Infusion Of Quinpirole Research Articles

Streptozotocin-induced diabetes in rats modifies the role D2 , D3 and D4 dopamine receptors play in cardiac sympathetic inhibition.

Diabetes mellitus is associated with abnormalities in peripheral/central catecholaminergic systems, including changes in catecholamine levels and receptor expression. Since quinpirole-induced cardiac sympathetic inhibition is greater in diabetic than in normoglycemic rats, this study pharmacologically investigated the dopamine D2 -like receptor subtypes that mediate cardiac sympathetic inhibition in diabetic (streptozotocin [STZ]-pretreated) pithed rats. Fifty male Wistar rats were pretreated with STZ, pithed and conditioned for spinal stimulation (C7 -T1 ) of the tachycardic sympathetic tone. The resulting increases in heart rate were evaluated following i.v. blocking doses of antagonists at D2 , D3 and D4 receptors during a continuous i.v. infusion of quinpirole (an agonist at D2 -like receptors) or saline (vehicle). With this experimental approach, the cardiac sympathetic inhibition produced by quinpirole in diabetic rats was:(i) unchanged after administration of vehicles and; (ii) abolished by the antagonists L-741,626 (D2 ), SB-277011-A (D3 ) or L-745,870 (D4 ). These findings in diabetic pithed rats imply that: (i) the cardiac sympathetic inhibition by quinpirole involves activation of D2/3/4 dopamine receptors; and (ii) there is a differential stimulation of these receptors compared to normoglycemic rats. These D2/3/4 receptor subtypes could be a novel drug target for the therapy of typical cardiac complications of diabetes.

Effects of dopamine modulation on chronic stress-induced deficits in reward learning.

Anhedonia is characteristically preceded by chronic stress, likely involving downstream effects of glucocorticoid alterations on dopamine (DA) function. To elucidate the neural underpinnings of this interaction, we examined whether acute pharmacological modulation of DA alters reward learning after chronic mild stress (CMS). Forty-eight male Wistar rats were exposed to a 21-day CMS regime (n = 48 nostress controls) before completing the probabilistic reward task (PRT), a well-validated cross-species test of reward learning. We first examined whether stress-induced reward dysfunction could be restored by systemic injections of low-dose amisulpride (AMI), which increases DA transmission via D2-like autoreceptor blockade. Then, we investigated region-specific effects through bilateral infusions of quinpirole (QUIN), a D2-like receptor agonist, into either the nucleus accumbens core (NAcc) or medial prefrontal cortex (mPFC). Blunted reward learning in CMS animals was reversed by acute AMI administration, but this treatment did not alter reward learning in the no stress group. Elevated adrenal gland weight, a proxy for stress reactivity, predicted lower reward learning in the untreated CMS group. This effect was extinguished following AMI treatment. These findings might be attributed to significantly higher D2 receptor density in the NAcc of high stress reactive animals. To this end, NAcc QUIN infusions potentiated reward learning relative to mPFC QUIN infusions in CMS rats, but there was no effect in no stress control rats. Collectively, these findings suggest that DA modulation reverses stress-induced reward dysfunction, even among the most stress-reactive animals. The effect might depend on D2-like receptor activation in the mesolimbic system.

Activation of dopamine D2 receptors in the shell of nucleus accumbens triggers conditioned avoidance responses in rats

Conditioned avoidance responses (CAR) behavior is a classical instrumental response paradigm, which is widely used to study aversive conditioning and defensive motivation behavior. Previous studies have shown that dopamine D1 and D2 receptors are involved in CAR behavior; however, it is unclear in which brain regions that dopamine evokes CAR behavior. The aim of the study is to investigate whether dopamine triggers CAR behavior via activating dopamine D1 or D2 receptors in the shell of nucleus accumbens or dorsolateral striatum. The present study found that infusion of the dopamine D2 receptor agonist quinpirole, but not D1 receptor agonist SKF38393, into the shell of nucleus accumbens evoked CAR behavior in reserpine-treated rats. Whereas, infusion of neither SKF38393 nor quinpirole into the dorsolateral striatum evoked CAR behavior. In addition, infusion of quinpirole into the shell of nucleus accumbens enhanced CAR behavior in the unsuccessful trained rats without affecting the motor function in the balance beam and locomotor tests. In conclusion, activation of dopamine D2, but not D1 receptors in the shell of nucleus accumbens evokes CAR behavior. However, activation of dopamine D1 and D2 receptors in the dorsolateral striatum does not evoke CAR behavior. It is suggested that the shell of nucleus accumbens is the critical brain region for dopamine to invoke CAR behavior, and activation of dopamine D2 receptors in the shell of nucleus accumbens is sufficient and necessary to evoke CAR behavior.

Activation of dopamine D2 receptors in the medial shell region of the nucleus accumbens increases Per1 expression to enhance alcohol consumption.

Circadian genes, including Per1, in the medial shell region of nucleus accumbens (mNAcSh), regulate binge alcohol consumption. However, the upstream mechanism regulating circadian genes-induced alcohol consumption is not known. Since activation of dopamine D2 receptors (D2R) increases Per1 gene expression, we hypothesised that local infusion of quinpirole, a D2R agonist, by increasing Per1 gene expression in the mNAcSh, will increase binge alcohol consumption in mice. We performed two experiments on male C57BL/6J mice, instrumented with bilateral guide cannulas above the mNAcSh, and exposed to a 4-day drinking-in-dark (DID) paradigm. The first experiment determined the effects of bilateral infusion of quinpirole (100 ng/300 nl/site) or DMSO (Vehicle group) in the mNAcSh on Per1 gene expression and alcohol consumption. The second experiment determined the effect of antisense-induced downregulation of Per1 in the mNAcSh on the quinpirole-induced increase in alcohol consumption. Control experiments were performed by exposing the animals to sucrose (10% w/v). After the experiment, animals were euthanised, brains removed and processed for localisation of injection sites and analysis of Per1 gene expression in the mNAcSh. As compared with the DMSO, local bilateral infusion of quinpirole significantly increased the expression of Per1 in the mNAcSh along with an increase in the amount of alcohol consumed in mice exposed to DID paradigm. In addition, local antisense-induced downregulation of Per1 significantly attenuated the effects of intro-accumbal infusion of quinpirole on alcohol consumption. Our results suggest that Per1 in the mNAcSh mediates D2R activation-induced increase in alcohol consumption.

Evidence of D2 receptor expression in the nucleus incertus of the rat

The nucleus incertus (NI), located in the caudal brainstem, mainly consists of GABAergic neurons with widespread projections across the brain. It is the chief source of relaxin-3 in the mammalian brain and densely expresses corticotropin-releasing factor type 1 (CRF1) receptors. Several other neurotransmitters, peptides and receptors are reportedly expressed in the NI. In the present investigation, we show the expression of dopamine type-2 (D2) receptors in the NI by reverse transcriptase-polymerase chain reaction (RT-PCR), western blotting (WB) and immunofluorescence (IF). RT-PCR did not show expression of D3 receptors. D2 receptor short isoform (D2S)-like, relaxin-3, CRF1/2 receptor and NeuN immunoreactivity were co-expressed in the cells of the NI. Behavioural effects of D2 receptor activation by intra-NI infusion of quinpirole (a D2/D3 agonist) were evaluated. Hypolocomotion was observed in home cage monitoring system (LABORAS) and novel environment-induced suppression of feeding behavioural paradigms. Thus the D2 receptors expressed in the NI are likely to play a role in locomotion. Based on its strong bidirectional connections to the median raphe and interpeduncular nuclei, the NI was predicted to play a role in modulating behavioural activity and the present results lend support to this hypothesis. This is the first evidence of expression of a catecholamine receptor, D2-like immunoreactivity, in the NI.

Reduced dopamine and glutamate neurotransmission in the nucleus accumbens of quinpirole-sensitized rats hints at inhibitory D2 autoreceptor function.

Dopamine from the ventral tegmental area and glutamate from several brain nuclei converge in the nucleus accumbens (NAc) to drive motivated behaviors. Repeated activation of D2 receptors with quinpirole (QNP) induces locomotor sensitization and compulsive behaviors, but the mechanisms are unknown. In this study, in vivo microdialysis and fast scan cyclic voltammetry in adult anesthetized rats were used to investigate the effect of repeated QNP on dopamine and glutamate neurotransmission within the NAc. Following eight injections of QNP, a significant decrease in phasic and tonic dopamine release was observed in rats that displayed locomotor sensitization. Either a systemic injection or the infusion of QNP into the NAc decreased dopamine release, and the extent of this effect was similar in QNP-sensitized and control rats, indicating that inhibitory D2 autoreceptor function is maintained despite repeated activation of D2 receptors and decreased dopamine extracellular levels. Basal extracellular levels of glutamate in the NAc were also significantly lower in QNP-treated rats than in controls. Moreover, the increase in NAc glutamate release induced by direct stimulation of medial prefrontal cortex was significantly lower in QNP-sensitized rats. Together, these results indicate that repeated activation of D2 receptors disconnects NAc from medial prefrontal cortex and ventral tegmental area. Repeated administration of the dopamine D2 receptor agonist quinpirole (QNP) induces locomotor sensitization. We found that the NAc of QNP-sensitized rats has reduced glutamate levels coming from prefrontal cortex together with a decreased phasic and tonic dopamine neurotransmission but a conserved presynaptic D2 receptor function. We suggest that locomotor sensitization is because of increased affinity state of D2 post-synaptic receptors.

D2-like receptor activation does not initiate a brain docosahexaenoic acid signal in unanesthetized rats.

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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2202-15-113) contains supplementary material, which is available to authorized users.

Dopaminergic modulation of neuropathic pain: analgesia in rats by a D2-type receptor agonist.

Experimental studies have shown that dopaminergic mechanisms can modulate both nociception and chronic pain perception, but such property is not exploited pharmacologically at the clinical level. We have previously shown that levodopa produces D2-receptor-mediated antiallodynic effects in rats with peripheral mononeuropathy. Here, we test the effects of a D2-type receptor (D2R) agonist, quinpirole, on neuropathic pain in rats. Allodynic responses to cooling and light touch were measured in the hind limbs of rats with chronic constriction injury of one sciatic nerve. Single intraperitoneal injection of quinpirole (1 mg/kg) totally inhibited cold and tactile allodynic responses for over 3 and 48 h, respectively. At that dose, quinpirole had no effect on nocifensive responses to heat. Lumbar intrathecal injection of quinpirole produced short-term inhibition of the responses to cold and tactile stimuli, suggesting that spinal mechanisms may contribute to the antiallodynic activity of quinpirole. Chronic subcutaneous infusion of quinpirole by implanted Alzet pumps (0.025 mg/kg·day) provided a slowly progressing inhibition of cold and tactile allodynic responses, which re-emerged after the pumps were removed. These experiments show the involvement of dopaminergic systems in the modulation of chronic allodynias and provide experimental support for proposing the use of D2R agonists for neuropathic pain relief.

The role of dopamine D2, but not D3 or D4, receptor subtypes, in quinpirole-induced inhibition of the cardioaccelerator sympathetic outflow in pithed rats.

Quinpirole (a dopamine D2-like receptor agonist) inhibits the cardioaccelerator sympathetic outflow in pithed rats by sympathoinhibitory D2-like receptors. The present study was designed to identify pharmacologically the specific D2-like receptor subtypes (i.e. D2 , D3 and D4) involved in this sympathoinhibition by quinpirole. One hundred fourteen male Wistar rats were pithed, artificially ventilated with room air and prepared for either preganglionic spinal (C7-T1) stimulation of the cardioaccelerator sympathetic outflow (n = 102) or i.v. bolus injections of exogenous noradrenaline (n = 12). This approach resulted in frequency-dependent and dose-dependent tachycardic responses, respectively, as previously reported by our group. I.v. continuous infusions of quinpirole (0.1-10 μg kg(-1) min(-1)), but not of saline (0.02 mL min(-1)), dose-dependently inhibited the sympathetically induced tachycardic responses. Moreover, the cardiac sympathoinhibition induced by 3 μg kg(-1) min(-1) quinpirole (which failed to affect the tachycardic responses to i.v. noradrenaline) was: (i) unchanged after i.v. injections of the antagonists SB-277011-A (D3 ; 100-300 μg kg(-1)) or L-745,870 (D4 ; 30-100 μg kg(-1)); and (ii) markedly blocked and abolished by, respectively, 100 and 300 μg kg(-1) of the D2 preferring receptor subtype antagonist L-741,626. These doses of antagonists, which did not affect per se the sympathetically induced tachycardic responses, were high enough to completely block their respective receptors. The cardiac sympathoinhibition induced by 3 μg kg(-1) min(-1) quinpirole involves the dopamine D2 receptor subtype, with no evidence for the involvement of the D3 or D4 subtypes. This provides new evidence for understanding the modulation of the cardioaccelerator sympathetic outflow.

The Role of Pre-junctional D2-like Receptors Mediating Quinpirole-Induced Inhibition of the Vasodepressor Sensory CGRPergic Out-flow in Pithed Rats

Calcitonin gene-related peptide (CGRP) released from perivascular sensory nerves plays a role in the regulation of vascular tone. Indeed, electrical stimulation of the perivascular sensory out-flow in pithed rats produces vasodepressor responses, which are mainly mediated by CGRP release. This study investigated the potential role of dopamine D1 -like and D2 -like receptors in the inhibition of these vasodepressor responses. For this purpose, male Wistar pithed rats (pre-treated i.v. with 25 mg/kg gallamine and 2 mg/kg min. hexamethonium) received i.v. continuous infusions of methoxamine (20 μg/kg min.) followed by physiological saline (0.02 ml/min.), the D1 -like receptor agonist SKF-38393 (0.1-1 μg/kg min.) or the D2 -like receptor agonist quinpirole (0.03-10 μg/kg min.). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the thoracic spinal cord (T9 -T12 ) resulted in frequency-dependent vasodepressor responses which were (i) unchanged during the infusions of saline or SKF-38393 and (ii) inhibited during the infusions of quinpirole (except at 0.03 μg/kg min.). Moreover, the inhibition induced by 0.1 μg/kg min. quinpirole (which failed to inhibit the vasodepressor responses elicited by i.v. bolus injections of exogenous α-CGRP; 0.1-1 μg/kg) was (i) unaltered after i.v. treatment with 1 ml/kg of either saline or 5% ascorbic acid and (ii) abolished after 300 μg/kg (i.v.) of the D2 -like receptor antagonists haloperidol or raclopride. These doses of antagonists (enough to completely block D2 -like receptors) essentially failed to modify per se the electrically induced vasodepressor responses. In conclusion, our results suggest that quinpirole-induced inhibition of the vasodepressor sensory CGRPergic out-flow is mainly mediated by pre-junctional D2 -like receptors.

Ventral tegmental ionotropic glutamate receptor stimulation of nucleus accumbens tonic dopamine efflux blunts hindbrain-evoked phasic neurotransmission: Implications for dopamine dysregulation disorders

Activation of glutamate receptors within the ventral tegmental area (VTA) stimulates extrasynaptic (basal) dopamine release in terminal regions, including the nucleus accumbens (NAc). Hindbrain inputs from the laterodorsal tegmental nucleus (LDT) are critical for elicitation of phasic VTA dopamine cell activity and consequent transient dopamine release. This study investigated the role of VTA ionotropic glutamate receptor (iGluR) stimulation on both basal and LDT electrical stimulation-evoked dopamine efflux in the NAc using in vivo chronoamperometry and fixed potential amperometry in combination with stearate-graphite paste and carbon fiber electrodes, respectively. Intra-VTA infusion of the iGluR agonists (±)-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; 1μg/μl) or N-methyl-d-aspartic acid (NMDA; 2μg/μl) enhanced basal NAc dopamine efflux. This iGluR-mediated potentiation of basal dopamine efflux was paralleled by an attenuation of LDT-evoked transient NAc dopamine efflux, suggesting that excitation of basal activity effectively inhibited the capacity of hindbrain afferents to elicit transient dopamine efflux. In line with this, post-NMDA infusion of the dopamine D2 autoreceptor (D2R) agonist quinpirole (1μg/μl; intra-VTA) partially recovered NMDA-mediated attenuation of LDT-evoked NAc dopamine, while concurrently attenuating NMDA-mediated potentiation of basal dopamine efflux. Post-NMDA infusion of quinpirole (1μg/μl) alone attenuated basal and LDT-evoked dopamine efflux. Taken together, these data reveal that hyperstimulation of basal dopamine transmission can stunt hindbrain burst-like stimulation-evoked dopamine efflux. Inhibitory autoreceptor mechanisms within the VTA help to partially recover the magnitude of phasic dopamine efflux, highlighting the importance of both iGluRs and D2 autoreceptors in maintaining the functional balance of tonic and phasic dopamine neurotransmission. Dysregulation of this balance may have important implications for disorders of dopamine dysregulation such as attention deficit hyperactivity disorder.

Increased drinking after intra-striatal injection of the dopamine D2/D3 receptor agonist quinpirole in the rat

Dopamine D2 receptor hyperactivity has been implicated in the development of psychogenic polydipsia in schizophrenic patients. Repeated treatment with dopamine agonists, including the D2/D3 agonist quinpirole, has been shown to induce hyperdipsia in a number of animal models. Despite these observations, obtained with systemic administrations, little attempt has been made to investigate where in the brain dopamine agonists act to induce hyperdipsia. The present study investigates the effects of repeated intra-caudate infusions of quinpirole on the intake of water by rats tested under free-drinking conditions. Rats with bilateral cannulae placed into the anterior, central or posterior caudate received quinpirole microinfusions (1 μg/side) for five consecutive days in their home cage. Water intake was measured 15 and 60 min after the treatment. When injected in the central caudate, quinpirole increased water intake, and this effect progressively increased over sessions, indicating the development of sensitization. When injected in the posterior caudate, the dipsogenic effect of quinpirole was less intense and did not undergo sensitization. The infusion of quinpirole in the anterior caudate did not affect drinking. The present study shows that caudate D2/3 receptors play an important role in the development of quinpirole-induced hyperdipsia, an animal model of psychotic polydipsia.

Repeated exposure to cocaine alters medial prefrontal cortex dopamine D2‐like receptor modulation of glutamate and dopamine neurotransmission within the mesocorticolimbic system

Repeated exposure to cocaine progressively increases drug-induced locomotor activity, which is termed behavioral sensitization. Previous studies have demonstrated that sensitization to cocaine is associated with a decrease in dopamine D₂ receptor function in the medial prefrontal cortex. The present report tested the hypothesis that reduced medial prefrontal cortex D₂ receptor function as a result of repeated cocaine exposure results in augmented excitatory transmission to the nucleus accumbens and ventral tegmental area, possibly as a partial result of enhanced inhibition of local dopamine release. Dual probe microdialysis experiments were conducted in male Sprague-Dawley rats 1, 7 or 30 days following the last of four daily injections of saline (1.0 mL/kg) or cocaine (15 mg/kg). Infusion of quinpirole (0.01, 1.0 and 100 μM), a D₂-like receptor agonist, into the medial prefrontal cortex produced a dose-dependent decrease in cortical, nucleus accumbens and ventral tegmental area extracellular glutamate levels in control but not sensitized animals. Quinpirole also reduced basal dopamine levels in the medial prefrontal cortex in sensitized animals following 1 day of withdrawal from cocaine. Following 30 days of withdrawal, quinpirole also reduced dopamine levels in sensitized animals relative to saline controls, but not relative to baseline levels. These findings indicate that the expression of sensitization to cocaine is associated with altered modulation of mesocorticolimbic glutamatergic transmission at the level of the medial prefrontal cortex.

Ventral striatum dopamine D2 receptor activity inhibits rat pups' vocalization response to loss of maternal contact.

Most mammalian infants vocalize when isolated. The vocalization promotes caregiver proximity, which is critical to survival. If, before isolation, a rat pup has contact with its dam, its isolation vocalization rate is increased (maternal potentiation) relative to isolation preceded only by littermate contact. Prior work showed that systemic administration of a D2 receptor agonist blocks maternal potentiation at doses that do not alter baseline vocalization. In this study, infusion of quinpirole (2 microg/side) into the nucleus accumbens also blocks maternal potentiation. Infusion of the accumbens with the D2 antagonist raclopride (4 microg/side) prevents systemic quinpirole from blocking potentiation. Quinpirole infusion in the dorsal striatum did not affect maternal potentiation and infusion of raclopride in the dorsal striatum did not reverse the block of maternal potentiation by systemic quinpirole. Vocalization results after a second vehicle infusion on a given day are no different than the results following an initial vehicle infusion, so experimental design can not account for the effects of drug infusions. Because activity level was increased by both dorsal and ventral striatum infusions, activity level can not account for the results.

Iron deficiency alters monoamine catabolism as well as feedback regulation of DA transporter functioning

Iron deficiency (ID) causes decreased dopamine (DA) D2 receptor density, decreased DA transporter (DAT) density and alters DA signaling in the brain. We found that post weaning ID results in a 61% decrease in MAO-B activity in striatum. No effect was seen on MAO-A or COMT activity. Direct infusion of 1 μM FeSO4 was found to rescue this deficit indicating iron is vital for proper catecholamine metabolism. We further explored iron’s role on the catecholamine system by using in vivo microdialysis and no net flux. We found that ID increases extracellular dopamine by 26% and decreases extraction fraction (Ed) by 20% implying the DAT function is decreased by ID. Furthermore, stimulation of the D2 system by infusion of 5 μM quinpirole during NNF results in a decrease in basal extracellular DA for both control (CN) and ID animals indicating that the feedback regulation of synthesis and release is intact, although D2 density is decreased. Additionally, quinpirole infusion increased Ed by 45% in CN animals, however there was no change in ID Ed. This lack of response indicates disruption in the signal pathway regulating DAT functionality. Infusion of 1 μM FeSO4 was not able to correct this.

Differential roles of dopamine D1 and D2 receptors in the nucleus accumbens in attentional performance on the five-choice serial reaction time task.

Nucleus accumbens (NAC) dopamine may play a role in attentional and executive processes, as it modulates cortico-limbic inputs, including afferents from the prefrontal cortex. The present study examined the role of NAC dopamine D1 and D2 receptors in visual attentional processes and response control in rats as assessed in the five-choice serial reaction time task (5CSRT). Rats were trained to detect the location of brief (0.5 s) visual targets presented randomly in an array of five apertures to receive food reward. They were tested after bilateral infusions of a D1 receptor antagonist (SCH 23390) and agonist (SKF 38393) and a D2 receptor antagonist (sulpiride) and agonist (quinpirole) into the NAC. While intra-NAC SCH 23390 decreased accurate responding and increased response omissions, SKF 38393 improved accuracy and decreased omissions at the lowest dose (0.1 microg/side). At higher doses, SKF 38393 increased premature 'impulsive' responding. Sulpiride impaired the attentional accuracy of responding and slowed the latency to collect the earned food reward. By contrast, intra-NAC infusions of quinpirole did not significantly affect attentional accuracy, but increased perseverative responding. Optimal performance on the 5CSRT depends on both D1 and D2 receptors in the NAC, but they modulate different aspects of performance. D1 receptor agents had more selective effects on attentional accuracy while D2 receptor stimulation did not affect accuracy or premature responses, but enhanced perseverative responding. The data are discussed in terms of the different functions of NAC dopamine receptors in the processing of information from its different cortico-limbic inputs.

The age-associated changes of dopamine–acetylcholine interaction in the striatum

The age-associated decline of dopamine D 2 receptor (D 2R) densities is one of the notable features of aging in mammalian brains. The concept of a functional dopamine (DA) –acetylcholine (ACh) interaction in the striatum has been strongly supported. However, the effects of this decline of D 2R on the striatal DA–ACh interaction still remain to be elucidated. In the current study we examined the effects of different concentrations of a D 2R agonist, quinpirole, on the striatal ACh release in three groups of rats at different ages (6-, 15-, 25-months-old) by in vivo microdialysis. The ACh release in the striatum was significantly decreased by quinpirole infusion in all three age groups. The old rats showed a significantly smaller decrease of the ACh release by quinpirole than that of the middle-aged rats at the dose of 0.1 μM and that of the young rats at the dose of 1 μM. The current study suggested that the striatal DA–ACh interaction was affected by the aging process.

Startle gating in rats is disrupted by chemical inactivation but not D2 stimulation of the dorsomedial thalamus

The neural regulation of sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle reflex, has been a focus of interest based on the consistent deficits in PPI reported in schizophrenia patients. While dorsomedial thalamus (MD) dysfunction has been implicated in the clinical ‘gating’ deficits of schizophrenia patients, relatively little is known regarding the regulation of PPI by the MD. We previously reported that PPI in rats is reduced after intra-MD infusion of the GABA agonist muscimol, or after excitotoxic lesions of the MD. In the present study, we tested the regulation of PPI by D2 receptors in the MD. PPI was measured after intra-MD infusion of the D2 agonist quinpirole (0, 1 or 10 μg/side) in a within-subject design. Infusion placement was confirmed functionally in later tests by reversible inactivation of the MD via intra-MD infusion of tetrodotoxin (TTX; 10 ng/side), and subsequently by direct histological examination. Intra-MD infusion of quinpirole had no significant effect on PPI, using doses that significantly disrupt PPI after infusion into the ventral forebrain (nucleus accumbens). TTX infusion into the MD caused a significant loss of PPI; this effect was not reversed by pretreatment with the atypical antipsychotic quetiapine (7.5 mg/kg). The MD regulation of PPI in rats is not mediated via D2 receptors, but is clearly manifested via PPI deficits after reversible MD inactivation via TTX.

Effects of individual and concurrent stimulation of striatal D1 and D2 dopamine receptors on electrophysiological and behavioral output from rat basal ganglia.

Bilateral infusions of d-amphetamine into the rat ventral-lateral striatum (VLS) were previously shown to cause a robust behavioral activation that was correlated temporally with a net increase in firing of substantia nigra pars reticulata (SNpr) neurons, a response opposite predictions of the basal ganglia model. The current studies assessed the individual and cooperative contributions of striatal D1 and D2 dopamine receptors to these responses. Bilateral infusions into VLS of the D1/D2 agonist apomorphine (10 microg/microl/side) caused intense oral movements and sniffing, and an overall increase in SNpr cell firing to 133% of basal rates, similar to effects of d-amphetamine. However, when striatal D2 receptors were stimulated selectively by infusions of quinpirole (30 microg/microl/side) + the D1 antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390; 10 microg/microl/side), no behavioral response and only modest and variable changes in SNpr cell firing were observed. Selective stimulation of striatal D1 receptors by (+/-) 6-chloro-APB hydrobromide (SKF 82958; 10 microg/microl/side) + the D2 antagonist cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-5-chloro-2-methoxy-4-methyl-aminobenzamide (YM 09151-2; 2 microg/microl/side) caused a weak but sustained increase in oral movements and modestly increased SNpr cell firing, but neither response was of the magnitude observed with apomorphine. When the two agonists were infused concurrently, however, robust oral movements and sniffing again occurred over the same time period that a majority of SNpr cells exhibited marked, sometimes extreme and fluctuating, changes in firing (net increase, 117% of basal rates). These data confirm that concurrent striatal D1/D2 receptor stimulation elicits a strong motor activation that is correlated temporally with a net excitation rather than inhibition of SNpr firing, and reveal that D1 and D2 receptors interact synergistically within the striatum to stimulate both forms of output.

Dopamine D 2 receptors and ingestive behavior: brainstem mediates inhibition of intraoral intake and accumbens mediates aversive taste behavior in male rats

One of the factors that terminate the ingestion of an intraorally infused solution of sucrose may be an increase in the perceived aversiveness of its taste. We tested the hypothesis that dopamine D(2), as opposed to D(1), receptors in the brainstem or nucleus accumbens inhibit intraoral intake by enhancing the aversiveness of the taste of the infused solution. Male rats were infused intraorally with a 2 M sucrose solution (1 ml/min) and intake and the display of gapes and chin rubs, i.e. taste-related aversive behavior, was measured. Gapes and chin rubs were also measured in rats during and 40 s after brief intraoral infusion (1 ml/min during 20 s) of a 0.3 mM solution of quinine HCl. The full D(1) receptor agonist dihydrexidine (0.1-3.0 mg/kg) and antagonist SCH-23390 (0.03-0.1 mg/kg), the D(2) receptor agonist quinpirole (0.3 mg/kg) and antagonist raclopride (1.7 mg/kg) were injected IP. Quinpirole (14-55 microg) and raclopride (5 microg) were also infused into the fourth brain ventricle. In addition, quinpirole (2 or 10 microg) was infused into the shell region of the nucleus accumbens. IP dihydrexidine and quinpirole inhibited the intraoral intake of sucrose and pretreatment with raclopride, but (in the case of dihydrexidine) not SCH-23390, attenuated this effect. Injection of quinpirole into the fourth ventricle produced raclopride-reversible inhibition of intraoral intake but did not stimulate the display of gapes and chin rubs. Infusion of quinpirole into the shell region of the nucleus accumbens had the opposite effects. The intake of sucrose was suppressed by the addition of quinine HCl but this suppression was unaffected by dopamine agonist or antagonist treatment. It is suggested that brainstem dopamine D(2) receptors mediate suppression of consummatory ingestive behavior and that D(2) receptors in the shell region of the nucleus accumbens mediate the display of gapes and chin rubs, but that neither of these D(2) receptor populations mediate the hedonic evaluation of taste.