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Background: The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear. Aims: The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) regarding fear generalization in adult, male Wistar rats, and aims to replicate previous findings in mice. Methods: In a series of five experiments, D2R (ant)agonists were injected systemically, immediately after differential cued fear conditioning (CS+ followed by shock, CS− without shock). All five experiments involved the administration of the D2R agonist quinpirole at different doses versus saline (n = 12, 16, or 44 rats/group). In addition, one of the studies administered the D2R antagonist raclopride (n = 12). One day later, freezing during the CS+ and CS− was assessed. Results: We found no indications for an effect of quinpirole or raclopride on fear generalization during this drug-free test. Importantly, and contradicting earlier research in mice, the evidence for the absence of an effect of D2R agonist quinpirole (1 mg/kg) on fear generalization was substantial according to Bayesian analyses and was observed in a highly powered experiment (N = 87). We did find acute behavioral effects in line with the literature, for both quinpirole and raclopride in a locomotor activity test. Conclusion: In contrast with prior studies in mice, we have obtained evidence against a preventative effect of post-training D2R agonist quinpirole administration on subsequent fear generalization in rats. [ABSTRACT FROM AUTHOR]

Abstract Introduction Epilepsy is a common neurological disorder that presents with challenging mechanisms and treatment strategies. This study investigated the neuroprotective effects of quinpirole on lithium chloride pilocarpine-induced epileptic rats and explored its potential mechanisms. Methods Lithium chloride pilocarpine was used to induce an epileptic model in rats, and the effects of quinpirole on seizure symptoms and cognitive function were evaluated. The Racine scoring method, electroencephalography, and Morris water maze test were used to assess seizure severity and learning and memory functions in rats in the epileptic group. Additionally, immunohistochemistry and Western blot techniques were used to analyze the protein expression levels and morphological changes in glutamate receptor 2 (GluR2; GRIA2), BAX, and BCL2 in the hippocampi of rats in the epileptic group. Results First, it was confirmed that the symptoms in rats in the epileptic group were consistent with features of epilepsy. Furthermore, these rats demonstrated decreased learning and memory function in the Morris water maze test. Additionally, gene and protein levels of GluR2 in the hippocampi of rats in the epileptic group were significantly reduced. Quinpirole treatment significantly delayed seizure onset and decreased the mortality rate after the induction of a seizure. Furthermore, electroencephalography showed a significant decrease in the frequency of the spike waves. In the Morris water maze test, rats from the quinpirole treatment group demonstrated a shorter latency period to reach the platform and an increased number of crossings through the target quadrant. Network pharmacology analysis revealed a close association between quinpirole and GluR2 as well as its involvement in the cAMP signaling pathway, cocaine addiction, and dopaminergic synapses. Furthermore, immunohistochemistry and Western blot analysis showed that quinpirole treatment resulted in a denser arrangement and a more regular morphology of the granule cells in the hippocampi of rats in the epileptic group. Additionally, quinpirole treatment decreased the protein expression of BAX and increased the protein expression of BCL2. Conclusion The current study demonstrated that quinpirole exerted neuroprotective effects in the epileptic rat model induced by lithium chloride pilocarpine. Additionally, it was found that the treatment not only alleviated the rats' seizure symptoms, but also improved their learning and memory abilities. This improvement was linked to the modulation of protein expression levels of GLUR2, BAX, and BCL2. These findings provided clues that would be important for further investigation of the therapeutic potential of quinpirole and its underlying mechanisms for epilepsy treatment.

Introduction: Epilepsy is a common neurological disorder that presents with challenging mechanisms and treatment strategies. This study investigated the neuroprotective effects of quinpirole on lithium chloride pilocarpine-induced epileptic rats and explored its potential mechanisms. Methods: Lithium chloride pilocarpine was used to induce an epileptic model in rats, and the effects of quinpirole on seizure symptoms and cognitive function were evaluated. The Racine scoring method, electroencephalography, and Morris water maze test were used to assess seizure severity and learning and memory functions in rats in the epileptic group. Additionally, immunohistochemistry and Western blot techniques were used to analyze the protein expression levels and morphological changes in glutamate receptor 2 (GluR2; GRIA2), BAX, and BCL2 in the hippocampi of rats in the epileptic group. Results: First, it was confirmed that the symptoms in rats in the epileptic group were consistent with features of epilepsy. Furthermore, these rats demonstrated decreased learning and memory function in the Morris water maze test. Additionally, gene and protein levels of GluR2 in the hippocampi of rats in the epileptic group were significantly reduced. Quinpirole treatment significantly delayed seizure onset and decreased the mortality rate after the induction of a seizure. Furthermore, electroencephalography showed a significant decrease in the frequency of the spike waves. In the Morris water maze test, rats from the quinpirole treatment group demonstrated a shorter latency period to reach the platform and an increased number of crossings through the target quadrant. Network pharmacology analysis revealed a close association between quinpirole and GluR2 as well as its involvement in the cAMP signaling pathway, cocaine addiction, and dopaminergic synapses. Furthermore, immunohistochemistry and Western blot analysis showed that quinpirole treatment resulted in a denser arrangement and a more regular morphology of the granule cells in the hippocampi of rats in the epileptic group. Additionally, quinpirole treatment decreased the protein expression of BAX and increased the protein expression of BCL2. Conclusion: The current study demonstrated that quinpirole exerted neuroprotective effects in the epileptic rat model induced by lithium chloride pilocarpine. Additionally, it was found that the treatment not only alleviated the rats' seizure symptoms, but also improved their learning and memory abilities. This improvement was linked to the modulation of protein expression levels of GLUR2, BAX, and BCL2. These findings provided clues that would be important for further investigation of the therapeutic potential of quinpirole and its underlying mechanisms for epilepsy treatment. [ABSTRACT FROM AUTHOR]

Introduction: The dopaminergic system plays a key role in the appropriate functioning of the central nervous system, where it is essential for emotional balance, arousal, reward, and motor control. The cell adhesion molecule close homolog of L1 (CHL1) contributes to dopaminergic system development, and CHL1 and the dopamine receptor D2 (D2R) are associated with mental disorders like schizophrenia, addiction, autism spectrum disorder and depression. Methods: Here, we investigated how the interplay between CHL1 and D2R affects the behavior of young adult male and female wild-type (CHL+/+) and CHL1- deficient (CHL1−/−) mice, when D2R agonist quinpirole and antagonist sulpiride are applied. Results: Low doses of quinpirole (0.02  mg/kg body weight) induced hypolocomotion of CHL1+/+ and CHL1−/− males and females, but led to a delayed response in CHL1−/− mice. Sulpiride (1  mg/kg body weight) affected locomotion of CHL1−/− females and social interaction of CHL1+/+ females as well as social interactions of CHL1−/− and CHL1+/+ males. Quinpirole increased novelty-seeking behavior of CHL1−/− males compared to CHL1+/+ males. Vehicle-treated CHL1−/− males and females showed enhanced working memory and reduced stress-related behavior. Discussion: We propose that CHL1 regulates D2R-dependent functions in vivo. Deficiency of CHL1 leads to abnormal locomotor activity and emotionality, and to sex-dependent behavioral differences. [ABSTRACT FROM AUTHOR]

Objective: As dopamine is closely linked to locomotor activities, animal studies on locomotor activities using dopaminergic agents were widely done. However, most of animal studies were performed for a short period that there is a lack of longitudinal study on the effects of dopaminergic agents on locomotor activities. This study aimed to examine the longterm effect of a dopamine D2, D3 agonist quinpirole on locomotor activities in mice using a home-cage monitoring system. Methods: The locomotor activities of Institute Cancer Research mice were measured by infrared motion detectors in home-cages under the 12-hour dark and 12-hour light condition for three days after the quinpirole injection. Quinpirole was injected at a concentration of 0.5 mg/kg intraperitoneally in the beginning of the dark phase. The locomotor activities before and after the quinpirole administration were compared by the Wilcoxon signed-rank test and one-way repeated measures ANOVA. Results: After the quinpirole administration, the 24-hour total locomotor activity did not change ( p = 0.169), but activities were significantly increased in the 12-hour dark phase sum ( p = 0.013) and decreased in the 12-hour light phase sum ( p = 0.009). Significant increases in the activities were observed in the dark-light difference ( p = 0.005) and dark-light ratio ( p = 0.005) as well. Conclusion: This study suggests that quinpirole injection entrains the circadian rest-activity rhythm of locomotor activities. Therefore, quinpirole can be a drug that mediates locomotor activity as a dopamine agonist as well as a modulator of the circadian rhythms. [ABSTRACT FROM AUTHOR]

IntroductionThe dopaminergic system plays a key role in the appropriate functioning of the central nervous system, where it is essential for emotional balance, arousal, reward, and motor control. The cell adhesion molecule close homolog of L1 (CHL1) contributes to dopaminergic system development, and CHL1 and the dopamine receptor D2 (D2R) are associated with mental disorders like schizophrenia, addiction, autism spectrum disorder and depression.MethodsHere, we investigated how the interplay between CHL1 and D2R affects the behavior of young adult male and female wild-type (CHL+/+) and CHL1-deficient (CHL1−/−) mice, when D2R agonist quinpirole and antagonist sulpiride are applied.ResultsLow doses of quinpirole (0.02 mg/kg body weight) induced hypolocomotion of CHL1+/+ and CHL1−/− males and females, but led to a delayed response in CHL1−/− mice. Sulpiride (1 mg/kg body weight) affected locomotion of CHL1−/− females and social interaction of CHL1+/+ females as well as social interactions of CHL1−/− and CHL1+/+ males. Quinpirole increased novelty-seeking behavior of CHL1−/− males compared to CHL1+/+ males. Vehicle-treated CHL1−/− males and females showed enhanced working memory and reduced stress-related behavior.DiscussionWe propose that CHL1 regulates D2R-dependent functions in vivo. Deficiency of CHL1 leads to abnormal locomotor activity and emotionality, and to sex-dependent behavioral differences.

Impulsive behaviour on the five-choice serial reaction time task (5CSRTT), a task measuring attention and impulsivity in rodents, is known to depend on dopamine (DA) neurotransmission in the mesolimbic DA pathway. Previous research in our lab reported that systemic administration of the D2/3 agonist quinpirole, which decreases DA release in the striatum, reduced premature responses in rats performing the 5CSRTT. It is unclear, however, whether this effect is mediated by the activation of inhibitory somatodendritic receptors in the ventral tegmental area (VTA), which in turn leads to a reduction in DA release in the nucleus accumbens, a major terminal region of the mesolimbic DA pathway. In the present study, we investigated this possibility by infusing quinpirole directly into the VTA of rats during performance on the 5CSRTT. We found that quinpirole, at the highest dose, significantly reduced the frequency of premature responses on the 5CSRTT. Thus, the effects of quinpirole and other D2/3 receptor agonists to reduce this form of impulsive behaviour appear to depend on the activation of somatodendritic D2/3 receptors in the VTA. [ABSTRACT FROM AUTHOR]

The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (D 2 R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D 2 R can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals. The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus. Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP. Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation. Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation. These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP D 2 Rs in the regulation of limbic information flow. • The intra-VP D 2 R agonist quinpirole induces LTP on the NAC shell-VP synapses. • Intra-VP quinpirole inhibits VP LFP response and LTP evoked by BLA stimulation. • Quinpirole increases the amplitude of the gamma frequency band in the VP LFP. • BLA tonically suppresses the NAC's HFS-induced gamma facilitation. • BLA plays a prominent role in the generation of the delta oscillations. [ABSTRACT FROM AUTHOR]

A dopamine D2 receptor (D2R) agonist and an anti-calcitonin gene-related peptide (CGRP) antibody were separately reported to reduce neuropathic pain. To further attenuate neuropathic pain, co-administration of a D2R agonist and an anti-CGRP antibody was performed in a rat with the infraorbital nerve (ION) ligation. However, this co-administration showed no further attenuation of mechanical hypersensitivity compared to the administration of anti-CGRP antibody alone. Our results also revealed that D2R immunoreactivity in the trigeminal spinal subnucleus caudalis (Vc) increased following the nerve ligation and decreased following administration of an anti-CGRP antibody. The ratio of immunoreactive neurons of phosphorylated cyclic adenosine monophosphate-response-element-binding protein in the Vc also increased following nerve ligation and decreased with the anti-CGRP antibody. Our results suggest that a decrease in D2R immunoreactivity reduces the effect of a D2R agonist, and transcription of D2R is activated following the ION ligation and suppressed by treatment with an anti-CGRP antibody. • Quinpirole did not improve attenuation of neuropathic pain by an anti-CGRP antibody. • Dopamine D2 receptor in the Vc increased after infraorbital nerve ligation. • Dopamine D2 receptor in the Vc decreased after treatment with an anti-CGRP antibody. • Ratio of pCREB positive neurons increased after infraorbital nerve ligation. • Ratio of pCREB positive neurons decreased after treatment with an anti-CGRP antibody. [ABSTRACT FROM AUTHOR]

Background The ventral pallidum (VP) is a dopaminoceptive forebrain structure regulating the ventral tegmental area (VTA) dopaminergic population activity. We have recently demonstrated that in the VP, the D2-like dopamine (DA) receptor agonist quinpirole dose dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. According to our hypothesis, quinpirole microinjected into the VP can modulate the VTA DAergic activity and influence motivation and learning processes of rats. Methods Quinpirole was microinjected at 3 different doses into the VP of male rats, and controls received vehicle. Single unit recordings were employed to assess VTA DAergic activity. To investigate the possible reinforcing or aversive effect of quinpirole in the VP, the conditioned place preference paradigm was used. Results Our results showed that intra-VP quinpirole microinjection regulates VTA DAergic neurons according to an inverted U-shaped dose-response curve. The largest dose of quinpirole decreased the population activity and strongly reduced burst activity of the DAergic neurons in the first hour after its application. In contrast, the 2 smaller doses increased DA population activity, but their effect started with a delay 1 hour after their microinjection. The CPP experiments revealed that the largest dose of quinpirole in the VP induced place aversion in the rats. Furthermore, the largest dose of quinpirole induced an acute locomotor activity reduction, while the medium dose led to a long-duration increase in locomotion. Conclusions In summary, quinpirole dose dependently regulates VTA DAergic activity as well as the motivation and motor behavior of the rats at the level of the VP. [ABSTRACT FROM AUTHOR]

Dopaminergic modulation of prefrontal cortex (PFC) is thought to play key roles in many cognitive functions and to be disrupted in pathological conditions, such as schizophrenia. We have previously described a phenomenon whereby dopamine D2 receptor (D2R) activation elicits afterdepolarizations (ADPs) in subcortically projecting (SC) pyramidal neurons within L5 of the PFC. These D2R-induced ADPs only occur following synaptic input, which activates NMDARs, even when the delay between the synaptic input and ADPs is relatively long (e.g., several hundred milliseconds). Here, we use a combination of electrophysiological, optogenetic, pharmacological, transgenic, and chemogenetic approaches to elucidate cellular mechanisms underlying this phenomenon in male and female mice. We find that knocking out D2Rs eliminates the ADP in a cell-autonomous fashion, confirming that this ADP depends on D2Rs. Hyperpolarizing current injection, but not AMPA receptor blockade, prevents synaptic stimulation from facilitating D2R-induced ADPs, suggesting that this phenomenon depends on the recruitment of voltage-dependent currents (e.g., NMDAR-mediated Ca2+ influx) by synaptic input. Finally, the D2R-induced ADP is blocked by inhibitors of cAMP/PKA signaling, insensitive to pertussis toxin or β-arrestin knock-out, and mimicked by Gs-DREADD stimulation, suggesting that D2R activation elicits the ADP by stimulating cAMP/PKA signaling. These results show that this unusual physiological phenomenon, in which D2Rs enhance cellular excitability in a manner that depends on synaptic input, is mediated at the cellular level through the recruitment of signaling pathways associated with Gs, rather than the Gi/o-associated mechanisms that have classically been ascribed to D2Rs.SIGNIFICANCE STATEMENT Dopamine D2 receptors (D2Rs) in the prefrontal cortex (PFC) are thought to play important roles in behaviors, including working memory and cognitive flexibility. Variation in D2Rs has also been implicated in schizophrenia, Tourette syndrome, and bipolar disorder. Recently, we described a new mechanism through which D2R activation can enhance the excitability of pyramidal neurons in the PFC. Here, we explore the underlying cellular mechanisms. Surprisingly, although D2Rs are classically assumed to signal through Gi/o-coupled G-proteins and/or scaffolding proteins, such as β-arrestin, we find that the effects of D2Rs on prefrontal pyramidal neurons are actually mediated by pathways associated with Gs-mediated signaling. Furthermore, we show how, via this D2R-dependent phenomenon, synaptic input can enhance the excitability of prefrontal neurons over timescales on the order of seconds. These results elucidate cellular mechanisms underlying a novel signaling pathway downstream of D2Rs that may contribute to prefrontal function under normal and pathological conditions.

Recent evidence suggests that SARS-CoV-2 hinders immune responses via dopamine (DA)-related mechanisms. Nonetheless, studies addressing the specific role of DA in the frame of SARS-CoV-2 infection are still missing. In the present study, we investigate the role of DA in SARS-CoV-2 replication along with potential links with innate immune pathways in CaLu-3 human epithelial lung cells. We document here for the first time that, besides DA synthetic pathways, SARS-CoV-2 alters the expression of D1 and D2 DA receptors (D1DR, D2DR), while DA administration reduces viral replication. Such an effect occurs at non-toxic, micromolar-range DA doses, which are known to induce receptor desensitization and downregulation. Indeed, the antiviral effects of DA were associated with a robust downregulation of D2DRs both at mRNA and protein levels, while the amount of D1DRs was not significantly affected. While halting SARS-CoV-2 replication, DA, similar to the D2DR agonist quinpirole, upregulates the expression of ISGs and Type-I IFNs, which goes along with the downregulation of various pro-inflammatory mediators. In turn, administration of Type-I IFNs, while dramatically reducing SARS-CoV-2 replication, converges in downregulating D2DRs expression. Besides configuring the CaLu-3 cell line as a suitable model to study SARS-CoV-2-induced alterations at the level of the DA system in the periphery, our findings disclose a previously unappreciated correlation between DA pathways and Type-I IFN response, which may be disrupted by SARS-CoV-2 for host cell invasion and replication. [ABSTRACT FROM AUTHOR]

Obsessive-compulsive disorder (OCD) is a mental affliction characterized by compulsive behaviors often manifested in intrusive thoughts and repetitive actions. The quinpirole model has been used with rats to replicate compulsive behaviors and study the neurophysiological processes associated with this pathology. Several changes in the dendritic spines of the medial prefrontal cortex (mPFC) and dorsolateral striatum (DLS) have been related to the occurrence of compulsive behaviors. Dendritic spines regulate excitatory synaptic contacts, and their morphology is associated with various brain pathologies. The present study was designed to correlate the occurrence of compulsive behaviors (generated by administering the drug quinpirole) with the morphology of the different types of dendritic spines in the mPFC and DLS. A total of 18 male rats were used. Half were assigned to the experimental group, the other half to the control group. The former received injections of quinpirole, while the latter rats were injected with physiological saline solution, for 10 days in both cases. After the experimental treatment, the quinpirole rats exhibited all the parameters indicative of compulsive behavior and a significant correlation with the density of stubby and wide neckless spines in both the mPFC and DLS. Dendritic spines from both mPFC and DLS neurons showed plastic changes correlatively with the expression of compulsive behavior induced by quinpirole. Further studies are suggested to evaluate the involvement of glutamatergic neurotransmission in the neurobiology of OCD. • Higher frequency of visits correlated (-) with less stubby spines in the mPFC. • Lower return times and duration correlated (-) with more wide spines in the DLS. • More visits and more distance were correlated (+) with more wide spines in the DLS. • Controls' repetitive patterns correlated (-) with thin and (+) with mushroom spines. [ABSTRACT FROM AUTHOR]

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Rationale: Palatability and incentive value influence animal food choice. Dopamine D2/3 receptor signaling may mediate the effects of palatability and incentive value on choice. Dopamine signaling is disrupted in attention-deficit hyperactivity disorder (ADHD). Investigating behavioral choice processes under D2/3 receptor agonists will help elucidate behavioral and pharmacological correlates of ADHD. Objectives: To determine (1) how changes in incentive value affects choice of actions for outcomes that differ in palatability; (2) the effects of the D2/3 agonist quinpirole on choice based on palatability and incentive value; (3) how choice differs in spontaneously hypertensive rats (SHR; ADHD model) compared with control strains. Methods: Rats responded instrumentally for two food outcomes (chocolate and grain pellets) that differed in palatability. Following specific satiety of one outcome, rats underwent a choice test. Prior to the choice test, rats were given intra-peritoneal quinpirole (0.01–0.1 mg/kg) body weight. These manipulations were conducted in three strains of rats: SHR rats; the normotensive Wistar-Kyoto (WKY) controls; and Wistar outbred (WIS) controls. Results: All rat strains responded more vigorously for chocolate pellets compared with grain pellets. Quinpirole reduced the effects of palatability and dose-dependently increased the effects of incentive value on choice. SHR rats were the least influenced by incentive value, whereas WKY rats were the least influenced by palatability. Conclusions: These results show that D2/3 signaling modulates choice based on palatability and incentive value. Disruption of this process in SHR rats may mirror motivational impairments observed in ADHD. [ABSTRACT FROM AUTHOR]

Background/Aims: Neonatal quinpirole (NQ) treatment to rats increases dopamine D2 (DAD2) receptor sensitivity in adult animals. We investigated if increased DAD2 sensitivity would be passed to the next (F1) generation, and if these animals demonstrated sensorimotor gating deficits and enhanced behavioral responses to nicotine. Methods: Male and female rats were intraperitoneal (IP) administered quinpirole (1 mg/kg) or saline (NS) from postnatal day (P)1–21. Animals were either behaviorally tested (F0) or raised to P60 and mated, creating F1 offspring. Results: Experiment 1 revealed that F1 generation animals that were the offspring of at least one NQ-treated founder increased yawning behavior, a DAD2-mediated behavioral event, in response to acute quinpirole (0.1 mg/kg). F1 generation rats also demonstrated increased striatal β arrestin-2 and decreased phospho-AKT signaling, consistent with increased G-protein independent DAD2 signaling, which was equal to F0 NQ-treated founders, although this was not observed in all groups. RNA-Seq analysis revealed significant gene expression changes in the F1 generation that were offspring of both NQ-treated founders compared to F0 NQ founders and controls, with enrichment in sensitivity to stress hormones and cell signaling pathways. In Experiment 2, all F1 generation offspring demonstrated sensorimotor gating deficits compared to controls, which were equivalent to F0 NQ-treated founders. In Experiment 3, all F1 generation animals demonstrated enhanced nicotine behavioral sensitization and nucleus accumbens (NAcc) brain-derived neurotrophic factor (BDNF) protein. Further, F1 generation rats demonstrated enhanced adolescent nicotine conditioned place preference equivalent to NQ-treated founders conditioned with nicotine. Conclusions: This represents the first demonstration of transgenerational effects of increased DAD2 sensitivity in a rodent model. [ABSTRACT FROM AUTHOR]

The nucleus accumbens (NAc) is a central component of the brain circuitry that mediates motivated behavior, including reward processing. Since the rewarding properties of social stimuli have a vital role in guiding behavior (both in humans and nonhuman animals), the NAc is likely to contribute to the brain circuitry controlling social behavior. In rodents, prior studies have found that focal pharmacological inhibition of NAc and/or elevation of dopamine in NAc increases social interactions. However, the role of the NAc in social behavior in nonhuman primates remains unknown. We measured the social behavior of eight dyads of male macaques following (1) pharmacological inhibition of the NAc using the GABA A agonist muscimol and (2) focal application of quinpirole, an agonist at the D2 family of dopamine receptors. Transient inhibition of the NAc with muscimol increased social behavior when drug was infused in submissive, but not dominant partners of the dyad. Focal application of quinpirole was without effect on social behavior when infused into the NAc of either dominant or submissive subjects. Our data demonstrate that the NAc contributes to social interactions in nonhuman primates., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Waguespack et al.)

BackgroundThe polyunsaturated fatty acid, docosahexaenoic acid (DHA), participates in neurotransmission involving activation of calcium-independent phospholipase A2 (iPLA2), which is coupled to muscarinic, cholinergic and serotonergic neuroreceptors. Drug induced activation of iPLA2 can be measured in vivo with quantitative autoradiography using 14C-DHA as a probe. The present study used this approach to address whether a DHA signal is produced following dompaminergic (D)2-like receptor activation with quinpirole in rat brain. Unanesthetized rats were infused intravenously with 14C-DHA one minute after saline or quinpirole infusion, and serial blood samples were collected over a 20-minute period to obtain plasma. The animals were euthanized with sodium pentobarbital and their brains excised, coronally dissected and subjected to quantitative autoradiography to derive the regional incorporation coefficient, k*, a marker of DHA signaling. Plasma labeled and unlabeled unesterified DHA concentrations were measured.ResultsThe incorporation coefficient (k*) for DHA did not differ significantly between quinpirole-treated and control rats in any of 81 identified brain regions. Plasma labeled DHA concentration over the 20-minute collection period (input function) and unlabeled unesterified DHA concentration did not differ significantly between the two groups.ConclusionThese findings demonstrate that D2-like receptor initiated signaling does not involve DHA as a second messenger, and likely does not involve iPLA2 activation.

Alterations of the dopaminergic system are associated with the cognitive and functional dysfunctions that characterize complex neuropsychiatric disorders. We modeled a dysfunctional dopaminergic system using mice with targeted ablation of dopamine (DA) D2 autoreceptors in mesencephalic dopaminergic neurons. Loss of D2 autoreceptors abolishes D2-mediated control of DA synthesis and release. Here, we show that this mutation leads to a profound alteration of the genomic landscape of neurons receiving dopaminergic afferents at distal sites, specifically in the prefrontal cortex. Indeed, we observed a remarkable downregulation of gene expression in this area of ~2000 genes, which involves a widespread increase in the histone repressive mark H3K9me2/3. This reprogramming process is coupled to psychotic-like behaviors in the mutant mice. Importantly, chronic treatment with a DA agonist can revert the genomic phenotype. Thus, cortical neurons undergo a profound epigenetic reprogramming in response to dysfunctional D2 autoreceptor signaling leading to altered DA levels, a process that may underlie a number of neuropsychiatric disorders.

The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Alterations in glutamatergic and GABAergic signaling were recently demonstrated in the NAcc of rats after chronic intermittent ethanol (CIE) treatment, a model of alcohol dependence. Here we studied dopamine (DA) modulation of GABAergic signaling and how this modulation might be altered by CIE treatment. We show that the tonic current (I(tonic)) mediated by extrasynaptic γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc core is differentially modulated by DA at concentrations in the range of those measured in vivo (0.01-1 μM), without affecting the postsynaptic kinetics of miniature inhibitory postsynaptic currents (mIPSCs). Use of selective D1 receptor (D1R) and D2 receptor (D2R) ligands revealed that I(tonic) potentiation by DA (10 nM) is mediated by D1Rs while I(tonic) depression by DA (0.03-1 μM) is mediated by D2Rs in the same MSNs. Addition of guanosine 5'-O-(2-thiodiphosphate) (GDPβS) to the recording pipettes eliminated I(tonic) decrease by the selective D2R agonist quinpirole (5 nM), leaving intact the quinpirole effect on mIPSC frequency. Recordings from CIE and vehicle control (CIV) MSNs during application of D1R agonist (SKF 38393, 100 nM) or D2R agonist (quinpirole, 2 nM) revealed that SKF 38393 potentiated I(tonic) to the same extent, while quinpirole reduced I(tonic) to a similar extent, in both groups of rats. Our data suggest that the selective modulatory effects of DA on I(tonic) are unaltered by CIE treatment and withdrawal.

Adolescence is a sensitive developmental period for limbic and dopamine systems that coincides with the typical age for onset of tobacco use. We have previously shown that a 4-day, low-dose nicotine (0.06 mg/kg) pretreatment enhances locomotor and penile response to the D2-like agonist, quinpirole (0.4 mg/kg), in adolescent but not adult rats. The present study is designed to determine mechanisms underlying this effect. Nicotine enhancement of adolescent quinpirole-induced locomotion was mediated by D2 receptors (D2Rs) since it was blocked by the D2R antagonist, L-741,626, but not by the D3R and D4R antagonists, NGB 2904 and L-745,870. Enhancement of quinpirole-induced erectile response was blocked by both L-741,626 and NGB 2904, indicating involvement of D3Rs. Whereas D2R binding was unaffected by adolescent nicotine pretreatment, effector coupling in the striatum was increased, as determined by GTPγS binding. Nicotine pretreatment enhanced quinpirole-induced c-fos mRNA expression in the hypothalamic paraventricular and supraoptic nuclei in adolescents only. Adolescent nicotine pretreatment enhanced c-fos mRNA expression in corticotropin releasing factor (CRF) cells of the paraventricular nucleus, and enhancement of penile erection was blocked by the CRF-1 receptor antagonist, CP 376,396. These findings suggest that adolescent dopamine and CRF systems are vulnerable to alteration by nicotine. This is the first evidence for a role of CRF in adolescent erectile response.

Recent evidence suggests that SARS-CoV-2 hinders immune responses via dopamine (DA)-related mechanisms. Nonetheless, studies addressing the specific role of DA in the frame of SARS-CoV-2 infection are still missing. In the present study, we investigate the role of DA in SARS-CoV-2 replication along with potential links with innate immune pathways in CaLu-3 human epithelial lung cells. We document here for the first time that, besides DA synthetic pathways, SARS-CoV-2 alters the expression of D1 and D2 DA receptors (D1DR, D2DR), while DA administration reduces viral replication. Such an effect occurs at non-toxic, micromolar-range DA doses, which are known to induce receptor desensitization and downregulation. Indeed, the antiviral effects of DA were associated with a robust downregulation of D2DRs both at mRNA and protein levels, while the amount of D1DRs was not significantly affected. While halting SARS-CoV-2 replication, DA, similar to the D2DR agonist quinpirole, upregulates the expression of ISGs and Type-I IFNs, which goes along with the downregulation of various pro-inflammatory mediators. In turn, administration of Type-I IFNs, while dramatically reducing SARS-CoV-2 replication, converges in downregulating D2DRs expression. Besides configuring the CaLu-3 cell line as a suitable model to study SARS-CoV-2-induced alterations at the level of the DA system in the periphery, our findings disclose a previously unappreciated correlation between DA pathways and Type-I IFN response, which may be disrupted by SARS-CoV-2 for host cell invasion and replication.

Abstract Background and Purpose Dopamine is well‐known to contribute to emergence from anesthesia. Previous studies have demonstrated that the paraventricular thalamus (PVT) in the midline nuclei is crucial for wakefulness. Moreover, the PVT receives dopaminergic projections from the brainstem. Therefore, we hypothesize that the dopaminergic signaling in the PVT plays a role in emergence from isoflurane anesthesia. Methods We used c‐Fos immunohistochemistry to reveal the activity of PVT neurons in three groups: The first group (iso+EM‐) underwent the anesthesia protocol and was sacrificed before emergence. The second group (iso+EM+) underwent passive emergence from the same anesthesia protocol. The last group (oxy+) received oxygen. D2‐like agonist quinpirole (2 or 4 mM) or D2‐like antagonist raclopride (2 or 5 mM) was microinjected into the PVT, and their effects on emergence and induction time were analyzed. Surface cortical electroencephalogram (EEG) recordings were used to explore the effects of quinpirole injection into the PVT on cortical excitability during isoflurane anesthesia. The activity of PVT neurons after quinpirole injection was assessed by c‐Fos immunohistochemistry. Results The number of c‐Fos‐positive nuclei for the iso+EM+ group was significantly higher than the oxy+ and iso+EM‐ groups. Application of quinpirole (4 mM) into the PVT shortened emergence time compared with the saline group (p

Background and Purpose: Dopamine is well‐known to contribute to emergence from anesthesia. Previous studies have demonstrated that the paraventricular thalamus (PVT) in the midline nuclei is crucial for wakefulness. Moreover, the PVT receives dopaminergic projections from the brainstem. Therefore, we hypothesize that the dopaminergic signaling in the PVT plays a role in emergence from isoflurane anesthesia. Methods: We used c‐Fos immunohistochemistry to reveal the activity of PVT neurons in three groups: The first group (iso+EM‐) underwent the anesthesia protocol and was sacrificed before emergence. The second group (iso+EM+) underwent passive emergence from the same anesthesia protocol. The last group (oxy+) received oxygen. D2‐like agonist quinpirole (2 or 4 mM) or D2‐like antagonist raclopride (2 or 5 mM) was microinjected into the PVT, and their effects on emergence and induction time were analyzed. Surface cortical electroencephalogram (EEG) recordings were used to explore the effects of quinpirole injection into the PVT on cortical excitability during isoflurane anesthesia. The activity of PVT neurons after quinpirole injection was assessed by c‐Fos immunohistochemistry. Results: The number of c‐Fos‐positive nuclei for the iso+EM+ group was significantly higher than the oxy+ and iso+EM‐ groups. Application of quinpirole (4 mM) into the PVT shortened emergence time compared with the saline group (p <.01). In contrast, administration of raclopride (2 mM) delayed emergence time (p <.05). Neither quinpirole nor raclopride exerted an effect on induction time. EEG analyses showed that quinpirole (4 mM) decreased the burst suppression ratio during isoflurane anesthesia (p <.01). The number of c‐Fos‐positive nuclei for the quinpirole (4 mM) group was significantly higher than saline group (p <.01). Conclusions: Our findings suggest that the activity of PVT neurons is enhanced after emergence from anesthesia, and the dopaminergic signaling in the PVT may facilitate emergence from isoflurane anesthesia. [ABSTRACT FROM AUTHOR]

Effective rational drug discovery hinges on understanding the functional states of the target protein and distinguishing it from homologues. However, for the G protein coupled receptors, both activation-related conformational changes (ACCs) and intrinsic divergence among receptors can be misled or obscured by ligand-specific conformational changes (LCCs). Here, we unraveled ACCs and intrinsic divergence from LCCs of the dopamine D3 and D2 receptors (D3R and D2R), by analyzing their experimentally determined structures and the molecular dynamics (MD) simulation results of the receptors bound with various ligands. In addition to the ACCs common to other aminergic receptors, we revealed unique ACCs for these two receptors, including the extracellular portion of TM5 (TM5e) and TM6e shifting away from TM2e and TM3e, with a subtle rotation of TM5e. In identifying intrinsic divergence, we found more outward tilting of TM6e in the D2R compared to the D3R in both the experimental structures and simulations bound with ligands in different scaffolds. However, this difference was drastically reduced in the simulations bound with nonselective agonist quinpirole, suggesting a misleading effect of LCCs. Further, in the quinpirole-bound simulations, TM1 showed a greater disparity between these receptors, indicating that LCCs may also obscure intrinsic divergence. Importantly, our MD simulations revealed divergence in the dynamics of these receptors. Specifically, the D2R exhibited heightened flexibility compared to the D3R in the extracellular loops and TMs 5e, 6e, and 7e, associated with its greater ligand binding site plasticity. Our results lay the groundwork for crafting ligands specifically targeting the D2R and D3R with more precise pharmacological profiles.

Background and Purpose: Glial cell-derived neurotrophic factor (GDNF) maintains gut homeostasis. Dopamine promotes GDNF release in astrocytes. We investigated the regulation by dopamine of colonic GDNF secretion., Experimental Approach: D 1 receptor knockout (D 1 R -/- ) mice, adeno-associated viral 9-short hairpin RNA carrying D 2 receptor (AAV9-shD 2 R)-treated mice, 6-hydroxydopamine treated (6-OHDA) rats and primary enteric glial cells (EGCs) culture were used. Incubation fluid from colonic submucosal plexus and longitudinal muscle myenteric plexus were collected for GDNF and ACh measurements., Key Results: D 2 receptor-immunoreactivity (IR), but not D 1 receptor-IR, was observed on EGCs. Both D 1 receptor-IR and D 2 receptor-IR were co-localized on cholinergic neurons. Low concentrations of dopamine induced colonic GDNF secretion in a concentration-dependent manner, which was mimicked by the D 1 receptor agonist SKF38393, inhibited by TTX and atropine and eliminated in D 1 R -/- mice. SKF38393-induced colonic ACh release was absent in D 1 R -/- mice. High concentrations of dopamine suppressed colonic GDNF secretion, which was mimicked by the D 2 receptor agonist quinpirole, and absent in AAV-shD 2 R-treated mice. Quinpirole decreased GDNF secretion by reducing intracellular Ca 2+ levels in primary cultured EGCs. Carbachol ( ACh analogue) promoted the release of GDNF. Quinpirole inhibited colonic ACh release, which was eliminated in the AAV9-shD 2 R-treated mice. 6-OHDA treated rats with low ACh and high dopamine content showed decreased GDNF content and increased mucosal permeability in the colon., Conclusion and Implications: Low concentrations of dopamine promote colonic GDNF secretion via D 1 receptors on cholinergic neurons, whereas high concentrations of dopamine inhibit GDNF secretion via D 2 receptors on EGCs and/or cholinergic neurons., (© 2023 British Pharmacological Society.)

Rationale: Checking is a functional behaviour that provides information to guide behaviour. However, in obsessive-compulsive disorder (OCD), checking may escalate to dysfunctional levels. The processes underpinning the transition from functional to dysfunctional checking are unclear but may be associated with individual differences that support the development of maladaptive behaviour. We examined one such predisposition, sign-tracking to a pavlovian conditioned stimulus, which we previously found associated with dysfunctional checking. How sign-tracking interacts with another treatment with emerging translational validity for OCD-like checking, chronic administration of the dopamine D2 receptor agonist quinpirole, is unknown. Objectives: We tested how functional and dysfunctional checking in the rat observing response task (ORT) was affected by chronic quinpirole administration in non-autoshaped controls and autoshaped animals classified as sign-trackers or goal-trackers. Methods: Sign-trackers or goal-trackers were trained on the ORT before the effects of chronic quinpirole administration on checking were assessed. Subsequently, the effects on checking of different behavioural challenges, including reward omission and the use of unpredictable reinforcement schedules, were tested. Results: Prior autoshaping increased checking. Sign-trackers and goal-trackers responded differently to quinpirole sensitization, reward omission and reinforcement uncertainty. Sign-trackers showed greater elevations in dysfunctional checking, particularly during uncertainty. By contrast, goal-trackers predominantly increased functional checking responses, possibly in response to reduced discrimination accuracy in the absence of cues signalling which lever was currently active. Conclusions: The results are discussed in terms of how pavlovian associations influence behaviour that becomes compulsive in OCD and how this may be dependent on striatal dopamine D2 receptors. [ABSTRACT FROM AUTHOR]

Obsessive–compulsive disorder (OCD) is an important neuropsychiatric disorder worldwide. Common treatments of OCD include serotonergic antidepressants, which can cause potentially serious side effects. We assessed the effects of Lactobacillus casei (L. casei) Shirota consumption in an animal model of OCD. OCD-like symptoms were induced in rats by the chronic injection of the D2/D3 dopamine agonist quinpirole hydrochloride. Rats were classified into five groups of 6 rats. Four groups were injected chronically with quinpirole (0.5 mg/kg, twice weekly for 5 weeks). They were fed with L. casei Shirota (109 CF/g, daily for 4 weeks) (group 1), fluoxetine (10 mg/kg, daily for 4 weeks) (group 2), combination of L. casei Shirota and fluoxetine (group 3), and normal saline (positive control group). The last group did not receive dopamine agonist and was only injected with saline (negative control group). Expression levels of brain-derived neurotrophic factor (Bdnf), solute carrier family 6 member 4 (Slc6a4), and 5-hydroxytryptamine receptor type 2A (Htr2a) were assessed in orbitofrontal cortex tissues of all rats. Behavioral tests showed improvement of OCD signs in rats treated with L. casei Shirota, fluoxetine, and a combination of drugs. Quantitative PCR analysis showed a remarkable decrease in the expression of Bdnf and an increase in the expression of Htr2a in quinpirole-treated rats. After treatment with L. casei Shirota and fluoxetine, the expression level of Bdnf was increased remarkably, whereas Htr2a expression was decreased. The current study showed the effectiveness of L. casei Shirota in the treatment of OCD in a rat model. The beneficial effects of this probiotic are possibly exerted through the modulation of serotonin-related genes expression. [ABSTRACT FROM AUTHOR]

The ventral tegmental area (VTA) has a central role in the neural processes that underlie motivation and behavioral reinforcement. Although thought to contain only dopamine and GABA neurons, the VTA also includes a recently discovered population of glutamate neurons identified through the expression of the vesicular glutamate transporter VGLUT2. A subset of VGLUT2(+) VTA neurons corelease dopamine with glutamate at terminals in the NAc, but others do not express dopaminergic markers and remain poorly characterized. Using transgenic mice that express fluorescent proteins in distinct cell populations, we now find that both dopamine and glutamate neurons in the medial VTA exhibit a smaller hyperpolarization-activated current (I(h)) than more lateral dopamine neurons and less consistent inhibition by dopamine D(2) receptor agonists. In addition, VGLUT2(+) VTA neurons project to the nucleus accumbens (NAc), lateral habenula, ventral pallidum (VP), and amygdala. Optical stimulation of VGLUT2(+) projections expressing channelrhodopsin-2 further reveals functional excitatory synapses in the VP as well as the NAc. Thus, glutamate neurons form a physiologically and anatomically distinct subpopulation of VTA projection neurons.

The monogamous prairie vole displays developmental sensitivity to early pharmacological manipulation in a number of species-typical social behaviors. The long-term consequences of altering the neonatal dopamine system are not well characterized. This study examined whether early manipulation of the dopamine system, a known mediator of adult prairie vole social behavior, during neonatal development would affect adult aggressive and attachment behaviors. Eight-day-old pups were given a single treatment with either 1 mg/kg of SKF38393 (D1 agonist), quinpirole (D2 agonist), SCH23390 (D1 antagonist), eticlopride (D2 antagonist), or saline vehicle. As adults, animals received tests for intrasexual aggression and partner preference. Activation of D1-like receptors in pups impaired partner preference formation, but had no effect on aggression. Other neonatal treatments had no effect on their behavior as adults. To determine whether D1 activation in pups induced changes in dopamine receptor expression, we performed autoradiography on striatal tissue from a second cohort of saline-treated and SKF38393-treated animals. Although sex differences were observed, we found no treatment differences in D1 or D2 receptor binding in any striatal subregion. This study shows that exposure to a single early pharmacological alteration of dopamine receptor activity may have long-term effects on the social behavior of prairie voles.

The strength of goal-oriented behaviors is regulated by midbrain dopamine neurons. Dysfunctions of dopaminergic circuits are observed in drug addiction and obsessive-compulsive disorder. Compulsive behavior is a feature that both disorders share, which is associated to a heightened dopamine neurotransmission. The activity of midbrain dopamine neurons is principally regulated by the homeostatic action of dopamine through D2 receptors (D2R) that decrease the firing of neurons as well as dopamine synthesis and release. Dopamine transmission is also regulated by heterologous neurotransmitter systems such as the kappa opioid system, among others. Much of our current knowledge of the kappa opioid system and its influence on dopamine transmission comes from preclinical animal models of brain diseases. In 1988, using cerebral microdialysis, it was shown that the acute activation of the Kappa Opioid Receptors (KOR) decreases synaptic levels of dopamine in the striatum. This inhibitory effect of KOR opposes to the facilitating influence of drugs of abuse on dopamine release, leading to the proposition of the use of KOR agonists as pharmacological therapy for compulsive drug intake. Surprisingly, 30 years later, KOR antagonists are instead proposed to treat drug addiction. What may have happened during these years that generated this drastic change of paradigm? The collected evidence suggested that the effect of KOR on synaptic dopamine levels is complex, depending on the frequency of KOR activation and timing with other incoming stimuli to dopamine neurons, as well as sex and species differences. Conversely to its acute effect, chronic KOR activation seems to facilitate dopamine neurotransmission and dopamine-mediated behaviors. The opposing actions exerted by acute versus chronic KOR activation have been associated with an initial aversive and a delayed rewarding effect, during the exposure to drugs of abuse. Compulsive behaviors induced by repeated activation of D2R are also potentiated by the sustained co-activation of KOR, which correlates with decreased synaptic levels of dopamine and sensitized D2R. Thus, the time-dependent activation of KOR impacts directly on dopamine levels affecting the tuning of motivated behaviors. This review analyzes the contribution of the kappa opioid system to the dopaminergic correlates of compulsive behaviors.

On postnatal day 8, prairie vole pups were randomly assigned a treatment of 1mg/kg SKF38393 (D1 agonist), quinpirole (D2 agonist), SCH23390 (D1 antagonist), eticlopride (D2 antagonist), or saline vehicle. As adults, females treated with eticlopride exhibited reduced anxiety-like behavior in an elevated plus maze and a reduction in infanticidal behavior. These behavioral effects were not seen in males. These data demonstrate that a single exposure to a D2 antagonist during development can have persistent, sex-specific effects on behavior into adulthood.

The orexinergic system supposedly plays a role in stress circuits for arousing behaviors during anxiety, suggesting that it may play a role also in neural circuits mediating the compulsive behavior characteristic of obsessive-compulsive disorder (OCD). This study aims to investigate the roles of the orexinergic system in the development of OCD behaviors, using as preparation the induction of compulsive checking by chronic treatment with the D2/D3 agonist, quinpirole. Repeated injections of quinpirole (0.5 mg/kg, twice per week for a total of 10 injections) were used to induce compulsive checking. In separate groups of rats, OX1R (SB334867-A; 10 μg i.c.v) and OX2R (TCS-OX2-29; 10 μg i.c.v) receptor antagonists were co-administered together with quinpirole. Checking behavior in a large open field was measured after the first, fifth, and tenth injections of the drugs. SB334867-A attenuated checking behavior and the level of anxiety. TCS-OX2-29 administration ameliorated anxiety but did not block the development of compulsive checking. Orexin 1 receptors seem to play a more critical role than orexin 2 receptors in the induction of compulsive checking. Considering that the quinpirole sensitization model of OCD involves activation of dopamine systems and sensitization to quinpirole, it is suggested that neural interaction between orexigenic and dopamine systems may be important in the pathogenesis of OCD. [ABSTRACT FROM AUTHOR]

The strength of goal-oriented behaviors is regulated by midbrain dopamine neurons. Dysfunctions of dopaminergic circuits are observed in drug addiction and obsessive-compulsive disorder. Compulsive behavior is a feature that both disorders share, which is associated to a heightened dopamine neurotransmission. The activity of midbrain dopamine neurons is principally regulated by the homeostatic action of dopamine through D2 receptors (D2R) that decrease the firing of neurons as well as dopamine synthesis and release. Dopamine transmission is also regulated by heterologous neurotransmitter systems such as the kappa opioid system, among others. Much of our current knowledge of the kappa opioid system and its influence on dopamine transmission comes from preclinical animal models of brain diseases. In 1988, using cerebral microdialysis, it was shown that the acute activation of the Kappa Opioid Receptors (KOR) decreases synaptic levels of dopamine in the striatum. This inhibitory effect of KOR opposes to the facilitating influence of drugs of abuse on dopamine release, leading to the proposition of the use of KOR agonists as pharmacological therapy for compulsive drug intake. Surprisingly, 30 years later, KOR antagonists are instead proposed to treat drug addiction. What may have happened during these years that generated this drastic change of paradigm? The collected evidence suggested that the effect of KOR on synaptic dopamine levels is complex, depending on the frequency of KOR activation and timing with other incoming stimuli to dopamine neurons, as well as sex and species differences. Conversely to its acute effect, chronic KOR activation seems to facilitate dopamine neurotransmission and dopamine-mediated behaviors. The opposing actions exerted by acute versus chronic KOR activation have been associated with an initial aversive and a delayed rewarding effect, during the exposure to drugs of abuse. Compulsive behaviors induced by repeated activation of D2R are also potentiated by the sustained co-activation of KOR, which correlates with decreased synaptic levels of dopamine and sensitized D2R. Thus, the time-dependent activation of KOR impacts directly on dopamine levels affecting the tuning of motivated behaviors. This review analyzes the contribution of the kappa opioid system to the dopaminergic correlates of compulsive behaviors. [ABSTRACT FROM AUTHOR]

The endogenous cannabinoid system is a new signaling system composed by the central (CB1) and the peripheral (CB2) receptors, and several lipid transmitters including anandamide and 2-arachidonylglycerol. This system is the target of natural cannabinoids, the psychoactive constituents of Cannabis sativa preparations (marijuana, hashish). Acute and chronic cannabis exposure has been associated with subjective feelings of pleasure and relaxation, but also to the onset of psychiatric syndromes, a decrease of the efficacy of neuroleptics and alterations in the extrapyramidal system regulation of motor activity. These actions point to a tight association of the cannabinoid system with the brain dopaminergic circuits involved in addiction, the clinical manifestation of positive symptoms of schizophrenia and Parkinson's disease. The present work discusses anatomical, biochemical and pharmacological evidences supporting a role for the endogenous cannabinoid system in the modulation of dopaminergic transmission. Cannabinoid CB1 receptors are present in dopamine projecting brain areas. In primates and certain rat strains it is also located in dopamine cells of the A8, A9 and A10 mesencephalic cell groups, as well as in hypothalamic dopaminergic neurons controlling prolactin secretion. CB1 receptors co-localize with dopamine D1/D2 receptors in dopamine projecting fields. Manipulation of dopaminergic transmission is able to alter the synthesis and release of anandamide as well as the expression of CB1 receptors. Additionally, CB1 receptors can switch its transduction mechanism to oppose to the ongoing dopamine signaling. Acute blockade of CB1 receptor potentiates the facilitatory role of dopamine D2 receptor agonists on movement. CB1 stimulation results in sensitization to the motor effects of indirect dopaminergic agonists. The dynamics of these changes indicate that the cannabinoid system is an activity-dependent modulator of dopaminergic transmission, an hypothesis relevant for the design of new therapeutic strategies for dopamine-related diseases such as the psychosis and Parkinson's disease.

Sleep loss is commonplace nowadays and profoundly impacts cognition. Dopamine receptor D2 (DRD2) makes a specific contribution to cognition, although the precise mechanism underlying how DRD2 affects the cognitive process after sleep deprivation remains unclear. Herein, we observed cognitive impairment and impaired synaptic plasticity, including downregulation of synaptophysin and PSD95, decreased postsynaptic density thickness, neuron complexity, and spine density in chronic sleep restriction (CSR) mice. We also observed downregulated hippocampal DRD2 and Cryab expression in the CSR mice. Meanwhile, NF-κB translocation from the cytoplasm to the nucleus occurred, indicating that neuroinflammation ensued. However, hippocampal delivery of the DRD2 agonist quinpirole effectively rescued these changes. In vitro, quinpirole treatment significantly decreased the release of proinflammatory cytokines in microglial supernatant, indicating a potential anti-neuroinflammatory effect of Drd2/Cryab/NF-κB in CSR mice. Our study provided the evidence that activation of the Drd2 may relieve neuroinflammation and improve sleep deprivation-induced cognitive deficits., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: : As dopamine is closely linked to locomotor activities, animal studies on locomotor activities using dopaminergic agents were widely done. However, most of animal studies were performed for a short period that there is a lack of longitudinal study on the effects of dopaminergic agents on locomotor activities. This study aimed to examine the longterm effect of a dopamine D2, D3 agonist quinpirole on locomotor activities in mice using a home-cage monitoring system., Methods: : The locomotor activities of Institute Cancer Research mice were measured by infrared motion detectors in home-cages under the 12-hour dark and 12-hour light condition for three days after the quinpirole injection. Quinpirole was injected at a concentration of 0.5 mg/kg intraperitoneally in the beginning of the dark phase. The locomotor activities before and after the quinpirole administration were compared by the Wilcoxon signed-rank test and one-way repeated measures ANOVA., Results: : After the quinpirole administration, the 24-hour total locomotor activity did not change ( p = 0.169), but activities were significantly increased in the 12-hour dark phase sum ( p = 0.013) and decreased in the 12-hour light phase sum ( p = 0.009). Significant increases in the activities were observed in the dark-light difference ( p = 0.005) and dark-light ratio ( p = 0.005) as well., Conclusion: : This study suggests that quinpirole injection entrains the circadian rest-activity rhythm of locomotor activities. Therefore, quinpirole can be a drug that mediates locomotor activity as a dopamine agonist as well as a modulator of the circadian rhythms.

L-DOPA-induced dyskinesia (LID) remains a major complication of Parkinson's disease management for which better therapies are necessary. The contribution of the striatonigral direct pathway to LID is widely acknowledged but whether the striatopallidal pathway is involved remains debated. Selective optogenetic stimulation of striatonigral axon terminals induces dyskinesia in mice rendered hemiparkinsonian with the toxin 6-hydroxydopamine (6-OHDA). Here we show that optogenetically-induced dyskinesia is increased by the D2-type dopamine receptor agonist quinpirole. Although the quinpirole effect may be mediated by D2 receptor stimulation in striatopallidal neurons, alternative mechanisms may be responsible as well. To selectively modulate the striatopallidal pathway, we selectively expressed channelrhodopsin-2 (ChR2) in D2 receptor expressing neurons by crossing D2-Cre and ChR2-flox mice. The animals were rendered hemiparkinsonian and implanted with an optic fiber at the ipsilateral external globus pallidus (GPe). Stimulation of ChR2 at striatopallidal axon terminals reduced LID and also general motility during the off L-DOPA state, without modifying the pro-motor effect of low doses of L-DOPA producing mild or no dyskinesia. Overall, the present study shows that D2-type dopamine receptors and the striatopallidal pathway modulate dyskinesia and suggest that targeting striatopallidal axon terminals at the GPe may have therapeutic potential in the management of LID., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Brain injury is a significant risk factor for chronic gliosis and neurodegenerative diseases. Currently, no treatment is available for neuroinflammation caused by the action of glial cells following brain injury. In this study, we investigated the quinpirole-mediated activation of dopamine D2 receptors (D2R) in a mouse model of traumatic brain injury (TBI). We also investigated the neuroprotective effects of quinpirole (a D2R agonist) against glial cell-induced neuroinflammation secondary to TBI in adult mice. After the brain injury, we injected quinpirole into the TBI mice at a dose of 1 mg/kg daily intraperitoneally for 7 days. Our results showed suppression of D2R expression and deregulation of downstream signaling molecules in ipsilateral cortex and striatum after TBI on day 7. Quinpirole administration regulated D2R expression and significantly reduced glial cell-induced neuroinflammation via the D2R/Akt/glycogen synthase kinase 3 beta (GSK3-β) signaling pathway after TBI. Quinpirole treatment concomitantly attenuated increase in glial cells, neuronal apoptosis, synaptic dysfunction, and regulated proteins associated with the blood–brain barrier, together with the recovery of lesion volume in the TBI mouse model. Additionally, our in vitro results confirmed that quinpirole reversed the microglial condition media complex-mediated deleterious effects and regulated D2R levels in HT22 cells. This study showed that quinpirole administration after TBI reduced secondary brain injury-induced glial cell activation and neuroinflammation via regulation of the D2R/Akt/GSK3-β signaling pathways. Our study suggests that quinpirole may be a safe therapeutic agent against TBI-induced neurodegeneration.

Quinpirole (QNP) sensitization is a well-established model of stereotypical checking relevant to obsessive-compulsive disorder. Previously, we found that QNP-treated rats display deficits in hippocampus-dependent tasks. The present study explores the expression of immediate early genes (IEG) during QNP-induced stereotypical checking in the hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and medial prefrontal cortex (mPFC). Adult male rats were injected with QNP (0.5 mg/mL/kg; n = 15) or saline (n = 14) daily for 10 days and exposed to an arena enriched with two objects. Visits to the objects and the corners of the arena were recorded. QNP-treated rats developed an idiosyncratic pattern of visits that persisted across experimental days. On day 11, rats were exposed to the arena twice for 5 min and sacrificed. The expression of IEGs Arc and Homer1a was determined using cellular compartment analysis of temporal activity by fluorescence in situ hybridization. IEG-positive nuclei were counted in the CA1 area of the hippocampus, ACC, OFC, and mPFC. We found significantly fewer IEG-positive nuclei in the CA1 in QNP-treated rats compared to controls. The overlap between IEG expressing neurons was comparable between the groups. We did not observe significant differences in IEG expression between QNP treated and control rats in ACC, OFC, and mPFC. In conclusion, treatment of rats with quinpirole decreases plasticity-related activity in the hippocampus during stereotypical checking.

We measured endogenous cannabinoid release in dorsal striatum of freely moving rats by microdialysis and gas chromatography/mass spectrometry. Neural activity stimulated the release of anandamide, but not of other endogenous cannabinoids such as 2-arachidonylglycerol. Moreover, anandamide release was increased eightfold over baseline after local administration of the D2-like (D2, D3, D4) dopamine receptor agonist quinpirole, a response that was prevented by the D2-like receptor antagonist raclopride. Administration of the D1-like (D1, D5) receptor agonist SKF38393 had no such effect. These results suggest that functional interactions between endocannabinoid and dopaminergic systems may contribute to striatal signaling. In agreement with this hypothesis, pretreatment with the cannabinoid antagonist SR141716A enhanced the stimulation of motor behavior elicited by systemic administration of quinpirole. The endocannabinoid system therefore may act as an inhibitory feedback mechanism countering dopamine-induced facilitation of motor activity.

Abstract Rationale Chronic quinpirole (QNP) sensitization is an established animal model relevant to obsessive-compulsive disorder (OCD) that has been previously shown to induce several OCD-like behavioral patterns, such as compulsive-like checking and increased locomotion. Objectives In current study we explored the effect of antiglutamatergic drugs, memantine and riluzole, on cognitive and behavioral performance of QNP sensitized rats. Methods During habituation phase, the rats (N = 56) were injected with QNP (0.25 mg/kg) or saline solution (every other day up to 10 injections) and placed into rotating arena without foot shocks for 50-min exploration. Active place avoidance task in rotating arena with unmarked to-be-avoided shock sector was used during acquisition phase. Rats were injected with memantine (1 mg/kg or 5 mg/kg), riluzole (1 mg/kg or 5 mg/kg) or saline solution 30 min before the trial and with QNP (0.25 mg/kg) or saline right before they were placed inside the rotating arena with 60° unmarked shock sector. Locomotion and number of entrances into the shock sector were recorded. Results QNP sensitization led to a robust deficit in place learning. However, neither memantine nor riluzole did reverse or alleviate the deficit induced by QNP. Contrarily, memantine significantly aggravated QNP induced deficit. Conclusions The exacerbation of cognitive deficit following antiglutamatergic agents could be mediated by decreased glutamate concentration in nucleus accumbens and decreased hippocampal activation in the QNP sensitization model. Highlights • Quinpirole sensitization produces hyperlocomotion and deficits in place learning. • Cognitive effects of quinpirole are independent of the hyperactivity. • Neither memantine nor riluzole alleviated the cognitive deficit induced by quinpirole. [ABSTRACT FROM AUTHOR]