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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.

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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.

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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 (D2R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D2R 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 D2Rs in the regulation of limbic information flow.

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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 GABAA 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.

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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.

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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.

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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.

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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.

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Growth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D2R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D2R heterodimers in nigral dopaminergic neurons in Parkinson's disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D2R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP+ or MPTP treatment. Application of QNP (10 µM) alone significantly increased the viability of MPP+-treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D2R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D2R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin.

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The dopaminergic neurotransmitter system is implicated in several brain functions and behavioral processes. Alterations in it are associated with the pathogenesis of several human neurological disorders. Pharmacological agents that interact with the dopaminergic system allow the investigation of dopamine-mediated cellular and molecular responses and may elucidate the biological bases of such disorders. Zebrafish, a translationally relevant biomedical research organism, has been successfully employed in prior psychopharmacology studies. Here, we evaluated the effects of quinpirole (dopamine D2/D3 receptor agonist) in adult zebrafish on behavioral parameters, brain-derived neurotrophic factor (BDNF) and neurotransmitter levels. Zebrafish received intraperitoneal injections of 0.5, 1.0, or 2.0 mg/kg quinpirole or saline (control group) twice with an inter-injection interval of 48 h. All tests were performed 24 h after the second injection. After this acute quinpirole administration, zebrafish exhibited decreased locomotor activity, increased anxiety-like behaviors and memory impairment. However, quinpirole did not affect social and aggressive behavior. Quinpirole-treated fish exhibited stereotypic swimming, characterized by repetitive behavior followed by immobile episodes. Moreover, quinpirole treatment also decreased the number of BDNF-immunoreactive cells in the zebrafish brain. Analysis of neurotransmitter levels demonstrated a significant increase in glutamate and a decrease in serotonin, while no alterations were observed in dopamine. These findings demonstrate that dopaminergic signaling altered by quinpirole administration results in significant behavioral and neuroplastic changes in the central nervous system of zebrafish. Thus, we conclude that the use of quinpirole administration in adult zebrafish may be an appropriate tool for the analysis of mechanisms underlying neurological disorders related to the dopaminergic system.

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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.

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Leveraging biased signaling of G protein-coupled receptors has been proposed as a promising strategy for the development of drugs with higher specificity. However, the consequences of selectively targeting G protein- or ß-arrestin-mediated signaling on cellular functions are not comprehensively understood. In this study, we utilized phosphoproteomics to gain a systematic overview of signaling induced by the four biased and balanced dopamine D2 receptor (D2R) ligands MS308, BM138, quinpirole, and sulpiride in an in vitro D2R transfection model. Quantification of 14,160 phosphosites revealed a low impact of the partial G protein agonist MS308 on cellular protein phosphorylation, as well as surprising similarities between the balanced agonist quinpirole and the inverse agonist sulpiride. Analysis of the temporal profiles of ligand-induced phosphorylation events showed a transient impact of the G protein-selective agonist MS308, whereas the ß-arrestin-preferring agonist BM138 elicited a delayed, but more pronounced response. Functional enrichment analysis of ligand-impacted phosphoproteins and treatment-linked kinases confirmed multiple known functions of D2R signaling while also revealing novel effects, for example of MS308 on sterol regulatory element-binding protein-related gene expression. All raw data were deposited in MassIVE (MSV000089457).

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DYT1 dystonia is an inherited early-onset movement disorder characterized by sustained muscle contractions causing twisting, repetitive movements, and abnormal postures. Most DYT1 patients have a heterozygous trinucleotide GAG deletion mutation (ΔGAG) in DYT1/TOR1A, coding for torsinA. Dyt1 heterozygous ΔGAG knock-in (KI) mice show motor deficits and reduced striatal dopamine receptor 2 (D2R). Striatal cholinergic interneurons (ChIs) are essential in regulating striatal motor circuits. Multiple dystonia rodent models, including KI mice, show altered ChI firing and modulation. However, due to the errors in assigning KI mice, it is essential to replicate these findings in genetically confirmed KI mice. Here, we found irregular and decreased spontaneous firing frequency in the acute brain slices from Dyt1 KI mice. Quinpirole, a D2R agonist, showed less inhibitory effect on the spontaneous ChI firing in Dyt1 KI mice, suggesting decreased D2R function on the striatal ChIs. On the other hand, a muscarinic receptor agonist, muscarine, inhibited the ChI firing in both wild-type (WT) and Dyt1 KI mice. Trihexyphenidyl, a muscarinic acetylcholine receptor M1 antagonist, had no significant effect on the firing. Moreover, the resting membrane property and functions of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, µ-opioid receptors, and large-conductance calcium-activated potassium (BK) channels were unaffected in Dyt1 KI mice. The results suggest that the irregular and low-frequency firing and decreased D2R function are the main alterations of striatal ChIs in Dyt1 KI mice. These results appear consistent with the reduced dopamine release and high striatal acetylcholine tone in the previous reports.

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Nucleus incertus (NI) is a brainstem structure involved in the control of arousal, stress responses and locomotor activity. It was reported recently that NI neurons express the dopamine type 2 (D2) receptor that belongs to the D2-like receptor (D2R) family, and that D2R activation in the NI decreased locomotor activity. In this study, using multiplex in situ hybridization, we observed that GABAergic and glutamatergic NI neurons express D2 receptor mRNA, and that D2 receptor mRNA-positive neurons belong to partially overlapping relaxin-3- and cholecystokinin-positive NI neuronal populations. Our immunohistochemical and viral-based retrograde tract-tracing studies revealed a dense innervation of the NI area by fibers containing the catecholaminergic biosynthesis enzymes, tyrosine hydroxylase (TH) and dopamine ß-hydroxylase (DBH), and indicated the major sources of the catecholaminergic innervation of the NI as the Darkschewitsch, raphe and hypothalamic A13 nuclei. Furthermore, using whole-cell patch clamp recordings, we demonstrated that D2R activation by quinpirole produced excitatory and inhibitory influences on neuronal activity in the NI, and that both effects were postsynaptic in nature. Moreover, the observed effects were cell-type specific, as type I NI neurons were either excited or inhibited, whereas type II NI neurons were mainly excited by D2R activation. Our results reveal that rat NI receives a strong catecholaminergic innervation and suggest that catecholamines acting within the NI are involved in the control of diverse processes, including locomotor activity, social interaction and nociceptive signaling. Our data also strengthen the hypothesis that the NI acts as a hub integrating arousal-related neuronal information.

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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.

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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.

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Synaptic events are important to define treatment strategies for brain disorders. In the present paper, freshly obtained rat brain striatal minces were incubated under different times and conditions to determine dopamine biosynthesis, storage, and tyrosine hydroxylase phosphorylation. Remarkably, we found that endogenous dopamine spontaneously accumulated during tissue incubation at 37 °C ex vivo while dopamine synthesis simultaneously decreased. We analyzed whether these changes in brain dopamine biosynthesis and storage were linked to dopamine feedback inhibition of its synthesis-limiting enzyme tyrosine hydroxylase. The aromatic-l-amino-acid decarboxylase inhibitor NSD-1015 prevented both effects. As expected, dopamine accumulation was increased with l-DOPA addition or VMAT2-overexpression, and dopamine synthesis decreased further with added dopamine, the VMAT2 inhibitor tetrabenazine or D2 auto-receptor activation with quinpirole, accordingly to the known synaptic effects of these treatments. Phosphorylation activation and inhibition of tyrosine hydroxylase on Ser31 and Ser40 with okadaic acid, Sp-cAMP and PD98059 also exerted the expected effects. However, no clear-cut association was found between dopamine feedback inhibition of its own biosynthesis and changes of tyrosine hydroxylase phosphorylation, assessed by Western blot and mass spectrometry. The later technique also revealed a new Thr30 phosphorylation in rat tyrosine hydroxylase. Our methodological assessment of brain dopamine synthesis and storage dynamics ex vivo could be applied to predict the in vivo effects of pharmacological interventions in animal models of dopamine-related disorders.

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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.

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Dysfunction of the central dopamine D2-receptor-related network has been proposed to play a critical role in dopamine-related diseases, such as schizophrenia and drug dependence. Generally, the stimulation of dopamine D2-receptors on medium spiny neurons (MSN) induces several behavioral effects, such as sedation, hallucination, aversion and motivation. Furthermore, such physiological responses through dopamine D2-receptor-containing MSN (D2-MSN) may be synchronized with the activity of dopamine D1-receptor-containing MSN (D1-MSN), or both may exhibit dual agonistic/antagonistic innervation. In the present study, we characterized the discriminative stimulus effect of the selective dopamine D2-receptor agonist quinpirole to further investigate the "D1/D2-MSN" interaction using dopamine-related agents, hallucinogens and sedatives in rats. Among dopamine receptor agonists, only selective dopamine D2-receptor agonists substituted for the discriminative stimulus effects of quinpirole. Neither the δ-opioid receptor agonist SNC80 nor the adenosine A2A-receptor antagonist istradefylline, both of which may act on D2-MSNs, substituted for the discriminative stimulus effects of quinpirole. Interestingly, the dopamine D1-receptor antagonist SCH23390 and the GABAB-receptor agonist baclofen, but not hallucinogens or sedatives, substituted for the discriminative stimulus effects of quinpirole. These results suggest that stimulation of central dopamine D2-receptors exerts a distinct discriminative stimulus effect, and blockade of dopamine D1-receptors and agonistic modulation of GABAB-receptors may share the discriminative stimulus effect via the activation of central dopamine D2-receptors.

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The human brain matures into a complex structure, and to reach its complete development, connections must occur along exact paths. If at any stage, the processes are altered, interrupted, or inhibited, the consequences can be permanent. Dopaminergic signaling participates in the control of physiological functions and behavioral processes, and alterations in this signaling pathway are related to the pathogenesis of several neurological disorders. For this reason, the use of pharmacological agents able to interact with the dopaminergic signaling may elucidate the biological bases of such disorders. We investigated the long-lasting behavioral effects on adult zebrafish after quinpirole (a dopamine D2/D3 receptor agonist) exposure during early life stages of development (24 h exposure at 5 days post-fertilization, dpf) to better understand the mechanisms underlying neurological disorders related to the dopaminergic system. Quinpirole exposure at the early life stages of zebrafish led to late behavioral alterations. When evaluated at 120 dpf, zebrafish presented increased anxiety-like behaviors. At the open tank test, fish remained longer at the bottom of the tank, indicating anxiety-like behavior. Furthermore, quinpirole-treated fish exhibited increased absolute turn angle, likely an indication of elevated erratic movements and a sign of increased fear or anxiety. Quinpirole-treated fish also showed altered swimming patterns, characterized by stereotypic swimming. During the open tank test, exposed zebrafish swims from corner to corner in a repetitive manner at the bottom of the tank. Moreover, quinpirole exposure led to memory impairment compared to control fish. However, quinpirole administration had no effects on social and aggressive behavior. These findings demonstrate that dopaminergic signaling altered by quinpirole administration in the early life stages of development led to late alterations in behavioral parameters of adult zebrafish.

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