Receptor Agonist Quinpirole Research Articles

Enhanced dopamine D2 autoreceptor function in the adult prefrontal cortex contributes to dopamine hypoactivity following adolescent social stress.

Adult psychiatric disorders characterized by cognitive deficits reliant on prefrontal cortex (PFC) dopamine are promoted by teenage bullying. Similarly, male Sprague-Dawley rats exposed to social defeat in mid-adolescence (P35-39) show impaired working memory in adulthood (P56-70), along with decreased medial PFC (mPFC) dopamine activity that results in part from increased dopamine transporter-mediated clearance. Here, we determined if dopamine synthesis and D2 autoreceptor-mediated inhibition of dopamine release in the adult mPFC are also enhanced by adolescent defeat to contribute to later dopamine hypofunction. Control and previously defeated rats did not differ in either DOPA accumulation following amino acid decarboxylase inhibition (NSD-1015 100mg/kg ip.) or total/phosphorylated tyrosine hydroxylase protein expression, suggesting dopamine synthesis in the adult mPFC is not altered by adolescent defeat. However, exposure to adolescent defeat caused greater decreases in extracellular dopamine release (measured using in vivo chronoamperometry) in the adult mPFC upon local infusion of the D2 receptor agonist quinpirole (3 nM), implying greater D2 autoreceptor function. Equally enhanced D2 autoreceptor-mediated inhibition of dopamine release is seen in the adolescent (P40 or P49) mPFC, which declines in control rats by adulthood. However, this developmental decrease in autoreceptor function is absent following adolescent defeat, suggesting retention of an adolescent-like phenotype into adulthood. Current and previous findings indicate adolescent defeat decreases extracellular dopamine availability in the adult mPFC via both enhanced inhibition of dopamine release and increased dopamine clearance, which may be viable targets for improving treatment of cognitive deficits seen in neuropsychiatric disorders promoted by adolescent stress.

The effects of intermittent dietary supplementation with fish oil on high fat diet‐induced enhanced sensitivity to the behavioral effects of dopaminergic drugs

Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat laboratory chow are more sensitive than rats eating standard chow to the behavioral effects of the dopamine receptor D2/D3 receptor agonist quinpirole. Specifically, quinpirole induces yawning in rats, and quinpirole‐induced yawning is enhanced in rats eating high fat chow as compared to rats eating standard chow. Daily dietary supplementation with 20% (w/w) fish oil prevents this high fat diet‐induced effect; however, for beneficial effects of fish oil in humans, doctors recommend that patients take fish oil only 2–3 times a week. To test the hypothesis that intermittent (e.g., 2/7 days per week) dietary supplementation with fish oil prevents high fat diet‐induced effects (e.g., weight gain and enhanced sensitivity to the behavioral effects of dopaminergic drugs) rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), and rats eating standard or high fat chow with 20% (w/w) intermittent (e.g., 2/7 days per week) dietary fish oil supplementation were tested once weekly with quinpirole (0.0032–0.32 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole. That is, the quinpirole‐induced yawning dose‐response curve was shifted significantly to the left for rats eating high fat chow as compared to rats eating standard chow. Intermittent access to fish oil prevented this effect, since quinpirole‐induced yawning was not different among rats eating standard chow and rats eating high fat chow supplemented with fish oil. Future experiments will examine other dopaminergic drugs (e.g., cocaine) and will focus on understanding the mechanism by which fish oil produces these beneficial effects, by examining the specific omega‐3 polyunsaturated fatty acids found in fish oil.Support or Funding InformationA portion of this project was supported by R25 GM069621.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dopamine D2 receptor upregulates leptin and IL-6 in adipocytes

Leptin is a pro-inflammatory cytokine secreted by the adipose tissue. Dopamine D2 receptors (D2Rs) have anti-inflammatory effects in the brain and kidney tissues. Mouse and human adipocytes express D2R; D2R protein was 10-fold greater in adipocytes from human visceral tissue than subcutaneous tissue. However, the function of D2R in adipocytes is not well understood. 3T3-L1 cells were treated with D2-like receptor agonist quinpirole, and immunoblot and quantitative PCR were performed. Quinpirole increased the protein and mRNA expression of leptin and IL-6, but not adiponectin and visfatin (24 h). It also increased the mRNA expression of TNF-α , MCP1, and NFkB-p50. An acute increase in the protein expression of leptin and TNF-α was also found in the cells treated with quinpirole. The leptin concentration in the culture media was increased by quinpirole-bathing the 3T3-L1 adipocytes. These quinpirole effects on leptin and IL-6 expression were prevented by the D2R antagonist L741,626. Similarly, siRNA-mediated silencing of Drd2 decreased the leptin, IL-6, mRNA, and protein expressions. The D2R-mediated increase in leptin expression was prevented by the phosphoinositide 3-kinase inhibitor LY294002. Acute quinpirole treatment in C57Bl/6J mice increased serum leptin concentration and leptin mRNA in visceral adipocyte tissue but not in subcutaneous adipocytes, confirming the stimulatory effect of D2R on leptin in vivo. Our results suggest that the stimulation of D2R increases leptin production and may have a tissue-specific pro-inflammatory effect in adipocytes.

Brain activation associated to olfactory conditioned same-sex partner preference in male rats

Sexual preferences can be strongly modified by Pavlovian learning. For instance, olfactory conditioned same-sex partner preference can occur when a sexually naïve male cohabits with an scented male during repeated periods under the effects of enhanced D2-type activity. Preference is observed days later via social and sexual behaviors. Herein we explored brain activity related to learned same-sex preference (Fos-Immunoreactivity, IR) following exposure to a conditioned odor paired with same-sex preference. During conditioning trials males received either saline or the D2-type receptor agonist quinpirole (QNP) and cohabitated during 24 h with a stimulus male that bore almond scent on the back as conditioned stimulus. This was repeated every 4 days, for a total of three trials. In a drug-free final test we assessed socio/sexual partner preference between the scented male and a receptive female. The results indicated that QNP-conditioned males developed a same-sex preference observed via contact, time spent, olfactory investigations, and non-contact erections. By contrast, saline-conditioned and intact (non-exposed to conditioning) males expressed an unconditioned preference for the female. Four days later the males were exposed to almond scent and their brains were processed for Fos-IR. Results indicated that the QNP-conditioned group expressed more Fos-IR in the nucleus accumbens (AcbSh), medial preoptic area (MPA), piriform cortex (Pir) and ventromedial nucleus of the hypothalamus (VMH) as compared to saline-conditioned. Intact males expressed the lowest Fos-IR in AcbSh and VMH, but the highest in MPA and Pir. We discuss the role of these areas in the learning process of same-sex partner preferences and olfactory discrimination.

Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson\u2019s disease

Parkinson’s disease (PD) is a neurodegenerative disorder in which genetic and environmental factors synergistically lead to loss of midbrain dopamine (DA) neurons. Mutation of leucine-rich repeated kinase2 (Lrrk2) genes is responsible for the majority of inherited familial cases of PD and can also be found in sporadic cases. The pathophysiological role of this kinase has to be fully understood yet. Hyperactivation of Lrrk2 kinase domain might represent a predisposing factor for both enhanced striatal glutamatergic release and mitochondrial vulnerability to environmental factors that are observed in PD. To investigate possible alterations of striatal susceptibility to mitochondrial dysfunction, we performed electrophysiological recordings from the nucleus striatum of a G2019S Lrrk2 mouse model of PD, as well as molecular and morphological analyses of G2019S Lrrk2-expressing SH-SY5Y neuroblastoma cells. In G2019S mice, we found reduced striatal DA levels, according to the hypothesis of alteration of dopaminergic transmission, and increased loss of field potential induced by the mitochondrial complex I inhibitor rotenone. This detrimental effect is reversed by the D2 DA receptor agonist quinpirole via the inhibition of the cAMP/PKA intracellular pathway. Analysis of mitochondrial functions in G2019S Lrrk2-expressing SH-SY5Y cells revealed strong rotenone-induced oxidative stress characterized by reduced Ca2+ buffering capability and ATP synthesis, production of reactive oxygen species, and increased mitochondrial fragmentation. Importantly, quinpirole was able to prevent all these changes. We suggest that the G2019S-Lrrk2 mutation is a predisposing factor for enhanced striatal susceptibility to mitochondrial dysfunction induced by exposure to mitochondrial environmental toxins and that the D2 receptor stimulation is neuroprotective on mitochondrial function, via the inhibition of cAMP/PKA intracellular pathway. We suggest new possible neuroprotective strategies for patients carrying this genetic alteration based on drugs specifically targeting Lrrk2 kinase domain and mitochondrial functionality.

Oleoylethanolamide-induced anorexia in rats is associated with locomotor impairment.

The endogenous peroxisome proliferator‐activated receptor alpha (PPAR‐α) agonist Oleoylethanolamide (OEA) inhibits eating in rodents, mainly by delaying the onset of meals. The underlying mechanisms of OEA‐induced anorexia, however, remain unclear. Animals treated with high OEA doses were shown to display signs of discomfort and impaired locomotion. Therefore, we first examined whether the impaired locomotion may contribute to OEA's anorectic effect. Second, it is controversial whether abdominal vagal afferents are necessary for OEA's anorectic effect. Thus, we explored alternative peripheral neural pathways mediating IP OEA's anorectic effect by performing a celiac‐superior mesenteric ganglionectomy (CGX) or a subdiaphragmatic vagal deafferentation (SDA) alone or in combination. Exogenously administered OEA at a commonly used dose (10 mg/kg BW, IP) concurrently reduced food intake and compromised locomotor activity. Attempts to dissociate both phenomena using the dopamine D2/D3 receptor agonist Quinpirole (1 mg/kg BW, SC) failed because Quinpirole antagonized both, OEA‐induced locomotor impairment and delay in eating onset. CGX attenuated the prolongation of the latency to eat by IP OEA, but neither SDA nor CGX prevented IP OEA‐induced locomotor impairment. Our results indicate that IP OEA's anorectic effect may be secondary to impaired locomotion rather than due to physiological satiety. They further confirm that vagal afferents do not mediate exogenous OEA's anorectic effects, but suggest a role for spinal afferents in addition to an alternative, nonneuronal signaling route.

Acute and chronic modulation of striatal endocannabinoid-mediated plasticity by nicotine.

The endocannabinoid (eCB) system modulates several phenomena related to addictive behaviors, and drug‐induced changes in eCB signaling have been postulated to be important mediators of physiological and pathological reward‐related synaptic plasticity. Here, we studied eCB‐mediated long‐term depression (eCB‐LTD) in the dorsolateral striatum, a brain region critical for acquisition of habitual and automatic behavior. We report that nicotine differentially affects ex vivo eCB signaling depending on previous exposure in vivo. In the nicotine‐naïve brain, nicotine facilitates eCB‐signaling and LTD, whereas tolerance develops to this facilitating effect after subchronic exposure in vivo. In the end, a progressive impairment of eCB‐induced LTD is established after protracted withdrawal from nicotine. Endocannabinoid‐LTD is reinstated 6 months after the last drug injection, but a brief period of nicotine re‐exposure is sufficient to yet again impair eCB‐signaling. LTD induced by the cannabinoid 1 receptor agonist WIN55,212‐2 is not affected, suggesting that nicotine modulates eCB production or release. Nicotine‐induced facilitation of eCB‐LTD is occluded by the dopamine D2 receptor agonist quinpirole, and by the muscarinic acetylcholine receptor antagonist scopolamine. In addition, the same compounds restore eCB‐LTD during protracted withdrawal. Nicotine may thus modulate eCB‐signaling by affecting dopaminergic and cholinergic neurotransmission in a long‐lasting manner. Overall, the data presented here suggest that nicotine facilitates eCB‐LTD in the initial phase, which putatively could promote neurophysiological and behavioral adaptations to the drug. Protracted withdrawal, however, impairs eCB‐LTD, which may influence or affect the ability to maintain cessation.

Anabolic-androgenic steroids (AAS) increase sensitivity to uncertainty by inhibition of dopamine D1 and D2 receptors.

Anabolic-androgenic steroid abuse is implicated in maladaptive behaviors such as impaired cognition in humans. In a rat model, our lab has shown that testosterone decreases preference for a large/uncertain reward in probability discounting. Other studies have shown that androgens decrease dopamine D1 and D2 receptors in the nucleus accumbens shell, a region important for decision-making behavior in probability discounting. Thus, we attempted to restore selection of the large/uncertain reward in testosterone-treated rats by administering the D2 receptor agonist quinpirole or the D1 receptor agonist SKF81297 and testing probability discounting. Adolescent male Long-Evans rats were treated chronically with high-dose testosterone (7.5mg/kg) or vehicle (13% cyclodextrin in water), and tested for probability discounting after injections of saline, 0.1 and 0.5mg/kg of quinpirole or SKF81297. Rats chose between a small/certain reward (1 sugar pellet, 100% probability) and a large/uncertain reward (4 pellets, decreasing probability: 100, 75, 50, 25, 0%). Testosterone-treated rats selected the large/uncertain reward significantly less than vehicle-treated controls after saline injection. However, acute injection with 0.1mg/kg quinpirole increased large/uncertain reward preference in testosterone-treated rats only, indicated by a testosterone × quinpirole interaction. At 0.5mg/kg, quinpirole increased large/uncertain reward preference in all rats. Acute injection with SKF81297 at 0.1 or 0.5mg/kg rescued large/uncertain reward preference in testosterone-treated rats by eliminating the difference between groups. It appears that altered probability discounting behavior in testosterone-treated rats is due to both decreased D1 and D2 receptor function.

Sex differences in high fat diet-induced impairments to striatal Akt signaling and enhanced sensitivity to the behavioral effects of dopamine D2/D3 receptor agonist quinpirole

Eating a high fat laboratory chow enhances sensitivity of rats to the behavioral effects of drugs that act on dopamine systems (e.g., cocaine). Further, in male rats, eating high fat chow impairs expression of insulin signaling phosphorylated protein kinase B (pAkt), which is vital for maintaining dopamine homeostasis. Eating high fat chow enhances sensitivity of female rats to drugs that act indirectly on dopamine receptors (e.g., cocaine); however, less is known about sensitivity of females to drugs that act directly on dopamine receptors (e.g., quinpirole). Further, it is not known if pAkt expression is impaired in female rats eating high fat chow. Some quinpirole-induced behaviors (e.g., penile erections and yawning) are either absent or occur at very low frequency in adult female rats. It is not known if quinpirole sensitivity in adolescent rats is more comparable between sexes. The present report examined another unconditioned behavioral effect (i.e., rearing) induced by once-weekly cumulative doses of quinpirole (0.0032–0.32mg/kg) in male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat), for several weeks throughout development, (spanning adolescence and early adulthood). Following behavioral assessments, pAkt expression was examined using western blot protein analysis. Eating high fat chow increased sensitivity of male rats to the quinpirole-induced yawning, as compared to male rats eating standard chow. However, other unconditioned behavioral effects of quinpirole (yawning and hypothermia) remained unchanged. Female rats yawned significantly less than male rats, and eating a high fat chow had no effect on any quinpirole-induced unconditioned behavioral effect in female rats. Eating high fat chow also reduced pAkt levels in male, but not female rats. Taken together, these data suggest that alternative behavioral and biochemical assays should be considered to measure sensitivity of female rats to the behavioral effects of dopamine receptor agonists, and further demonstrate the importance of studying drug sensitivity in both male and female subjects.

The effects of local microinjection of selective dopamine D1 and D2 receptor agonists and antagonists into the dorsal raphe nucleus on sleep and wakefulness in the rat

The effects of the dopamine (DA) D1 and D2 receptor agonists SKF38393, bromocriptine and quinpirole, respectively, on spontaneous sleep were analyzed in adult rats prepared for chronic sleep recordings. Local administration of the DAergic agonists into the dorsal raphe nucleus (DRN) during the light phase of the light-dark cycle induced a significant reduction of rapid-eye movement sleep (REMS) and the number of REM periods. Additionally, bromocriptine and quinpirole significantly increased wakefulness (W). Opposite, the microinjection into the DRN of the DA D1 and D2 receptor antagonists SCH23390 and sulpiride, respectively, significantly augmented REMS and the number of REM periods. Pretreatment with SCH23390 and sulpiride prevented the effects of SKF38393 and bromocriptine, respectively, on sleep variables. Our results tend to indicate that DAergic neurons located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) contribute to the regulation of predominantly W and REMS by DRN serotonergic neurons.

A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission

1q21.1 hemizygous microdeletion is a copy number variant leading to eightfold increased risk of schizophrenia. In order to investigate biological alterations induced by this microdeletion, we generated a novel mouse model (Df(h1q21)/+) and characterized it in a broad test battery focusing on schizophrenia-related assays. Df(h1q21)/+ mice displayed increased hyperactivity in response to amphetamine challenge and increased sensitivity to the disruptive effects of amphetamine and phencyclidine hydrochloride (PCP) on prepulse inhibition. Probing of the direct dopamine (DA) pathway using the DA D1 receptor agonist SKF-81297 revealed no differences in induced locomotor activity compared to wild-type mice, but Df(h1q21)/+ mice showed increased sensitivity to the DA D2 receptor agonist quinpirole and the D1/D2 agonist apomorphine. Electrophysiological characterization of DA neuron firing in the ventral tegmental area revealed more spontaneously active DA neurons and increased firing variability in Df(h1q21)/+ mice, and decreased feedback reduction of DA neuron firing in response to amphetamine. In a range of other assays, Df(h1q21)/+ mice showed no difference from wild-type mice: gross brain morphology and basic functions such as reflexes, ASR, thermal pain sensitivity, and motor performance were unaltered. Similarly, anxiety related measures, baseline prepulse inhibition, and seizure threshold were unaltered. In addition to the central nervous system-related phenotypes, Df(h1q21)/+ mice exhibited reduced head-to tail length, which is reminiscent of the short stature reported in humans with 1q21.1 deletion. With aspects of both construct and face validity, the Df(h1q21)/+ model may be used to gain insight into schizophrenia-relevant alterations in dopaminergic transmission.

Olfactory conditioned same-sex partner preference in female rats: Role of ovarian hormones

The dopamine D2-type receptor agonist quinpirole (QNP) facilitates the development of conditioned same-sex partner preference in males during cohabitation, but not in ovariectomized (OVX) females, primed with estradiol benzoate (EB) and progesterone (P). Herein we tested the effects of QNP on OVX, EB-only primed females. Females received a systemic injection (every four days) of either saline (Saline-conditioned) or QNP (QNP-conditioned) and then cohabited for 24h with lemon-scented stimulus females (CS+), during three trials. In test 1 (female-female) preference was QNP-free, and females chose between the CS+ female and a novel female. In test 2 (male-female) they chose between the CS+ female and a sexually experienced male. In test 1 Saline-conditioned females displayed more hops & darts towards the novel female, but QNP-conditioned females displayed more sexual solicitations towards the CS+ female. In test 2 Saline-conditioned females displayed a clear preference for the male, whereas QNP-conditioned females displayed what we considered a bisexual preference. We discuss the effect of dopamine and ovarian hormones on the development of olfactory conditioned same-sex preference in females.

Sex differences in high fat diet-induced enhancement of sensitivity to the behavioral effects of the dopamine D2/D3 receptor agonist quinpirole in adolescent rats

Sex differences in high fat diet-induced enhancement of sensitivity to the behavioral effects of the dopamine D2/D3 receptor agonist quinpirole in adolescent rats

Role of D2 dopamine receptors of the ventral pallidum in inhibitory avoidance learning

In our present experiments, the role of D2 dopamine (DA) receptors of the ventral pallidum (VP) was investigated in one trial step-through inhibitory avoidance paradigm.Animals were shocked 3 times in the conditioning trial, with 0.5mA current for 1s. Subsequently bilateral microinjection of the D2 DA receptor agonist quinpirole was administered into the VP in three doses (0.1μg, 1.0μg or 5.0μg in 0.4μl saline). We also applied the D2 DA receptor antagonist sulpiride (0.4μg in 0.4μl saline) alone or 15min prior to the agonist treatment to elucidate whether the agonist effect was specific for the D2 DA receptors. Control animals received saline. In a supplementary experiment, it was also investigated whether application of the same conditioning method leads to the formation of short-term memory in the experimental animals.In the experiment with the D2 DA receptor agonist, only the 0.1μg quinpirole increased significantly the step-through latency during the test trials: retention was significant compared to the controls even 2 weeks after conditioning. The D2 DA receptor antagonist sulpiride pretreatment proved that the effect was due to the agonist induced activation of the D2 DA receptors of the VP. The supplementary experiment demonstrated that short-term memory is formed after conditioning in the experimental animals, supporting that the agonist enhanced memory consolidation in the first two experiments.Our results show that the activation of the D2 DA receptors in the VP facilitates memory consolidation as well as memory-retention in inhibitory avoidance paradigm.

Intravitreally-administered dopamine D2-like (and D4), but not D1-like, receptor agonists reduce form-deprivation myopia in tree shrews.

We examined the effect of intravitreal injections of D1-like and D2-like dopamine receptor agonists and antagonists and D4 receptor drugs on form-deprivation myopia (FDM) in tree shrews, mammals closely related to primates. In eleven groups (n = 7 per group), we measured the amount of FDM produced by monocular form deprivation (FD) over an 11-day treatment period. The untreated fellow eye served as a control. Animals also received daily 5 µL intravitreal injections in the FD eye. The reference group received 0.85% NaCl vehicle. Four groups received a higher, or lower, dose of a D1-like receptor agonist (SKF38393) or antagonist (SCH23390). Four groups received a higher, or lower, dose of a D2-like receptor agonist (quinpirole) or antagonist (spiperone). Two groups received the D4 receptor agonist (PD168077) or antagonist (PD168568). Refractions were measured daily; axial component dimensions were measured on day 1 (before treatment) and day 12. We found that in groups receiving the D1-like receptor agonist or antagonist, the development of FDM and altered ocular component dimensions did not differ from the NaCl group. Groups receiving the D2-like receptor agonist or antagonist at the higher dose developed significantly less FDM and had shorter vitreous chambers than the NaCl group. The D4 receptor agonist, but not the antagonist, was nearly as effective as the D2-like agonist in reducing FDM. Thus, using intravitreally-administered agents, we did not find evidence supporting a role for the D1-like receptor pathway in reducing FDM in tree shrews. The reduction of FDM by the dopamine D2-like agonist supported a role for the D2-like receptor pathway in the control of FDM. The reduction of FDM by the D4 receptor agonist, but not the D4 antagonist, suggests an important role for activation of the dopamine D4 receptor in the control of axial elongation and refractive development.

Mechanisms underlying the endogenous dopaminergic inhibition of spinal locomotor circuit function in Xenopus tadpoles.

Dopamine plays important roles in the development and modulation of motor control circuits. Here we show that dopamine exerts potent effects on the central pattern generator circuit controlling locomotory swimming in post-embryonic Xenopus tadpoles. Dopamine (0.5–100 μM) reduced fictive swim bout occurrence and caused both spontaneous and evoked episodes to become shorter, slower and weaker. The D2-like receptor agonist quinpirole mimicked this repertoire of inhibitory effects on swimming, whilst the D4 receptor antagonist, L745,870, had the opposite effects. The dopamine reuptake inhibitor bupropion potently inhibited fictive swimming, demonstrating that dopamine constitutes an endogenous modulatory system. Both dopamine and quinpirole also inhibited swimming in spinalised preparations, suggesting spinally located dopamine receptors. Dopamine and quinpirole hyperpolarised identified rhythmically active spinal neurons, increased rheobase and reduced spike probability both during swimming and in response to current injection. The hyperpolarisation was TTX-resistant and was accompanied by decreased input resistance, suggesting that dopamine opens a K+ channel. The K+ channel blocker barium chloride (but not TEA, glybenclamide or tertiapin-Q) significantly occluded the hyperpolarisation. Overall, we show that endogenously released dopamine acts upon spinally located D2-like receptors, leading to a rapid inhibitory modulation of swimming via the opening of a K+ channel.

D2-like receptors in the descending dopaminergic pathway are not involved in the decreased postoperative nociceptive threshold induced by plantar incision in adult rats.

BackgroundApproximately half of all patients who undergo surgery develop postoperative pain, the mechanisms of which are not well understood by anesthesiologists. D2-like receptors in the descending dopaminergic pathway play an important role in regulation of pain transmission in the spinal cord. Impairment of inhibitory neurons in the spinal cord is suggested as part of the mechanism for neuropathic pain, which is one component of postoperative pain. The purpose of this study was to investigate whether impairment of D2-like receptors in the descending dopaminergic pathway in the spinal cord is involved in the decreased postoperative nociceptive threshold in rats.MethodsMale Sprague-Dawley rats (250–300 g) were anesthetized with sevoflurane and an intrathecal (IT) catheter was implanted. Six days later, a plantar incision was made. On the following day, saline, a D2-like receptor agonist (quinpirole), or a D2-like receptor antagonist (sulpiride) was administered intrathecally. Thermal and mechanical nociceptive responses were assessed by exposure to infrared radiant heat and the von Frey filament test before and after plantar incision.ResultsPlantar incision decreased both thermal latency and the mechanical nociceptive threshold. IT administration of quinpirole inhibited the nociceptive responses induced by plantar incision, but sulpiride had no effect.ConclusionA D2-like receptor agonist had antinociceptive effects on the hypersensitivity response triggered by a surgical incision, but a D2-like receptor antagonist had no effect on this response. These results suggest that impairment and/or modification of D2-like receptors in the descending dopaminergic pathway in the spinal cord is not involved in the postoperative decrease in nociceptive threshold.

Increased sensitivity in the interaction of the dopaminergic/adenosinergic system at the level of the adenylate cyclase activity in the striatum of the “weaver” mouse

The specific antagonistic interaction between dopamine D1 and adenosine A1 receptors (D1/A1), as well as between dopamine D2 and adenosine A2a receptors (D2/A2a) exist not only at the receptor/receptor level, but also at the level of the secondary messengers. In this study, we examined the possible changes in these interactions at the level of cAMP formation in membrane preparation from “weaver” mouse striatum (a genetic model of Parkinson disease), by using specific agonists of these receptors. We also examined in the striatum of the “weaver” mouse the interaction between D1 and D2 dopamine receptors.Our results showed that in the striatum of “weaver” mice: a) the cAMP synthesis induced by D1 receptor activation (SKF 38393), was significantly reduced compared to control mice, while A1 receptor activation (L-PIA) leaded to a more intense inhibition of the D1-induced cAMP-formation compared to the controls, b) the cAMP synthesis which was induced by A2a receptor activation (CGS 21680), was significantly increased compared to the control mice. The specific D2 receptor agonist Quinpirole, added in low concentrations, caused a significant reduction of the A2a-induced cAMP formation, which was not observed in the control mouse. Furthermore, the D1 receptor induced cAMP synthesis was significantly higher in control compared to “weaver” striatum, which was more efficiently downregulated by D2 receptor agonist Quinpirole.These results suggest that the sensitivity to D1 and A2a receptor agonists is altered and that the interaction between D1/A1 and D2/A2a receptors is enhanced in the striatum of the “weaver” mutation, while an uncoupling between D1 and D2 receptors was observed. Since the adenylate cyclase basal activity did not differ between “weaver” and control striatum, the above-mentioned changes seem to be due to alterations in the function of the adenosine/dopamine receptors and their coupling to the G-proteins.

Role of ventral pallidal D2 dopamine receptors in the consolidation of spatial memory

The role of dopamine (DA) receptors in spatial memory consolidation has been demonstrated in numerous brain regions, among others in the nucleus accumbens which innervates the ventral pallidum (VP). The VP contains both D1 and D2 DA receptors. We have recently shown that the VP D1 DA receptor activation facilitates consolidation of spatial memory in Morris water maze test. In the present study, the role of VP D2 DA receptors was investigated in the same paradigm.In the first experiment, the D2 DA receptor agonist quinpirole was administered into the VP of male Wistar rats in three doses (0.1, 1.0 or 5.0μg, respectively in 0.4μl physiological saline). In the second experiment, the D2 DA receptor antagonist sulpiride was applied to elucidate whether it can antagonise the effects of quinpirole. The antagonist (4.0μg, dissolved in 0.4μl physiological saline) was microinjected into the VP either by itself or prior to 1.0μg agonist treatment. Control animals received saline in both experiments.The two higher doses (1.0 and 5.0μg) of the agonist accelerated memory consolidation relative to controls and increased the stability of the consolidated memory against extinction. Sulpiride pretreatment antagonised the effects of quinpirole. In addition, the antagonist microinjected into the VP immediately after the second conditioning trial impaired learning functions.The present data provide evidences for the important role of VP D2 DA receptors in the consolidation and stabilization of spatial memory.

The Rapidly Acting Antidepressant Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Rapidly Engage Dopaminergic Mood Circuits.

Ketamine is a rapidly acting antidepressant in patients with treatment-resistant depression (TRD). Although the mechanisms underlying these effects are not fully established, inquiry to date has focused on the triggering of synaptogenesis transduction pathways via glutamatergic mechanisms. Preclinical data suggest that blockade of metabotropic glutamate (mGlu2/3) receptors shares many overlapping features and mechanisms with ketamine and may also provide rapid efficacy for TRD patients. Central dopamine circuitry is recognized as an end target for mood regulation and hedonic valuation and yet has been largely neglected in mechanistic studies of antidepressant-relevant effects of ketamine. Herein, we evaluated the changes in dopaminergic neurotransmission after acute administration of ketamine and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid ] in preclinical models using electrophysiologic, neurochemical, and behavioral endpoints. When given acutely, both ketamine and LY341495, but not the selective serotonin reuptake inhibitor (SSRI) citalopram, increased the number of spontaneously active dopamine neurons in the ventral tegmental area (VTA), increased extracellular levels of dopamine in the nucleus accumbens and prefrontal cortex, and enhanced the locomotor stimulatory effects of the dopamine D2/3 receptor agonist quinpirole. Further, both ketamine and LY341495 reduced immobility time in the tail-suspension assay in CD1 mice, which are relatively resistant to SSRI antidepressants. Both the VTA neuronal activation and the antidepressant phenotype induced by ketamine and LY341495 were attenuated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo- (9CI)-benzo[f]quinoxaline-7-sulfonamide, indicating AMPA-dependent effects. These findings provide another overlapping mechanism of action of ketamine and mGlu2/3 receptor antagonism that differentiates them from conventional antidepressants and thus support the potential rapidly acting antidepressant actions of mGlu2/3 receptor antagonism in patients.