Non-selective Dopamine Antagonist Research Articles

Dopamine and Norepinephrine Differentially Mediate the Exploration-Exploitation Tradeoff.

Dopamine (DA) and norepinephrine (NE) have been repeatedly implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision-making processes. Although two neuromodulators share a synthesis pathway and are coactivated under states of arousal, they engage in distinct circuits and modulatory roles. However, the specific role of each neuromodulator in decision-making, in particular the exploration-exploitation tradeoff, remains unclear. Revealing how each neuromodulator contributes to exploration-exploitation tradeoff is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To understand the differences and overlaps of the roles of these two catecholamine systems in regulating exploration, a direct comparison using the same dynamic decision-making task is needed. Here, we ran male and female mice in a restless two-armed bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol) and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine on exploration. Increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulatory effect of beta-noradrenergic receptor activity on exploration was mediated by sex. Reinforcement learning model parameters suggested that dopamine modulation affected exploration via decision noise and norepinephrine modulation affected exploration via sensitivity to outcome. Together, these findings suggested that the mechanisms that govern the exploration-exploitation transition are sensitive to changes in both catecholamine functions and revealed differential roles for NE and DA in mediating exploration.

The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats

Nicotine is a psychomotor stimulant with ‘reinforcement enhancing’ effects — the actions of nicotine in the brain increase responding for non-nicotine rewards. We hypothesized that this latter effect of nicotine depends on increased incentive properties of anticipatory cues; consistent with this hypothesis, multiple laboratories have reported that nicotine increases sign tracking, i.e. approach to a conditioned stimulus (CS), in Pavlovian conditioned-approach tasks. Incentive motivation and sign tracking are mediated by mesolimbic dopamine (DA) transmission and nicotine facilitates mesolimbic DA release. Therefore, we hypothesized that the incentive-promoting effects of nicotine would be impaired by DA antagonists. To test this hypothesis, separate groups of rats were injected with nicotine (0.4mg/kg base) or saline prior to Pavlovian conditioning sessions in which a CS (30s illumination of a light or presentation of a lever) was immediately followed by a sweet reward delivered in an adjacent location. Both saline and nicotine pretreated rats exhibited similar levels of conditioned approach to the reward location (goal tracking), but nicotine pretreatment significantly increased approach to the CS (sign tracking), regardless of type (lever or light). The DAD1 antagonist SCH-23390 and the DAD2/3 antagonist eticlopride reduced conditioned approach in all rats, but specifically reduced goal tracking in the saline pretreated rats and sign tracking in the nicotine pretreated rats. The non-selective DA antagonist flupenthixol reduced sign-tracking in nicotine rats at all doses tested; however, only the highest dose of flupenthixol reduced goal tracking in both nicotine and saline groups. The reductions in conditioned approach behavior, especially those by SCH-23390, were dissociated from simple motor suppressant effects of the antagonists. These experiments are the first to investigate the effects of dopaminergic drugs on the facilitation of sign-tracking engendered by nicotine and they implicate dopaminergic systems both in conditioned approach as well as the incentive-promoting effects of nicotine.

Simultaneous determination of L-tetrahydropalmatine and cocaine in human plasma by simple UPLC-FLD method: application in clinical studies.

Currently, there are no FDA approved medications for treatment of cocaine addiction underscoring the dire need to develop such a product. There is an accumulating body of evidence that l-tetrahydropalmatine (l-THP), a non-selective dopamine antagonist, can be used for the treatment of cocaine addiction. Indeed, the FDA recently approved its usage in a Phase I study in cocaine abusers and it was indispensable to develop a simple and sensitive method for the simultaneous determination of l-THP and cocaine in human plasma. We developed a UPLC-FLD method for quantitation of these molecules using an ACQUITY BEH C18 column (2.1 mm × 50mm, 1.7 μm) and a mobile phase that consisted of 10mM ammonium phosphate (pH=4.75), methanol, and acetonitrile (v:v:v, 78:16:6). Venlafaxine was used as the internal standard while hexane was used for the liquid-liquid extraction. The flow rate was 0.4 mL/min with fluorescence detection using an excitation wavelength of 230 nm and emission detection wavelength of 315 nm. This method was selective, linear and sensitive with a lower limit of quantification of 2.5 ng/mL for both cocaine and l-THP. The intra-day precision of cocaine and l-THP was <9.50% while the accuracy was <4.29%. The inter-day precision of cocaine and l-THP was <9.14%, and the accuracy was <12.49%. The recovery for cocaine and l-THP ranged from 43.95 to 50.02% and 54.65 to 58.31%, respectively. In comparison to forty reported cocaine quantitation methods this method is simple, sensitive and cost-effective and can be used for simultaneous quantitation of l-THP and cocaine. This method meets the FDA guidelines and can be used in current and future clinical studies.

The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats

The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats

Accelerated habit formation following amphetamine exposure is reversed by D1, but enhanced by D2, receptor antagonists

Repeated exposure to the psychostimulant amphetamine has been shown to disrupt goal-directed instrumental actions and promote the early and abnormal development of goal-insensitive habitual responding (Nelson and Killcross, 2006). To investigate the neuropharmacological specificity of this effect as well as restore goal-directed responding in animals with pre-training amphetamine exposure, animals were treated with the non-selective dopamine antagonist α-flupenthixol, the selective D1 antagonist SCH 23390 or the selective D2 antagonist eticlopride, prior to instrumental training (three sessions). Subsequently, the reinforcer was paired with LiCL-induced gastric-malaise and animals were given a test of goal-sensitivity both in extinction and reacquisition. The effect of these dopaminergic antagonists on the sensitivity of lever press performance to outcome devaluation was assessed in animals with pre-training exposure to amphetamine (Experiments 1A–C) or in non-sensitized animals (Experiment 2). Both α-flupenthixol and SCH23390 reversed accelerated habit formation following amphetamine sensitization. However, eticlopride appeared to enhance this effect and render instrumental performance compulsive as these animals were unable to inhibit responding both in extinction and reacquisition, even though a consumption test confirmed they had acquired an aversion to the reinforcer. These findings demonstrate that amphetamine induced-disruption of goal-directed behavior is mediated by activity at distinct dopamine receptor subtypes and may represent a putative model of the neurochemical processes involved in the loss of voluntary control over behavior.

Dopamine antagonism inhibits anorectic behavior in an animal model for anorexia nervosa

Excessive physical activity is commonly described as symptom of Anorexia Nervosa (AN). Activity-based anorexia (ABA) is considered an animal model for AN. The ABA model mimics severe body weight loss and increased physical activity. Suppression of hyperactivity by olanzapine in anorectic patients as well as in ABA rats suggested a role of dopamine and/or serotonin in this trait. Here, we investigated the effect of a non-selective dopamine antagonist in the ABA model. A dose–response curve of chronic treatment with the non-selective dopaminergic antagonist cis-flupenthixol was determined in the ABA model. Treatment reduced activity levels in both ad libitum fed and food-restricted rats. Treated ABA rats reduced body weight loss and increased food intake. These data support a role for dopamine in anorexia associated hyperactivity. Interestingly, in contrast to leptin treatment, food-anticipatory activity still persists in treated ABA rats.

Enhanced apomorphine sensitivity and increased binding of dopamine D2 receptors in nucleus accumbens in prepubertal rats after neonatal blockade of the dopamine D3 receptors by (+)‐S14297

The role of dopamine (DA) D3 receptors is controversial in early developmental stages of specially locomotor activity. Past studies have only tested behavioral changes induced by neonatal administration of nonselective dopamine antagonist such as haloperidol or sulpiride in adult rats. We investigated the role of neonatal blockade of DA D3 receptors at (postnatal day, P1 to P12) using the DA D3 receptor antagonist (+)-S14297 on paradigms related to DA behaviors including locomotor activity in novel environment and after administration of the DA nonspecific agonists d-amphetamine, and apomorphine. Additionally, autoradiographic studies were performed to correlate behavioral alterations with DA D1-like, D2-like, and D3 receptors. All studies were performed at two critical ages, prepubertal (P35) and postpubertal (P60). The quantitative autoradiogaphic study revealed increases in the expression of DA D2-like receptor expression in the nucleus accumbens (NAcc) in prepubertal animals that received the DA D3 antagonist (+)-S14297 at neonatal age. In addition, novel environment and apomorphine administration (0.5 mg/kg, s.c.), induced increases of locomotor activity in prepubertal animals that received the DA D3 antagonist (+)-S14297. Autoradiographic and behavioral results suggest that blockade of DA D3 receptors after birth may mediate different neurodevelopmental aspects of the dopaminergic pathway before and after puberty.

Evaluation of the effects of the herbal product Catuama® in inflammatory and neuropathic models of nociception in rats

Here we evaluated the antinociceptive effects of the herbal drug Catuama in rat inflammatory and neuropathic models of pain, in order to assess some of the mechanisms involved in its actions. Catuama given orally, in both acute and chronic schedules of treatment, consistently inhibited the mechanical allodynia induced by the intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). The same treatment with Catuama failed to significantly affect CFA-caused thermal hyperalgesia. In addition, Catuama did not significantly modify the mechanical allodynia or hyperalgesia observed following the partial ligation of the sciatic nerve or the diabetic polyneuropathy, respectively. In another series of experiments, Catuama caused a striking reduction of the mechanical allodynia induced by LPS. Oral treatment with Catuama was not, however, effective in altering the production of the pro-inflammatory mediators IL-1beta, TNFalpha, PGE(2) or LTB(4) following i.pl. administration of LPS in the rat paw. Of high interest, the antinociceptive effects of Catuama in the LPS model were reversed significantly by the non-selective dopamine antagonist haloperidol, but not by serotonin methysergide or adrenergic yohimbine receptor antagonists. Our results indicate that the herbal drug Catuama diminishes inflammatory, but not neuropathic, nociceptive responses in rats, by mechanisms involving an interference with dopaminergic pathways. Catuama might represent a potential therapeutic tool for the management of persistent inflammatory pain.

Behavioral, neuroendocrine and thermoregulatory actions of apelin-13

As the distribution of apelinergic neurons in the brain suggests an important role of apelin-13 in the regulation of neuroendocrine processes, in the present experiments the effects of this recently identified neuropeptide on the open-field activity, the hypothalamo–pituitary–adrenal (HPA) system and the body temperature were investigated. I.c.v. administration of apelin-13 (1–10 μg) to rats caused significant increases in square crossing, rearing, plasma corticosterone release and core temperature, whereas it did not influence the spontaneous motor activity during telemetric observation. To determine the mediation of the actions of apelin, a corticotropin-releasing hormone (CRH) antagonist, the nonselective dopamine antagonist haloperidol, the selective dopamine D1 receptor antagonist SCH-23390 and the nitric oxide synthase inhibitor Nω-nitro- l-arginine-methyl ester ( l-NAME) were administered to the rats. The apelin-evoked HPA activation was diminished by preadministration of the CRH antagonist, while the dopamine antagonist and l-NAME attenuated only the square crossing and rearing induced by apelin-13. To characterize the transmission of the thermoregulatory action of apelin, animals were pretreated either with l-NAME, the CRH antagonist or with the cyclooxygenase inhibitor noraminophenazone. l-NAME and the CRH antagonist did not cause significant inhibition of the apelin-evoked increase in core temperature, while the cyclooxygenase inhibitor, applied 30 min before peptide treatment, did not prove effective in preventing the apelin-evoked thermoregulatory response, whereas when it was administered 2 h after the peptide treatment, it transiently and significantly reduced the hyperthermic response. The present data suggest that apelin-13 plays an important role in the regulation of behavioral, endocrine and homeostatic responses in the CNS, and dopamine, nitric oxide and prostaglandins seem to take part in the mediation of its effects. Since the corticosterone response could be blocked by the CRH antagonist, it is likely to be mediated through the activation of the CRH neurons.

Changes in dopaminergic neurotransmission do not alter somatic or motivational opiate withdrawal-induced symptoms in rats.

Opiate withdrawal has been correlated with decreased extracellular dopamine (DA) levels in the nucleus accumbens (NAC) of morphine-dependent rats. The authors tested the hypothesis that DA transmission plays a critical role in the induction of motivational and somatic withdrawal symptoms. First, the authors used a 6-hydroxydopamine-induced lesion of the NAC to chronically disrupt mesolimbic DA transmission. Second, global DA neurotransmission was acutely stimulated by the nonselective DA agonist (apomorphine) or inhibited by nonselective DA antagonists (droperidol or flupentixol). Morphine-dependent rats bearing 6-hydroxydopamine-induced lesions displayed naloxone-precipitated motivational and somatic withdrawal symptoms similar to those of sham-lesioned rats. Administration of apomorphine did not reduce naloxone-induced opiate withdrawal. Moreover, in total absence of naloxone, DA antagonists did not precipitate either conditioned place aversion or somatic abstinence signs in dependent rats. Taken together, these findings suggested that DA transmission is not critical for the induction of opiate withdrawal syndrome.

Reinforcing effects of methamphetamine in planarians.

Reinforcing properties of dopamine agonist, methamphetamine, for planarians were examined with the conditioned place preference (CPP) procedure. The planarians showed preference for the environment associated with methamphetamine administration. This reinforcing effect was antagonized by pretreatment with non-selective dopamine antagonist, haloperidol. Both selective D1 antagonist SCH23390 and selective D2 antagonist sulpiride also blocked the reinforcing effect of methamphetamine. These results suggest that reinforcing effects of dopaminergic drugs can be traced back to invertebrates such as planarians.

The involvement of dopamine in nociception: the role of D 1 and D 2 receptors in the dorsolateral striatum

Determination of the neuroanatomical and neurochemical factors that contribute to nociception is an essential element in the study and treatment of pain. Several lines of evidence have implicated nuclei and neurotransmitters within the basal ganglia in nociception. For example, previous studies have shown that dopamine receptors in the striatum are involved in acute nociception, however, it remains to be determined if dopamine receptors in the dorsolateral striatum are involved in persistent nociception. The purpose of the present study was therefore to determine whether activation or antagonism of dopamine receptors in the dorsolateral striatum influences the nociceptive responses of rats in the formalin test, a model of persistent pain. It was found that micro-injection of the non-selective dopamine antagonist haloperidol into the dorsolateral striatum increases formalin-induced nociception whereas injection of the non-selective dopamine agonist apomorphine reduces formalin-induced nociception. Injection of the D 1 antagonist SCH23390 or the D 1 agonist SKF38393 does not affect formalin-induced nociception. In contrast, injection of the D 2 antagonist eticlopride enhances formalin-induced nociception, whereas injection of the D 2 agonist quinpirole reduces formalin-induced nociception. These results provide additional evidence that dopamine receptors in the striatum are involved in nociception. Furthermore, this study strongly suggests that D 2, but not D 1, dopamine receptors in the dorsolateral striatum are involved in modulation of persistent nociception.

Constitutive activity of a chimeric D2/D1 dopamine receptor.

Chimeric D1/D2 receptors were constructed to identify structural determinants of drug affinity and efficacy. We previously reported that chimeras that had D1 receptor transmembrane domain VII together with amino-terminal sequence from the D2 receptor were nonfunctional. D2/D1 chimeras were constructed that contained D2 receptor sequence at the amino- and carboxyl-terminal ends and D1 receptor sequence in the intervening region. Chimeric receptors with D2 sequence from transmembrane domain 7 to the carboxyl terminus together with D2 receptor sequence from the amino terminus through transmembrane helix 4 (D2[1-4,7]) and 5 (D2[1-5,7]) bound [3H]spiperone with high affinity, consistent with the hypothesis that D2 receptor transmembrane domain I or II is incompatible with D1 receptor transmembrane domain VII. D2[1-4,7] and D2[1-5,7] had affinities similar to D1 and D2 receptors for most nonselective dopamine antagonists and had affinities for most of the selective antagonists that were intermediate between those of the parent receptors. D2[1-4,7] and D2[1-5,7] mediated dopamine receptor agonist-induced stimulation and inhibition, respectively, of cAMP accumulation. The more efficient coupling of D2[1-5,7] to inhibition of cAMP accumulation, compared with the coupling of D2[5-7] and D2[3-7], supports the view that multiple D2 receptor cytoplasmic domains acting in concert are necessary for receptor activation of Gi. In contrast, D2[1-4,7], which contains only one cytoplasmic loop (the third) from the D1 receptor, is capable of activating Gs. D2[1-4,7] exhibited several characteristics of a constitutively active receptor, including enhanced basal (unliganded) stimulation of cAMP accumulation, high affinity for agonists even in the presence of GTP, and blunted agonist-stimulated cAMP accumulation. A number of dopamine receptor antagonists were inverse agonists at D2[1-4,7], inhibiting basal cAMP accumulation. Some of these drugs were also inverse agonists at the D1 receptor. Interestingly, several antagonists also potentiated forskolin-stimulated cAMP accumulation via D2[1-5,7] and via the D2 receptor, which could reflect inverse agonist inhibition of native constitutive activity of this receptor.

Dopamine-independent and adenosine-dependent mechanisms involved in the effects of N-methyl- d-aspartate on motor activity in mice

The involvement of dopamine and adenosine mechanisms in the motor effects of systemically administered N-methyl- d-aspartate (NMDA) was studied in non-reserpinized and in reserpinized mice. In non-reserpinized mice NMDA induced motor depression (with 8, 25 and 75 mg/kg i.p.) during the first hour and motor activation (with 25 and 75 mg/kg i.p.) during the second hour after its administration. The non-selective adenosine antagonist, theophylline (3, 10 and 30 mg/kg i.p.), induced motor activation during both 1-h periods of observation. NMDA-induced motor depression in non-reserpinized mice was antagonized by theophylline. Higher doses of theophylline were needed to counteract the motor depressant effect induced by higher doses of NMDA. The motor activation induced by NMDA and theophylline in non-reserpinized mice was not additive and theophylline did not enhance the motor activation induced by high doses of NMDA. Both NMDA (25 and 75 mg/kg i.p.) and theophylline (10 and 30 mg/kg) induced motor activation in reserpinized mice and, when coadministered, NMDA counteracted the effect of theophylline. NMDA (8 and 25 mg/kg i.p.) antagonized and theophylline (3, 10 and 30 mg/kg i.p.) potentiated the motor activation induced by the non-selective dopamine agonist, apomorphine (0.1 mg/kg s.c.), in reserpinized mice. In reserpinized mice, the non-selective dopamine antagonist, haloperidol (0.5 mg/kg s.c.), antagonized the motor activation induced by apomorphine (0.1 mg/kg s.c.) and that induced by theophylline (10 mg/kg i.p.) and did not modify NMDA-induced motor activation. The present results suggest the existence of two different mechanisms in the elicitation of motor activity: a dopamine-independent NMDA-mediated mechanism, which is not modulated by adenosine, and a dopamine-dependent adenosine-modulated mechanism. NMDA-induced adenosine release might provide a connection between both mechanisms.

DA1 receptor-mediated renin release from isolated rat glomeruli.

The present study was performed in order to examine the effects of dopamine (DA) on renin release and to clarify which subtype of DA receptor, DA1 or DA2 contributes to renin release. Male Wistar rats aged seven weeks were used. Glomeruli were isolated by the modified Beierwaltes' sieving method and were transferred to a sealed chamber and superfused with Krebs-Ringer solution. In the first experiment, the changes in renin release induced by DA and the effects of a non-selective DA antagonist, haloperidol and a beta antagonist, propranolol on DA-induced renin release were examined. In the second experiment, the effect of a DA2 receptors antagonist, spiperone and of a DA1 receptor antagonist, SCH-23390 on renin release were investigated. Basal levels of renin release were 2.46 +/- 0.36 ng ATI/h/10(4) glomeruli (mean +/- SEM). DA caused a dose-dependent increase in renin release. The renin release induced by DA was inhibited by haloperidol but not by propranolol. The maximum level of renin release induced by 10(-5)M DA was 4.13 +/- 0.63 ng ATI/h/10(4) glomeruli. SCH-23390 at 10(-5)M caused significant suppression of DA-induced renin (p < 0.05). In contrast, 10(-5)M spiperone failed to suppress DA-induced renin release. These results suggest that DA induced renin release from isolated glomeruli through the DA1 receptors.

The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task.

1. To examine the role of dopamine receptors in the prefrontal cortex (PFC) on working memory, we injected dopamine antagonists (SCH23390, SCH39166, haloperidol, sulpiride, and raclopride) locally into the dorsolateral PFC in two monkeys trained to perform an oculomotor delayed-response (ODR) task. In the ODR task, monkeys fixate a central spot on a cathode ray tube (CRT) monitor while a visual cue is briefly (300 ms) presented in one of several peripheral locations in the visual field. After a delay of 1.5-6 s, the fixation spot is turned off, instructing the monkey to move its eyes to the target location that had been indicated by the visuospatial cue before the delay. Each monkey also performed a control task in which the cue remained on during the delay period. In this task the monkey's response was sensory rather than memory guided. 2. Local intracerebral injection of the selective dopamine antagonists SCH23390 (10-80 micrograms) and SCH39166 (1-5 micrograms) and/or the nonselective dopamine antagonist haloperidol (10-100 micrograms) induced deficits in ODR task performance at a total of 22 sites in the dorsolateral PFC. The deficit was characterized by a decrease in the accuracy of the memory-guided saccade as well as an increase in the latency of the response. The deficit usually appeared within 1-3 min after the injection, reached a peak at 20-40 min, and recovered at 60-90 min. 3. Performance change was restricted to a few specific target locations, which varied with the injection site and were most often contralateral to the injection site. 4. The degree of impairment in the ODR task occasioned by the injection of the dopamine antagonists was sensitive to the duration of delay; longer delays were associated with larger decreases in the accuracy and delayed onset of the memory-guided saccade. 5. The deficit was dose dependent; higher doses induced larger errors and increases in the onset of the memory-guided saccade. 6. Dopamine antagonists did not affect performance on the control task, which required the same eye movements but was sensory guided. Thus, in the same experimental session in which ODR performance was impaired, the accuracy and the latency of the sensory-guided saccades were normal for every target location.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiovascular responses to intrathecal dopamine receptor agonists after spinal transection in conscious rats.

The cardiovascular responses to transient intrathecal administration of dopamine agonists were studied daily in chronically prepared rats that had been spinally transected or were sham operated. The goals were (1) to determine the group differences in evoked heart rate and arterial pressure responses and (2) to determine, within the transected group, whether or not the long term responses could be dissociated. The hypothesis tested is that cord transection releases a tonic inhibition of cardiovascular responsiveness independently of the mechanism of receptor hypersensitivity. Changes in mean aortic blood pressure and heart rate induced by intrathecal administration of the mixed D1/D2 dopamine receptor agonist apomorphine (150 nmol per rat) were measured in conscious rats during a 10 d experimental period following spinal transection. Complete spinal transection did not affect aortic pressure but increased basal heart rate values by about 33% with respect to normal rats (p < 0.001). When apomorphine was injected caudally to the section (at T9-T10) but not rostrally (at T2-T4), it induced a 50% greater and an 800% more long lasting decrease in mean aortic pressure and a 230% greater and 70% more long lasting decrease in heart rate in spinal than in sham operated rats. These increases in cardiovascular responses were corroborated by a leftward shift of the apomorphine dose-response curves. They were also found after intrathecal administration of highly selective D1 and D2 receptor agonists fenoldopam (50 nmol per rat) and quinpirole (150 nmol per rat), and were specifically blocked by intrathecal haloperidol (27 nmol per rat), a non-selective dopamine antagonist. Complete spinal transection induces different increases in hypotensive and bradycardic responses to the stimulation of caudally located spinal dopamine receptors which could be due to the destruction of a tonically inhibiting spinal system rather than to hypersensitivity of the dopamine receptors.

Dopaminergic regulation of dopamine release from PC12 cells via a pertussis toxin-sensitive G protein

Regulation of dopamine (DA) release from PC12 cells was investigated. Apomorphine and quinpirole, a selective D 2 agonist, significantly reduced K +-evoked DA release, and this reduction was reversed by haloperidol. Furthermore, spiroperidol, a selective D 2 antagonist, and haloperidol, a nonselective DA antagonist, enhanced the K +-evoked DA release. Pertussis toxin treatment of the cells abolished the quinpirole-induced reduction of K +-evoked DA release. Also, the haloperidol-induced enhancement of K +-evoked DA release was not seen in pertussis toxin treated cells. These results, therefore, suggest the presence of D 2 receptors on PC12 cells which result in the modulation of K +-evoked DA release via a pertussis toxin-sensitive G protein.

Effects of dopamine antagonists on neuronal activity related to a delayed response task in monkey prefrontal cortex

1. Using iontophoretic techniques, we investigated the influence of dopamine (DA) antagonists [haloperidol (HAL), a non-selective DA antagonist; sulpiride (SUL), a selective antagonist for D2 receptors; and fluphenazine (FLU), a potent antagonist for D1 receptors] on neuronal activity related to a delayed response (DR) task in the monkey prefrontal cortex (PFC). The DR task was initiated by the rotation of a handle to a central zone and consisted of seven distinct periods: an initial intertrial interval of 0.3 s, a precue period of 1 s (a center green lamp), a cue period of 1 s (left or right lamp), a delay period of 4 s, a go period (red lamp in the center; rotation of the handle to either the left or right zone), a hold period (holding of the handle in either the left or right zone), and a final reward period. Because it was shown, as described in the companion paper (Sawaguchi et al. 1990), that DA augments the increased activity of prefrontal neurons related to the cue, delay, and go periods of the DR task, effects of the DA antagonists were examined in a total of 61 neurons that showed increases in activity related to these periods and a response to DA. 2. Consistent with previous studies (Sawaguchi et al. 1988a, 1990), iontophoretically applied DA increased DR task-related activity in prefrontal neurons. Iontophoretically applied HAL and FLU antagonized the increased effect of DA on the task-related activity. By contrast, SUL did not have any clear effects on the influence of DA. 3. By themselves, HAL and FLU reduced prefrontal neuronal activity related to the cue, delay, and go periods of the DR task. The ratio of the reduction by HAL and FLU was significantly larger for activity during the cue, delay, or go period than for background activity during the precue period; and, as a result, the signal-to-noise (S/N) ratio of the task-related activity to background activity was reduced during the application of HAL and FLU. In contrast, SUL did not have any clear effects on activity related to the cue, delay, and go periods of the DR task, and the S/N ratio during the application of SUL did not significantly differ from that before the application of the drug.(ABSTRACT TRUNCATED AT 400 WORDS)

Apomorphine potentiates vagal bradycardia

The effects of apomorphine, a dopamine (DA) agonist, on vagal bradycardia were investigated in chloraloseanesthetized dogs. Negative chronotopic responses to vagal nerve stimulation were significantly potentiated by apomorphine (10, 20 or 200 μg/kg i.v.). Pretreatment with the non-selective DA antagonist, haloperidol, or the selective DA2 antagonist, domperidone (but not the selective DA1 antagonist, SCH 23390), antagonized the effect of apomorphine. These results demonstrate that apomorphine potentiates electrically induced vagal bradycardia by a specific action on DA2 receptors which could be located on vagal nerve endings.