Renal effects of exogenous dopamine: modulation by renal nerves and dopamine receptor antagonists

The modulation of the renal response to exogenous dopamine by renal denervation (DNX) and dopamine receptor antagonists was investigated in thiopental-anesthetized Sprague-Dawley rats. Experiments were performed after reaching stable systemic hemodynamics and urinary flow rate. These conditions were obtained with an infusion rate of approximately 1.2% of body weight per hour. In the vehicle group (VHC) i.v. infusion of dopamine (1, 3 and 9 μg kg^–1 min^–1) significantly increased glomerular filtration rate (GFR), assessed by renal clearance of [³H]inulin, by 14±1.5, 16±1.6 and 31±2.6%, respectively. Infusion of 1 and 3 μg kg^–1 min^–1 dopamine did not change systemic hemodynamics while the highest dose elevated heart rate, potentially contributing to the GFR increase. The specific D₁ receptor antagonist SCH 23390 (10 μg kg^–1 min^–1 i.v.) did not affect the GFR response to dopamine infusion. In contrast, domperidone (DOM; 8 μg kg^–1 min^–1 i.v.), a specific, peripherally acting D₂ antagonist, attenuated the glomerular hyperfiltration induced by the three doses of dopamine to 11±1.7, 13±2.2 and 16±2.6%, respectively. DNX diminished the GFR response to dopamine infusion to almost the same extent (11±2.8, 10±2.2 and 17±2.6%, respectively) as did DOM. When DNX animals were treated with DOM, the GFR responses to dopamine were further attenuated to non-significant increases. These additive effects of DOM and DNX suggest that two different mechanisms are involved. Both DNX and SCH 23390 decreased sodium excretion at baseline whereas DOM enhanced it. Under the present experimental condition, neither D₁ nor D₂ receptor blockade affected the natriuretic and diuretic response to dopamine. Whereas D₁ receptors do not appear to be involved, both D₂ receptors and renal nerves play a role in the renal hemodynamic response to dopamine, indicating involvement of both pre- and postsynaptical dopamine receptors. Received: 19 September 1997 / Accepted: 7 July 1998     

Potency mismatch for behavioral and biochemical effects by dopamine receptor antagonists: implications for the mechanism of action of clozapine

Clozapine (3.8–60.0 µmol kg^?1) did not produce any alterations in DOPA accumulation (following inhibition of cerebral aromaticl-amino acid decarboxylase) in the prefrontal cortex or in three regions of the neostriatum, i.e. the ventral, the dorso-lateral and the posterior regions, in the rat. In contrast, clozapine produced a reduction in the 5-HTP accumulation in all these brain areas, except for the prefrontal cortex. Raclopride (0.08–20.0 µmol kg^?1) produced a marked increase in DOPA accumulation in all four brain regions and an increase in 5-HTP accumulation in the dorso-lateral neostriatum (2.5–20.0 µmol kg^?1), but not in the other forebrain regions. Treatment with SCH-23390 (0.4–1.6 µmol kg^?1) resulted in increased DOPA accumulation in the ventral and posterior parts of the neostriatum. No other changes in the DOPA or 5-HTP accumulation were seen with SCH-23390. Considering the doses of these three compounds needed for suppression of conditioned avoidance behavior and for the induction of cataleptic rigidity, it is concluded that raclopride produces an increased DA synthesis at much lower doses than those needed for behavioral effects. In contrast, the behavioral effects of SCH-23390 or clozapine precedes effects on brain DA synthesis on the dose-effect curve. In fact, the only biochemical effect of clozapine, which was observed in low, yet behaviorally active doses, was a decrease in forebrain 5-HTP accumulation. In conclusion, the present results demonstrate a mismatch, in different directions for raclopride and SCH-23390, as regards the doses needed to produce effects on brain dopamine synthesis and on behavior. Thus, the biochemical effects are seen with lower doses than the behavioral effects for the DA D₂ receptor blocking agent, whereas the opposite relationship is the case for the DA D₁ receptor antagonist. Taking these two DA receptor subtypes into consideration, the possibility should be considered that clozapine produces its antipsychotic-like behavioral effects on animal behavior primarily by a blockade of brain DA D₁, rather than D₂, receptors.     

Differential contributions of dopaminergic D1- and D2-like receptors to cognitive function in rhesus monkeys

Rationale Dopaminergic neurotransmission is critically involved in many aspects of complex behavior and cognition beyond reward/reinforcement and motor function. Mental and behavioral disorders associated with major disruptions of dopamine neurotransmission, including schizophrenia, attention deficit/hyperactivity disorder, Parkinson’s disease, Huntington’s disease, and substance abuse produce constellations of neuropsychological deficits in learning, memory, and attention in addition to other defining symptoms.Objective To delineate the role dopaminergic D₁- and D₂-like receptor subtypes play in complex brain functions.Materials and methods Monkeys (N=6) were trained on cognitive tests adapted from a human neuropsychological assessment battery (CAmbridge Neuropsychological Test Automated Battery). The battery included tests of spatial working memory (self-ordered spatial search task), visuo-spatial associative memory and learning (visuo-spatial paired associates learning task, vsPAL) and motivation (progressive ratio task, PR). Tests of motor function (bimanual motor skill task, BMS; rotating turntable task, RTT) were also included. The effects of the dopamine D₂-like antagonist raclopride (10–56 μg/kg, i.m.) and the D₁-like antagonist SCH23390 (SCH, 3.2–56 μg/kg, i.m.) on cognitive performance were then determined.Results Deficits on PR, RTT, and BMS performance were observed after both raclopride and SCH23390. Spatial working memory accuracy was reduced to a greater extent by raclopride than by SCH, which was unexpected, given prior reports on the involvement of D₁ signaling for spatial working memory in monkeys. Deficits were observed on vsPAL performance after raclopride, but not after SCH23390.Conclusions The intriguing results suggest a greater contribution of D₂- over D₁-like receptors to both spatial working memory and object–location associative memory.     

The discriminative stimulus effects of methamphetamine in pigeons

This experiment was designed to elucidate the neurotransmitter systems that mediate the discriminative stimulus effects of methamphetamine. Four pigeons were trained to peck one key following saline injections and a second key following methamphetamine injections (1.0 or 1.7 mg/kg, IM). Substitution tests revealed drug-appropriate responding following administration of the psychomotor stimulants methamphetamine, amphetamine and cocaine, the dopamine (DA) reuptake inhibitor bupropion, norepinephrine (NE) reuptake inhibitors imipramine and tomoxetine, and the serotonin (5-HT) releaser fenfluramine. Salinekey responding occurred following administration of the D₁ agonist SKF-38393, the D₁ antagonist SCH-23390, the α₂ receptor agonist clonidine, the α₁ antagonist prazosin, a nonselective β-antagonist propranolol and the selective 5-HT reuptake inhibitor fluoxetine. The D₂/D₃ agonist quinpirole produced drug-appropriate responding in two pigeons and partial substitution in the remaining two pigeons. The 5HT_1A agonist 8-OH-DPAT produced drug-appropriate responding at higher doses (0.3–1.0 mg/kg), whereas much lower doses (0.003–0.1 mg/kg) antagonized the methamphetamine stimulus. The stimulus effects of methamphetamine were attenuated by pretreatment with prazosin, SCH-23390 and eticlopride, whereas pretreatment with propranolol and the 5-HT₃ antagonist, MDL 72222, failed reliably to attenuate drug key responding. These results suggest that NE and DA reuptake inhibition and 5-HT release mediate the discriminative stimulus effects of methamphetamine as do the 5-HT_1A and DA D₁ and D₂ receptors.     

Microcatalepsy and disruption of forelimb usage during operant behavior: differences between dopamine D1 (SCH-23390) and D2 (raclopride) antagonists

In an experiment designed to distinguish between the behavioral consequences of treatment with SCH-23390, a D₁ dopamine receptor blocker, and raclopride, a D₂ antagonist, rats were trained to perform a water-reinforced forelimb operant response. Response rate and the duration of each forelimb contact with the operandum were recorded. In addition, the durations of the rat's visits to the reward well were detected by a photobeam which was blocked by the rat's muzzle as it remained at the reward well. In a between-groups dosing design, separate groups of rats (11–13 rats/group) received SCH-23390 (0, 0.01, 0.02, 0.04, 0.08, 0.12 mg/kg, IP, 30 min) or raclopride (0. 0.05, 0.1, 0.2, 0.4, 0.8 mg/kg, IP, 30 min) for 21 consecutive days. Quantitative analyses indicated that for comparable amounts of operant rate reduction, raclopride had a significantly greater tendency than SCH-23390 to increase the duration of operant responses and to increase the maximum muzzle entry duration (i.e., to induce microcatalepsy). The results support the idea that at relatively low doses D₂ antagonism is more likely than D₁ antagonism to produce effects identified preclinically with extrapyramidal side effects.     

Pharmacological Profile of the Vascular Responses to Dopamine in the Canine External Carotid Circulation*

Abstract: The present study investigated the effects of dopamine on the canine external carotid circulation. One min. intracarotid artery (i.c.) infusions of dopamine (10–310 μg min.^?1) produced dose‐dependent decreases in the canine external carotid conductance without affecting blood pressure or heart rate. This effect was mimicked by the D_1/2‐like receptor agonist apomorphine (1–310 μg min^?1), but not by the D₂‐like receptor agonist, bromocriptine (31–310 μg min.^?1). In contrast, fenoldopam (1–310 μg min.^?1, intracarotid), a D₁‐like receptor agonist, produced dose‐dependent increases in external carotid conductance. The vasoconstrictor response to dopamine was abolished after intravenous administration of the antagonists, phentolamine (α_1/2; 2000 μg kg^?1) or rauwolscine (α₂; 100 μg kg^?1), but remained unaffected after prazosin (α₁; 100 μg kg^?1) or haloperidol (D₂‐like; 1000 μg kg^?1). Interestingly, after phentolamine not only were the vasoconstrictor responses to dopamine abolished, but even a dose‐dependent vasodilator component was unmasked. These vasodilator responses to dopamine remained unchanged after intravenous haloperidol or propranolol (1000 μg kg^?1 each). On the other hand, the vasodilator responses to fenoldopam, which remained unchanged after intravenous saline (0.1 ml kg^?1), propranolol (1000 μg kg^?1) or vagosympathectomy, were abolished by the D₁‐like receptor antagonist, SCH‐23390 (10 μg kg^?1). Lastly, the responses to dopamine and fenoldopam were not significantly altered after intraperitoneal pretreatment with reserpine (5 mg kg^?1; ?24 hr). The above results suggest that the canine external carotid vasoconstrictor responses to dopamine: (i) are mainly mediated by α₂‐adrenoceptors; and (ii) overshadow a vasodilator component, which involves vascular D₁‐like receptors.     

Lack of evidence for an involvement of nucleus accumbens dopamine D1 receptors in the initiation of heroin self-administration in the rat

The involvement of dopamine D₁ receptor systems in the reinforcing properties of opiate reward was studied by examining the effect of the dopamine D₁ antagonist SCH23390 on the initiation of heroin self-administration in rats. The D₁ antagonist was administered daily systemically or locally in the nucleus accumbens (NAC), after which the animals were allowed to self-administer heroin (IV) in a 3-h session for 5 consecutive days. Systemic treatment with SCH23390 (0.17 and 0.5 mg.kg^–1) significantly decreased heroin intake during initiation of heroin self-administration, while a dose of 0.06 mg.kg^–1 was not effective. Local administration of SCH23390 (0.5 and 2.5 µg/site) in the NAC did not affect heroin intake. Both systemic and intra-accumbal administration of SCH23390 dose dependently decreased motor behavior measured in a small open field. The attenuation of heroin intake during initiation of heroin self-administration by blockade of dopamine D₁ receptor systems may be due to a decrease in the reinforcing effects of heroin or more likely to a reduction in non-reinforcement-related behavior. The dopamine D₁ receptors present in the NAC are probably not involved in opiate reward.     

Dopamine antagonist effects on locomotor activity in naive and ethanol-treated FAST and SLOW selected lines of mice

The FAST and SLOW lines of mice are being selectively bred in replicate for differential sensitivities to the locomotor activating effects of ethanol. Whereas FAST-1 and FAST-2 mice are stimulated by 2.0 g/kg ethanol, SLOW-1 and SLOW-2 mice are not stimulated, and are often depressed, by this dose. The dopamine antagonists, SCH-23390 (D₁) and raclopride (D₂), produced dose-dependent decreases in the locomotor activity of EtOH-naive mice of both lines and replicates; however, FAST and SLOW mice were not differentially sensitive to these effects. The absence of a line difference in activity response to the dopamine antagonists suggests that dopamine receptor function has not been altered by selective breeding for differences in sensitivity to the stimulant effects of ethanol. The ethanol-stimulated activity of FAST-1 and FAST-2 mice was decreased by administration of the dopamine antagonists, haloperidol and raclopride, at doses that had no effect on basal locomotor activity. SCH-23390 decreased ethanol-stimulated activity of FAST-1, but not FAST-2 mice. The ethanol-induced activity changes of SLOW mice were generally unaffected by antagonist administration. These results suggest a role for dopaminergic systems in mediating ethanol-stimulated activity in selectively bred FAST mice. Coadministration of SCH-23390 and raclopride decreased ethanol-induced activation to a greater degree than either drug alone, further suggesting that both D₁ and D₂ receptor systems contribute to the full expression of the ethanol stimulant response.This work was supported by the Department of Veterans Affairs, by NIAAA grants AA06498 and AA08621 (J.C.C. and T.J.P.), and by an N. L. Tartar Research Fellowship from the Medical Research Foundation of Oregon (E.H.S.). A portion of this work was completed in partial fulfillment of the requirements for Master of Science degree, Department of Medical Psychology, Oregon Health Sciences University (E.H.S.).     

Chronic treatment with the D1 receptor antagonist,SCH 23390, and the D2 receptor antagonist,raclopride, in cebus monkeys withdrawn from previous haloperidol treatment

The effects of chronic treatment with dopamine (DA) D₁ and D₂ receptor antagonists were evaluated in eightcebus apella monkeys with mild oral dyskinesia after previous haloperidol treatment. SCH 23390 (D₁ antagonist) was given daily to investigate the direct behavioural effect during long-term treatment and the subsequent supersensitivity to DA agonists. Raclopride (D₂ antagonist) was investigated for comparison. All drugs were given subcutaneously. SCH 23390 and raclopride induced dystonic syndromes, catalepsy, sedation and reduced locomotor activity. The monkeys developed marked tolerance to the dystonic effect of SCH 23390, while they showed increased sensibility to the dystonic effect of raclopride. Baseline oral dyskinesia (24 h after injection) remained unchanged during D₁ antagonist treatment, while it increased during D₂ antagonist treatment. SCH 23390 induced supersensitivity to the oral dyskinesia- and grooming-inducing effects of SKF 81297 (D₁ agonist) after 9 weeks, while the subsequent treatment with raclopride induced supersensitivity to the reactivity- and stereotypy-inducing effects of quinpirole (D₂ receptor agonist) after 3 weeks. Because of the possibility of a carry-over effect (SKF 81297-induced oral hyperkinesia and grooming), other changes in raclopride-induced behaviours cannot be ruled out. The development of tolerance to the dystonic effect of SCH 23390 and the unchanged baseline oral dyskinesia during SCH 23390 treatment indicate an advantageous profile of side effects of DA D₁ receptor blockade.     

Disprocynium24 induces a dopamine-independent, eukaliuric diuresis and natriuresis in the anaesthetized rat

In the anaesthetized rat, intravenous administration of the isocyanine 1,1′-diisopropyl-2,4′-cyanine (disprocynium24) at doses up to 600 μg/kg resulted in marked diuresis and natriuresis without affecting urinary potassium excretion. Fractional sodium excretion was increased over 10-fold indicating a high ceiling-diuretic action. The effects of disprocynium24 on renal function were accompanied by a dose-dependent reduction in heart rate (HR) and mean arterial blood pressure (MAP). Acute administration of 600 μg/kg disprocynium24 decreased MAP by 25% and, in addition, caused a fall in glomerular filtration rate (GFR). Since i) disprocynium24 has been shown to interfere with urinary dopamine excretion (U_DAV) and ii) dopamine has been implicated with the regulation of renal sodium excretion, we hypothesized that the effects of disprocynium24 might be mediated by its effects on renal dopamine handling. The following findings, however, argue against this hypothesis. First, administration of disprocynium24 in single doses up to 600 μg/kg caused a diuresis and natriuresis, but did not significantly affect U_DAV. Second, neither the systemic nor the renal response to disprocynium24 were markedly altered by pretreatment with the dopamine D₁- or D₂-receptor blockers SCH23390 (10 μg · kg^–1· min^–1) or S(-)sulpiride (15 μg · kg^–1· min^–1), respectively. Received: 25 August 1997 / Accepted: 23 September 1997     

The anti-influenza drug oseltamivir evokes hypothermia in mice through dopamine D2 receptor activation via central actions

Oseltamivir has a hypothermic effect in mice when injected intraperitoneally (i.p.) and intracerebroventricularly (i.c.v.). Here we show that the hypothermia evoked by i.c.v.-oseltamivir is inhibited by non-selective dopamine receptor antagonists (sulpiride and haloperidol) and the D₂-selective antagonist L-741,626, but not by D₁/D₅-selective and D₃-selective antagonists (SCH-23390 and SB-277011-A, respectively). The hypothermic effect of i.p.-administered oseltamivir was not inhibited by sulpiride, haloperidol, L-741,626 and SCH-23390. In addition, neither sulpiride, haloperidol nor SCH-23390 blocked hypothermia evoked by i.c.v.-administered oseltamivir carboxylate (a hydrolyzed metabolite of oseltamivir). These results suggest that oseltamivir in the brain induces hypothermia through activation of dopamine D₂ receptors.     

Striatal and nigral D1 mechanisms involved in the antiparkinsonian effects of SKF 82958 (APB): studies of tremulous jaw movements in rats

  Rationale: Previous work has demonstrated that cholinomimetic-induced tremulous jaw movements in rats have temporal and pharmacological characteristics similar to parkinsonian tremor. Objective: This rodent model was used to characterize the putative antiparkinsonian effects of the full D₁ dopamine receptor agonist, SKF 82958. Methods: Jaw movement activity was induced by the muscarine agonist pilocarpine (4.0 mg/kg IP), and a series of experiments studied the pharmacological characteristics of the reversal of pilocarpine-induced jaw movements by SKF 82958. Results: SKF 82958 (0.5–2.0 mg/kg IP) reduced the tremulous jaw movements induced by pilocarpine. The suppressive effects of SKF 82958 on jaw movements were dose-dependently reversed by systemic pretreatment with the selective D₁ dopamine receptor antagonist SCH 23390 (0.025–0.2 mg/kg IP); SCH 23390 was about 16 times more potent than the D₂ antagonist raclopride at reversing the effects of SKF 82958. Intracranial injection of SCH 23390 (0.5–2.0 μg/side) into the ventrolateral striatum, the rodent homologue of the human ventral putamen, dose-dependently reversed the reduction of pilocarpine-induced jaw movements produced by SKF 82958. Intracranial injection of SCH 23390 (0.5–2.0 μg/side) into the substantia nigra pars reticulata also dose-dependently reversed the reduction by SKF 82958 of pilocarpine-induced jaw movements. Injections of SCH 23390 (2.0 μg/side) into control sites dorsal to the striatum or substantia nigra had no effects on the action of SKF 82958. Intranigral (SNr) injections of the GABA-A antagonist bicuculline blocked the suppressive effect of systemically administered SKF 82958 on jaw movement activity. Conclusions: These data suggest that the antiparkinsonian actions of SKF 82958 may be due to stimulation of D₁ receptors in the ventrolateral striatum and substantia nigra pars reticulata. In addition, these results indicate that GABA mechanisms in the substantia nigra pars reticulata may be important for the antiparkinsonian effects of D₁ agonists. Received: 9 June 1998 / Final version: 10 October 1998     

Clozapine: Dopamine D1 Receptor Agonism in the Prefrontal Cortex as the Code to Decipher a Rosetta Stone of Antipsychotic Drugs

Abstract: A large number of ligand binding studies have shown that clozapine has a number of receptor affinities, including those of the dopamine (DA) D₁ and D₂ receptor families. The study of intrinsic efficacy at these receptors is less straightforward. In the experiments summarised here, evidence is presented that clozapine behaves as an agonist at DA D₁ receptors. Thus, the hypothermia produced by clozapine (2.5 mg kg^–1) in the rat is fully antagonised by either of the selective DA D₁ receptor antagonists SCH-23390 (0.1 mg kg^–1) or NNC-687 (4 mg kg^–1). These results provide an intriguing explanation for the clinical profile of clozapine as an atypical antipsychotic drug. Thus, there are supporting clinical and laboratory observations implicating DA D₁ receptors in the prefrontal cortex in cognitive functions. Finally, clozapine displays features with regard to extrapyramidal motor mechanisms, and seizure thresholds, that could be explained by its properties as a DA D₁ receptor agonist.     

The role of dopamine receptors in ventrolateral orbital cortex-evoked antinociception in a rat formalin test model

The present study examined the roles of dopamine and D(1)- and D(2)-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked antinociception in rats with persistent inflammatory pain. Following formalin injection into the rat unilateral hindpaw pad, the effects of dopamine receptor agonist and antagonist microinjections into the VLO on nociceptive behavior were observed. Results demonstrated that VLO microinjection of the non-selective dopamine receptor agonist apomorphine (R(-)-apomorphine hydrochloride, 1.0, 2.5 and 5.0μg) depressed later-phase nociceptive behavior induced by formalin injection; this effect was attenuated by the D(2)-like dopamine receptor antagonist S(-)-raclopride(+)-tartrate salt (raclopride, 3.0μg), but not by the D(1)-like dopamine receptor antagonist R(+)-SCH-23390 hydrochloride (SCH-23390, 1.0μg). Apomorphine-induced antinociception was mimicked by microinjection of the D(2)-like dopamine receptor agonist (-)-quinpirole hydrochloride (2.0 and 5.0μg) into the same VLO site, and this effect was antagonized by raclopride (3.0μg). In addition, microinjection of the D(1)-like dopamine receptor agonist R(+)-SKF-38393 hydrochloride (5.0μg) had no effect on formalin-induced nociceptive behavior during the later phase. However, the D(1)-like dopamine receptor antagonist SCH-23390 (2.5, 5.0 and 10μg) depressed nociceptive behavior in a dose-dependent manner. These results suggested that dopamine mediated VLO-induced antinociception via different mechanisms in the persistent inflammatory pain model; D(2)-like receptors mediated dopamine-induced antinociception, while D(1)-like dopamine receptors exhibited tonic facilitatory action on nociceptive behavior, thereby blocking D(1)-like dopamine receptors could induce antinociception.     

Porcine carotid vascular effects of eletriptan (UK-116,044): a new 5-HT1B/1D receptor agonist with anti-migraine activity

It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine. Indeed, a number of acutely acting anti-migraine drugs, including the ergot alkaloids and sumatriptan, constrict porcine carotid arteriovenous anastomoses. In this study, using pentobarbital anaesthetised pigs, we investigated the effects of eletriptan, a close structural analogue of sumatriptan, on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient (capillary) fractions. Eletriptan (10, 30, 100, 300 and 1000 μg kg^–1, i.v.) decreased the total carotid blood flow, exclusively by decreasing cephalic arteriovenous anastomotic blood flow; nutrient blood flow, particularly to the ear, skin and fat, was significantly increased. The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50% (ED ₅₀) were, respectively, 117±21 μg kg^–1 (251±45 nmol kg^–1) and 184±42 μg kg^–1 (396±91 nmol kg^–1); the highest dose caused reductions of 84±3% and 77±4%, respectively. The eletriptan-induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective 5-HT_1B/1D receptor antagonist GR127935 (0.5 mg kg^–1). On the basis of these results, we conclude that (1) the eletriptan-induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by 5-HT_1B/1D receptors, and (2) eletriptan should be effective in aborting migraine headache. Clinical studies have already demonstrated its therapeutic action in migraine patients. Received: 9 February 1998 / Accepted: 28 March 1998     

Evidence for selective inhibition of limbic forebrain dopamine synthesis by 8-OH-DPAT in the rat

Summary Regional dopamine synthesis in the rat striatum was estimated by measuring DOPA accumulation following inhibition of cerebral aromatic l-amino acid decarboxylase by means of NSD-1015, 100 mg kg^–1 intraperitoneally. In animals treated with reserpine, 5 mg kg^–1 subcutaneously –18 h, there was a statistically significant increase in DOPA accumulation in the nucleus accumbens, the ventro-medial neostriatum, the dorso-lateral neostriatum and in the posterior limb of the neostriatum. This increase in DOPA accumulation was antagonized dose-dependently in the nucleus accumbens and ventro-medial neostriatum, but not in the other two regions, by treatment with the 5-HT_1A receptor agonist 8-OH-DPAT, 0.15–2.4 mol kg^–1, whereas the partial dopamine D₂ receptor agonist (–)3-PPP, 2.5–10.0 mol kg^–1, or the full dopamine D₂ receptor agonist quinpirole, 0.05–0.8 mol kg^–, antagonized the reserpine-induced increase in DOPA accumulation uniformly in all four regions of the striatum. The suppression of DOPA accumulation by 8-OH-DPAT in reserpine-treated animals, was completely antagonized by raclopride, 1 mol kg^–1, but not by (–)pindolol, 8 mol kg^–1. The accumulation of 5-HTP in all regions of the striatum as well as in the neocortex following decarboxylase inhibition and reserpine pretreatment, was also inhibited by 8-OH-DPAT, and this inhibition was unaffected by treatment with raclopride or (–)pindolol. It is concluded that 8-OH-DPAT, in addition to general effects on forebrain 5-hydroxytryptamine synthesis, selectively affects limbic forebrain dopamine synthesis. This latter effect is probably due to direct stimulation of dopamine autoreceptors, since it was obtained in reserpine-treated rats, and was completely antagonized by raclopride, but not (–)pindolol.Presented in part at the 7th General Meeting of the European Society for Neurochemistry, June 12–17th 1988, Göteborg, Sweden Send offprint requests to S. Ahlenius at the above address     

Effects of dopamine agonists and antagonists on cocaine-induced operant responding for a cocaine-associated stimulus

The present study examined the effects of receptor subtype-selective dopamine agonists and antagonists on (i) cocaine-induced responding for a cocaine-associated stimulus and (ii) on responding for food and cocaine reinforcement. Rats implanted with intravenous catheters were trained to lever-press for food or cocaine reinforcers on an FR5-FR5 multiple schedule, which was preceded by a 5-min component during which only stimuli previously associated with the primary reinforcers were available response-contingently. (i) Non-contingent delivery of cocaine at the beginning of the stimulus component significantly increased responding for the cocaine-associated stimulus, compared to responding for the food-associated cue. Changes in the dose of cocaine administered non-contingently before the stimulus component resulted in an inverted U-shaped dose-effect curve in responding for the cocaine-associated cue. In subsequent experiments, pretreatment with the dopamine D₂ receptor agonist bromocriptine (4.0–16.0 mg/kg IP) attenuated the cocaine-induced increase in responding for the cocaine-associated cue. In contrast, pretreatment with low doses of SDZ 208–911, a dopamine D₂ partial agonist (0.025–0.1 mg/kg SC), further potentiated the cocaine-induced response. Pretreatment with low and medium doses of the dopamine D₁ and D₂ receptor subtype-selective antagonists SCH 23390 (D₁; 5–10 µg/kg SC) and raclopride (D₂; 100–200 µg/kg SC) blocked responding for cocaine-associated cues, with SCH 23390 acting more selectively than raclopride. At higher doses (SCH 23390: 20 µg/kg SC; raclopride: 400 µg/kg SC), both drugs produced nonselective effects by inhibiting responses for the food-associated cue. (ii) Varying the dose of cocaine self-administered during the multiple schedule resulted in an inverted U-shaped dose-effect curve during the cocaine components, while the number of food pellets earned remained unchanged. Pretreatment with bromocriptine selectively reduced the number of cocaine infusions obtained. The compensatory increases in responding for cocaine typically associated with SCH 23390, raclopride or SDZ 208–911 pretreatment were also observed under the present schedule conditions, although the effect did not reach statistical significance in the case of SCH 23390 and raclopride, possibly due to methodological constraints. The results indicate that the present rat model of cocaine-seeking behavior is sensitive to pharmacological manipulations and may yield important information regarding the neurobiological mechanisms underlying conditioned and unconditioned reinforcing aspects of cocaine addiction.     

Effects of dopamine receptor antagonists on the acquisition of ethanol-induced conditioned place preference in mice

Rationale

Studies support differential roles of dopamine receptor subfamilies in the rewarding and reinforcing properties of drugs of abuse, including ethanol. However, the roles these receptor subfamilies play in ethanol reward are not fully delineated.

Objective

To examine the roles of dopamine receptor subfamilies in the acquisition of ethanol-induced conditioned place preference (CPP), we pretreated animals systemically with antagonist drugs selective for dopamine D1-like (SCH-23390) and D2-like (raclopride) receptors prior to ethanol conditioning trials.

Methods

Effects of raclopride (0–1.2 mg/kg) and SCH-23390 (0–0.3 mg/kg) on the acquisition of ethanol-induced CPP were examined in DBA/2J mice (experiments 1 and 2). Based on significant effects of SCH-23390, we then determined if SCH-23390 (0.3 mg/kg) produced a place preference on its own (experiment 3). To evaluate whether SCH-23390 impaired learning, we used a conditioned place aversion (CPA) paradigm and pretreated animals with SCH-23390 (0–0.3 mg/kg) before conditioning sessions with LiCl (experiment 4).

Results

Whereas raclopride (0–1.2 mg/kg) did not affect acquisition, SCH-23390 (0.1–0.3 mg/kg) impaired the development of ethanol-induced CPP. SCH-23390 (0.3 mg/kg) did not produce place preference when tested alone and SCH-23390 (0.1–0.3 mg/kg) did not perturb the acquisition of LiCl-induced CPA.

Conclusions

Our results support a role for dopamine D1-like but not D2-like receptors in ethanol’s unconditioned rewarding effect as indexed by CPP. Blockade of D1-like receptors did not affect aversive learning in this procedure.     

Antipsychotics possessing antidepressive efficacy increase G<Subscript>olf</Subscript> protein in rat striatum

Rationale Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects. Objectives In this study, we measured striatal and extrastriatal dopamine D₂ receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose. Materials and methods Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [¹¹C]raclopride and one with [¹¹C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D₂ receptor occupancy was calculated. Results The dopamine D₂ receptor occupancies in the striatum measured with [¹¹C]raclopride and the temporal cortex measured with [¹¹C]FLB 457 were 54.2–85.5% and 34.5–87.3%, respectively. ED₅₀ values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D₂ receptor occupancy between the striatum and the temporal cortex. Conclusions The data from this study suggest that paliperidone ER at 6–9 mg provides an estimated level of dopamine D₂ receptor occupancy between 70–80% and that the magnitude of dopamine D₂ receptor occupancy is similar between the striatum and temporal cortex.