models under anesthesia and integrating multiple techniques, the current study found that acute, but not chronic, ongoing noxious stimuli delayed the recovery from sevoflurane anesthesia. Furthermore, we identified the vlPAGGABA-VTA circuit as a critical target for mediating this effect by inhibiting the VTA dopaminergic neurons, reducing dopamine release, and decreasing the activation of dopamine D1-like receptors in the brain. This study presents the initial finding that the absence of pain perception under anesthesia does not equate to the absence of harm, offering a new perspective on guiding the administration of anesthesia medications.

Dopaminergic modulation of sensitivity to immediate and delayed punishment during decision-making.

Effective decision-making involves careful consideration of all rewarding and aversive outcomes. Importantly, negative outcomes often occur later in time, leading to underestimation, or "discounting," of these consequences. Despite the frequent occurrence of delayed outcomes, little is known about the neurobiology underlying sensitivity to delayed punishment during decision-making. The Delayed Punishment Decision-making Task (DPDT) addresses this by assessing sensitivity to delayed versus immediate punishment in rats. Rats initially avoid punished reinforcers, then select this option more frequently when delay precedes punishment.We used DPDT to examine effects of acute systemic administration of catecholaminergic drugs on sensitivity to delayed punishment in male and female adult rats. Cocaine did not affect choice of rewards with immediate punishment but caused a dose-dependent reduction in choice of delayed punishment. Neither activation nor blockade of D1-like dopamine receptor affected decision-making, but activation of D2-like dopamine receptors reduced choice of delayed punishment. D2 blockade did not attenuate cocaine's effects on decision-making, suggesting that cocaine's effects are not dependent on D2 receptor activation. Increasing synaptic norepinephrine via atomoxetine also reduced choice of delayed (but not immediate) punishment. Notably, when DPDT was modified from ascending to descending pre-punishment delays, these drugs did not affect choice of delayed or immediate punishment, although high-dose quinpirole impaired behavioral flexibility. In summary, sensitivity to delayed punishment is regulated by both dopamine and norepinephrine transmission in task-specific fashion. Understanding the neurochemical modulation of decision-making with delayed punishment is a critical step toward treating disorders characterized by aberrant sensitivity to negative consequences.

The iron-dopamine D1 coupling modulates neural signatures of working memory across adult lifespan

Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention.

Dopamine D1-like receptor activation decreases nicotine intake in rats with short or long access to nicotine.

The use of nicotine and tobacco products is highly addictive. The dopaminergic system plays a key role in the initiation and maintenance of nicotine intake. Dopamine D1-like receptor blockade diminishes nicotine intake in rats with daily short (1h) access to nicotine, but little is known about the effects of dopamine receptor antagonists or agonists on nicotine intake in rats with intermittent long (23 h) access. Because of the extended access conditions and high nicotine intake, the intermittent long access procedure might model smoking and vaping better than short access models. We investigated the effects of the dopamine D1-like receptor antagonist SCH 23390 and the D1-like receptor agonist A77636 on nicotine intake in male rats with intermittent short or long access to nicotine. The rats self-administered nicotine for 5days (1h/day) and were then given 15 intermittent short (1h/day) or long (23 h/day) access sessions (3 sessions/week, 0.06 mg/kg/inf). The D1-like receptor antagonist SCH 23390 decreased nicotine intake to a similar degree in rats with short or long access to nicotine. The D1-like receptor agonist A77636 induced a greater decrease in nicotine intake in the rats with long access to nicotine than in rats with short access. Treatment with A77636 induced a prolonged decrease in nicotine intake that lasted throughout the dark and light phase in the long access rats. These findings indicate that blockade and stimulation of D1-like receptors decrease nicotine intake in an intermittent long access animal model that closely models human smoking and vaping.

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.

Modulation of intracellular calcium concentration by D2-like DA receptor agonists in non-peptidergic DRG neurons is mediated mainly by D4 receptor activation

Nociceptive stimuli attributes are codified in the periphery; at this level, D2-like dopamine (DA) receptor activation decreases the high voltage-gated Ca2+ current predominantly in mechanonociceptive neurons, which explains the presynaptic action mechanism of the antinociception produced by quinpirole when it is intrathecally administered in rats. However, the identity of D2-like DA receptor subtype that mediates this effect remains unknown. To answer this question, we used Fluo-4-based Ca2+ microfluorometry to study the depolarization-elicited [Ca2+]i increase in small non-peptidergic DRG neurons (identified by its binding to the Isolectin B4), and to test the effect of D2-like DA receptor activation by quinpirole in presence of selective antagonists for D2, D3, and D4 DA receptors. The results showed a significantly greater contribution of the D4 DA receptor in the down-modulation of depolarization-elicited [Ca2+]i increase in small non-peptidergic DRG neurons compared to the other receptors. Although the D2 and D3 receptor antagonists also slightly inhibited the effect of quinpirole, their effects were significantly weaker than those of the D4 receptor antagonist. Furthermore, we showed that quinpirole selectively inhibits the CaV2.2 Ca2+ channels. Our results suggest that the activation of the D4 DA receptors is a promising strategy for pain management at the spinal cord level.

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.

Endocannabinoids Interact With the Dopaminergic System to Increase Sexual Motivation: Lessons From the Sexual Satiety Phenomenon.

In male rats, copulation to satiety induces a long-lasting sexual inhibitory state, considered to rely on a decreased sexual motivation. Dopaminergic transmission at the mesolimbic system plays a central role in the regulation of male sexual motivation. Endocannabinoids (eCBs) modulate the activity of the mesolimbic system and both dopamine (DA) and cannabinoid receptor activation reverses the sexual inhibition that characterizes sexually satiated rats. The eCB anandamide reverses sexual satiety when systemically administered or infused into the ventral tegmental area (VTA), the region where the activity of mesolimbic dopaminergic neurons is regulated. Thus, it could be thought that sexual motivation is diminished during the long-lasting sexual inhibition of sexually satiated rats and that eCBs reverse that inhibition through the modulation of the dopaminergic system. To test this hypothesis, we assessed the motivational state of sexually satiated male rats and determined if 2-arachidonoylglycerol (2-AG), the most abundant eCB and a full cannabinoid receptor agonist, also reversed the sexual inhibitory state. To establish the possible interaction between 2-AG and anandamide with the dopaminergic system for the reversal of sexual satiety, we analyzed the effects of the co-administration of each eCB and DA receptor agonists or antagonists. Results showed that 24-h after copulation to satiety, when the sexual inhibition is well established, the males’ sexual motivation is diminished as measured in the sexual incentive motivation test. 2-AG, similarly to anandamide, reverses sexual satiety through the activation of CB1 receptors and both eCBs interact with the dopaminergic system to reverse the sexual inhibitory state. 2-AG effects are mediated by the modulation of the D2-like DA receptor family, whereas anandamide’s effects are clearly mediated by the modulation of the D1-like DA receptor family and the activation of D2-like DA receptors. Present results evidence that a reduced sexual motivation underlies the sexual inhibitory state of sexually satiated rats and support the notion that eCBs reverse sexual satiety by modulating dopaminergic transmission, presumably at the mesolimbic system. Anandamide and 2-AG have a different interaction with D1-like and D2-like DA receptor families. Altogether present data endorse the association of the eCB system with the regulation of the motivational tone at the mesolimbic system.

The Dopamine D1 Receptor and Angiotensin II Type-2 Receptor are Required for Inhibition of Sodium Transport Through a Protein Phosphatase 2A Pathway.

Activation of the renal D1R (dopamine D1-like receptor) or AT2R (angiotensin II type-2 receptor), individually or both, simultaneously, is necessary in the normal regulation of renal sodium (Na+) transport and blood pressure. However, little is known regarding the precise mechanism of this interaction. Pharmacological stimulation, membrane biotinylation, and cell surface immunofluorescence were used to study the effect of the D1R/AT2R interaction in human renal proximal tubule cells. D1R activation of GαS stimulates AC (adenylyl cyclase) and induces apical plasma membrane recruitment of AT2Rs. We now show for the first time the reciprocal reaction, AT2R stimulation with Ang III (angiotensin III) leads to the apical plasma membrane recruitment of the D1R. The cell-permeable second messenger analogs of cAMP (8-Br-cAMP) or cGMP (8-Br-cGMP) induce translocation of both D1R and AT2R to the plasma membrane. Inhibition of PKA (protein kinase A) with Rp-cAMPS and PKG (protein kinase G) with Rp-8-CPT-cGMPS blocks D1R and AT2R recruitment, respectively, indicating that both PKA and PKG are necessary for D1R and AT2R trafficking. Both 8-Br-cAMP and 8-Br-cGMP activate PP2A (protein phosphatase 2A), which is necessary for both plasma membrane recruitment of D1R and AT2R and the inhibition of sodium hydrogen exchanger 3-dependent Na+ transport. These studies provide insights into the D1R/AT2R transregulation mechanisms that play a crucial role in maintaining Na+ and ultimately blood pressure homeostasis.

Spatial Cumulant Analysis to Study D2-Like Dopamine Receptor Dynamics on Plasma Membrane

Fluorescence fluctuation spectroscopy (FFS) measures physical properties of fluorescent samples by analyzing the statistical nature of signals measured by photodetectors. In biological contexts, the most frequently measured parameters include concentration, molecular brightness, and motion characteristics (i.e. diffusion coefficients). Molecular brightness holds salience because it can be used to determine the stoichiometry of homomeric and heteromeric interactions between fluorescent species. We use spatial cumulant analysis (SpCA), an adaptation of cumulant analysis of point measurements, to determine molecular brightness from images recorded using two-photon laser scanning microscopy. Spatial cumulant analysis combines the advantages of imaging and single point cumulant analysis. Imaging provides decreased photobleaching, the ability to measure fluctuations from a larger set of molecules, and spatial resolution of the measured parameters. Cumulants are favorable in FFS because they are additive for multiple molecular species and provide computational ease. Accurate determination of stoichiometry from molecular brightness can be difficult for several reasons including non-ideal photodetection, incomplete chromophore maturation, photobleaching, and resonance energy transfer. Our approach accounts for these complications. D2-like dopamine receptors (D2Rs) are cell surface receptors that couple to trimeric G-protein complexes. Activation of D2Rs catalyzes the dissociation of the G-protein complex into Gα and Gβγ subunits. Gα and Gβγ subunits mediate the action of D2Rs by interaction with downstream effectors including adenylyl cyclase, inwardly rectifying K+ channels, and voltage-gated Ca2+ channels. Physiologically, D2R activation inhibits cAMP production and Ca2+ influx while activating hyperpolarizing K+ currents. While it is known that D2Rs, G-proteins, and their effectors interact to produce these physiological effects, the details of these interactions are difficult to probe experimentally in live cells. We show how multicolor spatial cumulant analysis of labeled proteins of interest can accurately measure the stoichiometry of receptors, G-proteins, and downstream signaling targets.

Layer-specific effects of dopaminergic D1 receptor activation on excitatory synaptic trains in layer V mouse prefrontal cortical pyramidal cells.

In humans, executive functions (e.g., working memory [WM]) are mediated in part by prefrontal cortical areas (PFC), where ventromedial areas may be homologous to ventromedial areas (mPFC) in rodents. Many executive functions are critically dependent on optimal dopamine levels within the PFC; however, our understanding of the role of dopamine in modulating PFC‐mediated tasks is incomplete. Stable patterns of neuronal activity have been associated with WM processes, and recurrent excitatory synaptic activity has been proposed to play a role in this sustained activity. This excitatory activity may be regulated in a frequency‐dependent manner. Thus, we examined the effects of dopamine D1‐like receptor (D1R) activation on short‐term excitatory postsynaptic potential (EPSP) dynamics in two subtypes of mouse layer V mPFC pyramidal neurons by varying evoked train frequency from 10 to 50 Hz. We isolated non‐NMDA receptor (non‐NMDAR) and NMDA receptor (NMDAR)‐mediated components of EPSP trains, which were evoked by stimulating fibers located either within layer V or layer I of the mPFC. Interestingly, no differences in the effects of D1R activation were observed between subcortically projecting (PT or pyramidal tract) and contralaterally projecting (IT or intratelencephalic) layer V pyramidal cells. However, we found that D1R activation had layer‐specific effects on NMDAR‐ and non‐NMDAR‐mediated EPSP trains: while D1R activation increased the amplitude of both components with layer V stimulation, with layer I stimulation D1R activation had no effect on non‐NMDAR‐mediated EPSP trains but decreased the amplitude of NMDAR‐mediated EPSP trains. Our results suggest that dopamine, acting at D1‐like receptors, increases the influence of local inputs from other layer V pyramidal cells, but may restrict the influence of layer I (tuft) inputs. Our demonstration of differential D1R regulation of excitatory synaptic dynamics in distinct compartments of mPFC layer V neurons may provide another important aspect linking cellular mechanisms of dopaminergic modulation to PFC network functioning, and ultimately to executive functions such as working memory.

A-Kinase Anchoring Protein 150 (AKAP150) Promotes Cocaine Reinstatement by Increasing AMPA Receptor Transmission in the Accumbens Shell.

Previous work indicated that activation of D1-like dopamine receptors (D1DRs) in the nucleus accumbens shell promoted cocaine seeking through a process involving the activation of PKA and GluA1-containing AMPA receptors (AMPARs). A-kinase anchoring proteins (AKAPs) localize PKA to AMPARs leading to enhanced phosphorylation of GluA1. AKAP150, the most well-characterized isoform, plays an important role in several forms of neuronal plasticity. However, its involvement in drug addiction has been minimally explored. Here we examine the role of AKAP150 in cocaine reinstatement, an animal model of relapse. We show that blockade of PKA binding to AKAPs in the nucleus accumbens shell of Sprague-Dawley rats attenuates reinstatement induced by either cocaine or a D1DR agonist. Moreover, this effect is specific to AKAP150, as viral overexpression of a PKA-binding deficient mutant of AKAP150 also impairs cocaine reinstatement. This viral-mediated attenuation of cocaine reinstatement was accompanied by decreased phosphorylation of GluA1-containing AMPARs and attenuated AMPAR eEPSCs. Collectively, these results suggest that AKAP150 facilitates the reinstatement of cocaine-seeking behavior by amplifying D1DR/PKA-dependent AMPA transmission in the nucleus accumbens.

Relief of Pain-Depressed Behavior in Rats by Activation of D1-Like Dopamine Receptors

Clinically significant pain often includes a decrease in both behavior and mesolimbic dopamine signaling. Indirect and/or direct dopamine receptor agonists may alleviate pain-related behavioral depression. To test this hypothesis, the present study compared effects of indirect and direct dopamine agonists in a preclinical assay of pain-depressed operant responding. Male Sprague-Dawley rats with chronic indwelling microelectrodes in the medial forebrain bundle were trained in an intracranial self-stimulation (ICSS) procedure to press a lever for pulses of electrical brain stimulation. Intraperitoneal injection of dilute lactic acid served as an acute noxious stimulus to depress ICSS. Intraperitoneal lactic acid-induced depression of ICSS was dose-dependently blocked by the dopamine transporter inhibitor methylphenidate and the D1-selective agonist SKF82958, but not by the D2/3-selective agonists quinpirole, pramipexole, or sumanirole. The antinociceptive effects of methylphenidate and SKF82958 were blocked by the D1-selective antagonist SCH39166. Acid-induced stimulation of a stretching response was evaluated in separate groups of rats, but all agonists decreased acid-stimulated stretching, and antagonism experiments were inconclusive due to direct effects of the antagonists when administered alone. Taken together, these results suggest that D1-receptor stimulation is both sufficient to block acid-induced depression of ICSS and necessary for methylphenidate antinociception in this procedure. Conversely, D2/3-receptor stimulation is not sufficient to relieve pain-depressed behavior. These results support the hypothesis that pain-related depression of dopamine D1 receptor signaling contributes to pain-related depression of behavior in rats. Additionally, these results support further consideration of indirect dopamine agonists and direct D1 receptor agonists as candidate treatments for pain-related behavioral depression.

Changes in Dopamine Signalling Do Not Underlie Aberrant Hippocampal Plasticity in a Mouse Model of Huntington's Disease.

Altered dopamine receptor labelling has been demonstrated in presymptomatic and symptomatic Huntington's disease (HD) gene carriers, indicating that alterations in dopaminergic signalling are an early event in HD. We have previously described early alterations in synaptic transmission and plasticity in both the cortex and hippocampus of the R6/1 mouse model of Huntington's disease. Deficits in cortical synaptic plasticity were associated with altered dopaminergic signalling and could be reversed by D1- or D2-like dopamine receptor activation. In light of these findings we here investigated whether defects in dopamine signalling could also contribute to the marked alteration in hippocampal synaptic function. To this end we performed dopamine receptor labelling and pharmacology in the R6/1 hippocampus and report a marked, age-dependent elevation of hippocampal D1 and D2 receptor labelling in R6/1 hippocampal subfields. Yet, pharmacological inhibition or activation of D1- or D2-like receptors did not modify the aberrant synaptic plasticity observed in R6/1 mice. These findings demonstrate that global perturbations to dopamine receptor expression do occur in HD transgenic mice, similarly in HD gene carriers and patients. However, the direction of change and the lack of effect of dopaminergic pharmacological agents on synaptic function demonstrate that the perturbations are heterogeneous and region-specific, a finding that may explain the mixed results of dopamine therapy in HD.

Role of dopamine D1-like receptor within the nucleus accumbens in acute food deprivation- and drug priming-induced reinstatement of morphine seeking in rats

Dopamine is a predominant neurotransmitter in the nervous system, which plays an important role in both drug priming- and cue-induced reinstatement of cocaine and heroin seeking. Therefore, in the present study, the conditioned place preference (CPP) paradigm was used to evaluate the effects of intra-accumbal administration of SCH23390 as a dopamine D1-like receptor antagonist on food deprivation (FD) and drug priming-induced reinstatement. Sixty-eight adult male albino Wistar rats weighing 200–280g were bilaterally implanted by cannulae into the nucleus accumbens (NAc). For induction of the CPP, subcutaneous (sc) administration of morphine (5mg/kg) was used daily during a three-day conditioning phase. The conditioning score and locomotor activity were recorded by using the Ethovision software. Under extinction conditions, rats were given an ‘off’ period and were tested for FD-induced reinstatement following the 24-h or 48-h FD condition, and for drug priming-induced reinstatement under the sated condition following an injection of 0.5 and 1mg/kg (sc) morphine. In the next experiments, animals received different doses of intra-accumbal SCH23390 (0.25, 1 and 4μg/0.5μl saline) bilaterally and were subsequently tested for FD- and morphine priming-induced reinstatement. Our findings indicated that only a dose of 1mg/kg and not 0.5mg/kg of morphine induced the reinstatement of morphine. 24-h FD similar to 48-h FD induced the reinstatement of seeking behaviors facilitated by an ineffective dose of morphine (0.5mg/kg). Furthermore, the D1-like receptor antagonist attenuated FD- and drug priming-induced reinstatement dose-dependently. It is concluded that FD- and drug priming-induced reinstatement may be mediated, at least in some way, by activation of dopamine D1-like receptors in the NAc.

Activation of D1-like dopamine receptors increases the NMDA-induced gain modulation through a PKA-dependent pathway in the premotor nucleus of adult zebra finches

Interaction between dopamine (DA) and N-methyl-d-aspartate (NMDA) in the brain plays an important role in learning and memory. In the songbirds, the premotor robust nucleus of the arcopallium (RA) receives excitatory glutamatergic inputs from the high vocal center (HVC) and lateral magnocellular nucleus of the anterior nidopallium (LMAN), as well as dopaminergic inputs mostly from the periaqueductal gray (PAG) and ventral tegmental area (VTA). In zebra finch, DA potentiates the excitability of projection neurons in the RA through activation of D1-like dopamine receptors (D1 receptors). The relationship between D1 receptors and NMDA in the RA projection neurons is essentially unknown. Our previous work showed that NMDA can induce gain modulation in the RA projection neurons. Here, using the whole-cell current-clamp recording from brain slices of male zebra finches, we observed whether D1 receptors regulate the NMDA-induced gain modulation in the RA projection neurons. Our results showed that activation of D1 receptors further increased the slope (gain) of the firing frequency–injected current (f–I) relationship induced by NMDA in the RA projection neurons. Blocking D1 receptors had no effect on the NMDA-induced gain modulation in the RA projection neurons. The enhanced effects of D1 receptors agonists were blocked by protein kinase A (PKA) inhibitors. Our results suggest that activation of D1 receptors can increase the NMDA-induced gain modulation through a PKA-dependent pathway.

Activation of D2-like dopamine receptors inhibits GABA and glycinergic neurotransmission to pre-motor cardiac vagal neurons in the nucleus ambiguus

The parasympathetic control of heart rate arises from premotor cardiac vagal neurons (CVNs) located in the nucleus ambiguus (NA). Previous microinjection studies in NA show that dopamine evokes a decrease in heart rate, but the underlying mechanisms responsible for these responses were not identified. This study tested whether dopamine modulates inhibitory GABAergic and glycinergic and/or excitatory glutamatergic neurotransmission to CVNs. Retrogradely labeled CVNs were identified in an in vitro rat brainstem slice preparation and synaptic events were recorded using whole cell voltage clamp techniques.Bath application of dopamine (100μM) had no effect on excitatory synaptic events, but reversibly inhibited the frequency (but not amplitude) of GABAergic inhibitory postsynaptic currents (IPSCs) in CVNs. Similarly, dopamine (10μM and 100μM) inhibited glycinergic IPSC frequency by ∼50% and 70% respectively. The reduction in inhibitory neurotransmission to CVNs by dopamine was prevented by the sodium channel blocker TTX (1μM) indicating that the dopamine mediated effects were action potential dependent. Dopamine evoked responses were mimicked by the D2-like receptor agonist, Quinpirole but not D1-like receptor agonist, SKF 38393. In addition, the dopamine mediated depression of inhibitory synaptic responses were prevented by the D2-like receptor antagonist sulpiride, but not by D1-like or adrenergic or serotonergic receptor antagonists, suggesting that these responses were D2-like receptor mediated and not D1-like or adrenergic or 5-HT receptor mediated. These data suggest that dopamine acts via dis-inhibition, and diminishes inhibitory GABAergic and glycinergic neurotransmission to CVNs, which would be predicted to increase parasympathetic activity to the heart and evoke a bradycardia.

Juvenile hormone synthesis is stimulated by activation of dopamine D1-like receptors in Drosophila

Juvenile hormone synthesis is stimulated by activation of dopamine D1-like receptors in Drosophila

Modulation of the activity of globus pallidus by dopamine D1-like receptors in parkinsonian rats

Morphological studies have shown that the globus pallidus receives dopaminergic innervation from the collaterals of nigrostriatal fibers. Dopamine D1-like receptors are expressed at both pre- and postsynaptic membrane. In the present study, we investigate the in vivo electrophysiological and behavioral effects of pallidal dopamine D1-like receptors in parkinsonian rats. On the lesioned side of 6-hydroxydopamine (6-OHDA) parkinsonian rats, micropressure ejection of dopamine D1-like receptor agonist, SKF38393, increased (88.2 ± 18.6%) the firing rate in 10 out of the 32 pallidal neurons, but decreased (49.5 ± 6.1%) the firing rate in 14 out of the 32 neurons. Furthermore, on the unlesioned side of parkinsonian rats, SKF38393 increased (43.0 ± 6.3%) the firing rate in 9 out of the 30 pallidal neurons, but decreased (47.1 ± 4.8%) the firing rate in 13 out of the 30 neurons. In behaving rats, unilateral microinjection of SKF38393 led to contralateral deflection in the presence of systemic haloperidol administration. The selective dopamine D1-like receptor antagonist, SCH23390, blocked both SKF38393-induced electrophysiological and behavioral effects. Combining electrophysiological and behavioral findings, we concluded that activation of dopamine D1-like receptors modulates the activity of globus pallidus neurons in rats.

P10.10 Dopamine D1-like receptor activation depolarizes medium spiny neurons of the mouse nucleus accumbens by inhibiting inwardly rectifying K+ currents

P10.10 Dopamine D1-like receptor activation depolarizes medium spiny neurons of the mouse nucleus accumbens by inhibiting inwardly rectifying K+ currents