Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice: reversal by antipsychotic drugs

Cortical metabotropic glutamate receptors (mGluRs) seem to be involved in habituation of simple stimulus-bound behaviors (e.g., habituation to acoustic startle or odor-elicited orienting response). Habituation deficits may contribute to the cognitive symptoms of schizophrenia. In the present study, male NMRI mice were injected with mGluR2/3 antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495) 30 min before being placed into novel arenas for automatic motor activity recording (2-h sessions). Administration of LY-341495 (1-10 mg/kg s.c.) dose-dependently prevented the habituation of the locomotor activity. Effects of LY-341495 (10 mg/kg) were fully and dose-dependently reversed by i.p. administration of haloperidol (0.03-0.3 mg/kg), clozapine (1-10 mg/kg), risperidone (0.01-0.1 mg/kg), olanzapine (0.3-3 mg/kg), aripiprazole (1-10 mg/kg), and sulpiride (3-30 mg/kg), each of which was given 15 min before the test. Effects of antipsychotic drugs were observed at the dose levels that did not affect spontaneous motor activity. LY-341495-induced delayed hyperactivity was also partially attenuated by lithium (50-200 mg/kg), amisulpride (1-10 mg/kg), and the selective dopamine D3 antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011A; 3-30 mg/kg). Application of diazepam, imipramine, or several agonists and/or antagonists acting at various receptors that are thought to be relevant for antipsychotic treatment [e.g., 5-hydroxytryptamine (5-HT)(2A), 5-HT(3), and 5-HT(6) antagonists; 5-HT(1A) agonist; D4 antagonist; CB1 antagonist; ampakines; and glycine transporter inhibitor) had no appreciable effects. Thus, behavioral deficits induced by mGluR2/3 blockade (such as delayed motor hyperactivity) are selectively reversed by clinically used antipsychotic drugs.     

Stimulation of D1 and D2 dopamine receptors produces additive anorectic effects

In food-deprived mice the D1 dopamine agonist SKF 38393 induced dose dependent anorexia (ED50 = 2.6 mg/kg). This effect was reversed by the D1 antagonist SCH 23390. In similar conditions, the D2 dopamine agonist RU 24926 also induced dose dependent anorexia (ED50 = 0.19 mg/kg). This effect was reversed by the D2 antagonist (+/-) sulpiride. The mixed D1/D2 agonist apomorphine also induced an anorectic effect (150 micrograms/kg sc) which was completely reversed by (+/-) sulpiride (25 mg/kg, ip) but unaffected by SCH 23390 (5-30 micrograms/kg). The dose response curve obtained by associating SKF 38393 (2.5 mg/kg) with increasing doses of RU 24926 was roughly parallel to that obtained with RU 24926 alone. This indicates that effects of two drugs were additive. Although both D1 and D2 receptors regulate food consumption, the anorectic effect of apomorphine appears to involve only D2 receptors.     

6-hydroxydopamine treatments enhance behavioral responses to intracerebral microinjection of D1- and D2-dopamine agonists into nucleus accumbens and striatum without changing dopamine antagonist binding

Behavioral responses to D1 and D2-dopamine agonists are enhanced when these agonists are administered systemically to 6-hydroxydopamine (6-OHDA)-lesioned rats. In the present investigation, microinjection of SKF-38393, a D1-dopamine agonist, into the nucleus accumbens of adult rats lesioned as neonates with 6-OHDA produced a dose-related increase in locomotor activity that was enhanced markedly compared to control. LY-171555, a D2-agonist, elicited less locomotor activity than did SKF-38393 after microinjection into this site. Administration of SKF-38393 or LY-171555 into the nucleus accumbens did not increase locomotion in unlesioned rats at the doses administered to lesioned animals. In adult-6-OHDA-lesioned rats, microinjection of SKF-38393 into the nucleus accumbens also increased locomotion more than did LY-171555. As described previously, systemic administration of SKF-38393 produced little locomotion in adult-6-OHDA-lesioned rats, whereas LY-171555 produced a markedly enhanced response. Administration of SKF-38393 or LY-171555 into the caudate nucleus of neonatally and adult-6-OHDA-lesioned rats produced negligible locomotor activity, but did induce stereotypic behaviors similar to those observed after systemic treatment with these drugs. Stereotypic behaviors occurred to a greater degree in the 6-OHDA-lesioned rats than in unlesioned controls. A regional specificity for certain behaviors induced by dopamine agonist administration was observed. In spite of the enhanced behavioral responses of D1 and D2-dopamine agonists after microinjection into the brain of 6-OHDA-lesioned rats, binding of [3H]spiperone (D2-receptor antagonist ligand) and [3H]SCH 23390 (D1-receptor antagonist ligand) to tissue from striatum and nucleus accumbens was not altered significantly. In contrast to this lack of change in binding characteristics in 6-OHDA-lesioned rats, blockade of dopaminergic transmission with haloperidol treatment caused an elevation of [3H]spiperone binding sites in striatum without affecting affinity for the site. However, chronic haloperidol treatment did not alter significantly [3H]SCH 23390 binding to striatal membranes. These latter findings suggest that chronic dopamine receptor blockade need not produce the same adaptive mechanisms as destruction of dopamine-containing neurons. Thus, a change in receptor characteristics as measured by dopamine antagonist binding does not account for the behavioral supersensitivity observed after D1- and D2-dopamine agonist administration to neonatally or adult-6-OHDA-treated rats.     

One year of continuous treatment with haloperidol or clozapine fails to induce a hypersensitive response of caudate putamen neurons to dopamine D1 and D2 receptor agonists

In a "blind" experimental design, the sensitivity of caudate-putamen (CPu) cells to the selective dopamine (DA) D1 receptor agonist SKF-38393 and D2 receptor agonist LY171555 (quinpirole) in rats treated with either haloperidol (HAL), clozapine or tap water for 1 year was compared using the techniques of single cell recording and microiontophoresis. Although the maximum binding value for D2 receptors was elevated in chronic HAL-treated rats, there was no sign of electrophysiological supersensitivity of CPu neurons to the selective DA D1 and D2 receptor agonists. CPu cells were subsensitive to LY-171555 in HAL-treated rats without a drug withdrawal period. This suggests that residual HAL in the rat brain actively blocked the D2 DA receptors. In contrast, in clozapine-treated rats with or without a drug withdrawal period, the sensitivity of CPu cells to either the D1 or D2 agonists was not altered. Coadministration of SKF-38393 and LY-171555 onto the CPu neurons primarily produced an additive effect and only two cells both from the HAL group showed a synergistic action. The majority of CPu cells failed to respond to iontophoretic application of CCK-8S in either the control or antipsychotic drug-treated rats. If these findings can be extended to humans, they do not support the view that tardive dyskinesia is the result of CPu DA receptor supersensitivity.     

Interactions of D1 and D2 dopamine receptors on the ipsilateral vs. contralateral side in rats with unilateral lesions of the dopaminergic nigrostriatal pathway

In rats with a unilateral lesion of the nigrostriatal dopaminergic pathway, the ipsilateral rotation produced by the enhanced actions of endogenous dopamine (DA) on the nonlesioned side, induced by either the DA-releasing drug amphetamine or the DA uptake inhibitor GBR 13069, was blocked effectively by pretreatment with either the selective D1 DA receptor antagonist, SCH 23390, or the D2 selective antagonist, haloperidol. In contrast, contralateral rotation produced by apomorphine or I-dihydroxyphenylalanine, which lead to the preferential activation of D1 and D2 receptors on the lesioned side, was effectively prevented only when both receptor subtypes were inhibited. The results of these experiments demonstrate that the interaction between D1 and D2 receptors in the lesioned side differs from that in the nonlesioned side. Whereas the simultaneous stimulation of both DA receptor subtypes in the normally innervated basal ganglia is required for the production of turning behavior, the stimulation of either subtype alone in the dopaminergic denervated side can produce rotation. However, the concurrent administration of the D1 agonist, SKF 38393, with the D2 agonist, LY 171555, produced a synergistic effect on contralateral rotation. These results suggest that there is preservation of at least some functional interaction between D1 and D2 receptors in the lesioned basal ganglia but that there may be in addition a mechanism by which the two receptor subtypes can function independently of each other. The unilaterally lesioned rat appears to be a very good model in which to study the interaction between D1 and D2 receptors under conditions of both normal innervation and of DA denervation.(ABSTRACT TRUNCATED AT 250 WORDS)     

D(2), but not D(1) dopamine receptor agonists potentiate cannabinoid-induced sedation in nonhuman primates

In primates, CB(1) cannabinoid receptor agonists produce sedation and psychomotor slowing, in contrast to behavioral stimulation produced by high doses of dopamine receptor agonists. To investigate whether dopamine agonists attenuate the sedative effects of a cannabinoid agonist in monkeys, we compared the effects of D(1) or D(2) dopamine receptor agonists on spontaneous behavior in three to six cynomolgus monkeys (Macaca fasicularis) alone and after administration of a low dose of the CB(1) agonist levonantradol. Alone, the CB(1) cannabinoid receptor agonist levonantradol (0.01-0. 3 mg/kg) induced sedation, ptosis, and decreased locomotor and general activity. Alone, D(2)-type dopamine agonists quinelorane (0. 001-1.0 mg/kg; n = 4) or pergolide (0.01-1.0 mg/kg) or a D(1) dopamine agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-3-allyl-[1H]-3-benzazepine (0.3-3.0 mg/kg) produced either no effect or promoted hyperactivity. Thirty minutes after administration of a threshold dose of levonantradol (0.03 mg/kg), D(2)-type agonists, but not the D(1) agonist, precipitated marked sedation, ptosis, and decreased general activity and locomotor activity. These data inducate the following: 1) D(2,) but not D(1) dopamine agonists, potentiate sedation in monkeys treated with a CB(1) cannabinoid agonist, at doses of agonists that alone do not produce sedation; 2) the threshold dose for cannabinoid-induced sedation is reduced by D(2) agonists, but not by a D(1) dopamine agonist, differentiating D(1) and D(2) dopamine receptor linkage to cannabinoid receptors; and 3) modulation of D(2) dopamine receptor activity by a nonsedating dose of a cannabinoid agonist has implications for the pathophysiology and treatment of dopamine-related neuropsychiatric disorders and drug addiction. Cannabinoid agonists and D(2) dopamine agonists should be combined with caution.     

D1 and D2 dopamine receptors independently regulate spontaneous blink rate in the vervet monkey.

Previous studies have revealed the involvement of a dopaminergic link in the regulation of spontaneous eye blink rate in primates. Based on the effect of dopamine D2 receptor-selective drugs and the anecdotal failure of the partial D1 agonist, SKF 38393, to alter blink rate in monkeys, it was assumed that D1 dopamine receptors did not control blink rate. The recent availability of dihydrexidine, a full D1 agonist, prompted us to reevaluate the role of D1 and D2 receptors in the regulation of blink rate. African green monkeys (n = 5) were used in all studies. Dihydrexidine produced a rapid and dose-dependent (up to 1 mg/kg, i.m.) increase in blink rate. The elevation in blink rate elicited by 0.3 mg/kg dihydrexidine was completely reversed by prior administration of a specific D1 antagonist, SCH 23390 (0.01 mg/kg, i.m.), but was unaffected by prior administration of a specific D2 antagonist, remoxipride (1 mg/kg, i.m.). Treatment with the specific D2 agonist, (+)-4-propyl-9-hydroxynaphthoxazine, led to a rapid and dose-dependent (up to 0.01 mg/kg, i.m.) increase in blink rate. The raised blink rate produced by (+)-4-propyl-9-hydroxynaphthoxazine (0.001 mg/kg) was abolished by pretreatment with remoxipride, but was not influenced by pretreatment with SCH 23390. These data indicate that spontaneous blink rate in the primate can be regulated by both D1 and D2 dopamine receptors. Furthermore, the receptor subtypes appear to affect blink rate in the same direction, yet function independently. Measurement of blink rate may provide a noninvasive method to assess the potency and selectivity of dopamine agonists and antagonists in primates.     

Dopamine D1 and D2 agonist effects on prepulse inhibition and locomotion: comparison of Sprague-Dawley rats to Swiss-Webster, 129X1/SvJ, C57BL/6J, and DBA/2J mice

D2 receptors have been studied in relation to therapeutic uses of dopaminergic drugs, and psychomotor stimulant effects [as manifested by decreased prepulse inhibition (PPI) of startle and increased locomotor activity] are hallmark behavioral effects of D2 agonists in rats. Genetic studies with mutant mice might be useful in this line of investigation; however, recent studies suggest that mice differ from rats with respect to D2 agonist effects. Accordingly, we studied a wide range of doses of the D2-like agonist quinelorane (0.0032-5.6 mg/kg) and the D1-like agonist R-6-Br-APB [R(+)-6-bromo-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide] (0.032-5.6 mg/kg) in outbred Sprague-Dawley rats, outbred Swiss-Webster mice, and inbred 129X1/SvJ, C57BL/6J, and DBA/2J mice. Whereas the D2 agonist dose-dependently decreased PPI and increased locomotion in rats, neither of these effects was observed in outbred or inbred mice. In contrast, the D1 agonist reduced PPI and increased locomotion in Sprague-Dawley rats and in Swiss-Webster, 129X1/SvJ, and C57BL/6J mice. Neither agonist decreased PPI in DBA/2J mice, although PPI was increased in this strain by a D2 antagonist. Pretreatment with either the D2 antagonist eticlopride (1 mg/kg) or the D1 antagonist SCH39166 [(-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo[d]naptho-(2,1-b)azepine] (1 mg/kg) prevented the PPI-disruptive effects of quinelorane in rats and R-6-Br-APB in mice, suggesting receptor interactions in both species. In summary, psychomotor stimulant effects of a D2 agonist that were robustly observed in outbred rats were absent in several outbred and inbred strains of mice. These results may have implications for the study of mutant mice to investigate genes involved in psychomotor function in humans.     

Dinapsoline: characterization of a D1 dopamine receptor agonist in a rat model of Parkinson's disease

Dinapsoline is a new potent, full agonist at D1 dopamine receptors with limited selectivity relative to D2 receptors. The efficacy of this compound was assessed in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle, a standard rat model of Parkinson's disease. Dinapsoline produced robust contralateral rotation after either subcutaneous or oral administration. This rotational behavior was attenuated markedly by the D1 receptor antagonist SCH-23390, but not by the D2 receptor antagonist raclopride. During a chronic 14-day treatment period in which rats received dinapsoline either once or twice a day, dinapsoline did not produce tolerance (in fact, some sensitization of the rotational response was observed in one experiment). Because dinapsoline shows less D1:D2 selectivity in vitro than other D1 agonists, the contribution of D2 activity to tolerance was assessed. Chronic daily cotreatment with dinapsoline and raclopride did not enable the development of tolerance to chronic dinapsoline treatment. In contrast, when dinapsoline was administered by osmotic minipump, rapid tolerance was observed. To explore further the contribution of D1 and D2 receptors to tolerance, experiments were performed with the selective D1 agonist A-77636. Daily dosing with A-77636 rapidly produced complete tolerance, as previously observed, whereas coadministration of the D2 agonist quinpirole plus A-77636 failed to either delay or prevent tolerance. Taken together, these results indicate that the development of tolerance to D1 receptor agonists is influenced by the pattern of drug exposure but not by the D1:D2 selectivity of the agonist.     

Effects of chronic SCH23390 treatment on the biochemical and behavioral properties of D1 and D2 dopamine receptors: potentiated behavioral responses to a D2 dopamine agonist after selective D1 dopamine receptor upregulation

Chronic treatment of rats with SCH23390 (0.5 mg/kg/day s.c.), a D1 dopamine receptor antagonist, for 21 days resulted in an increase in D1 dopamine receptors but produced no change in D2 dopamine receptors. During habituation to locomotor activity cages the rats treated chronically with SCH23390 showed significantly higher locomotor activity than controls treated chronically with saline. When injected with the selective D1 dopamine receptor agonist SKF38393 (3 mg/kg), rats treated chronically with SCH23390 showed significantly greater stereotypy and locomotor activity responses. Surprisingly, rats treated chronically with SCH23390 also showed significantly higher locomotor activity and stereotypy responses when treated with the selective D2 dopamine receptor agonist, quinpirole (LY171555) (0.3 mg/kg). These results indicate that a selective increase in D1 receptors may not be necessary, but is sufficient, to lead to an enhanced behavioral response to either selective D1 or D2 dopamine receptor agonists. If, indeed, an enhanced stereotypy and locomotor activity response to dopaminergic agonists in rats after a brief chronic treatment with a neuroleptic drug is predictive of tardive dyskinesia potential in the clinical setting, these results can suggest that SCH23390 may also induce tardive dyskinesia in humans. Adenylate cyclase activity stimulated by guanine nucleotides, forskolin or dopamine was enhanced after chronic treatment with SCH23390. However, dopamine-stimulated adenylate cyclase activity was not potentiated detectably by the increase in receptor number over the more general increase in guanine nucleotide-stimulated cyclic AMP production. Additionally, no change was observed in dopamine competition for [3H]SCH23390 binding, with dopamine's RH/RL ratio remaining unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alpha1-adrenergic receptors augment P2X3 receptor-mediated nociceptive responses in the uninjured state.

In the present study, the adrenergic receptor (AR) subtype mediating adrenergic augmentation of P2X(3) receptor-mediated nociceptive responses on sensory nerve endings was examined by using selective AR receptor agonists and antagonists in Sprague Dawley rats in the uninjured state. Local administration of alphabeta-methyleneATP (ligand for P2X3/P2X2/3 receptors) into the plantar hind paw produced few pain behaviors when given alone in this strain of rats; combination with adrenaline (alpha1- and alpha2-AR agonist) and phenylephrine (alpha1-AR agonist) but not clonidine or UK 14,304 (alpha2-AR agonists) increased flinching behaviors. Flinching produced by noradrenaline (NA)/alphabeta-methyleneATP was suppressed by low doses of prazosin (alpha1-AR antagonist), and this reduction was selective compared with yohimbine (alpha2-AR antagonist). Prazosin also reduced flinching produced by phenylephrine/alphabeta-methyleneATP. Using thermal threshold determinations, adrenaline and phenylephrine but not clonidine or UK 14,304, mimicked the action of NA in augmenting reductions in thermal thresholds produced by alphabeta-methyleneATP. Terazosin (another alpha1-AR antagonist) inhibited hyperalgesia produced by NA/alphabeta-methyleneATP. These results provide evidence for alpha1-AR involvement in adrenergic augmentation of P2X3/P2X2/3 receptor-mediated responses on sensory nerve endings in the uninjured state in Sprague Dawley rats. PERSPECTIVE: This study indicates the alpha1-adrenergic receptor subtype mediates adrenergic augmentation of the activation of sensory nerves by purinergic P2X3 receptors (respond to ATP) in the periphery. Observations are potentially relevant to chronic pain conditions in which sympathetic nerves influence sensory nerves.     

S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors: I. Cellular, electrophysiological, and neurochemical profile in comparison with ropinirole

S32504 [(+)-trans-3,4,4a,5,6,10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine] displayed marked affinity for cloned, human (h)D(3) receptors (pK(i), 8.1) at which, in total G-protein ([(35)S]GTPgammaS binding, guanosine-5'-O-(3-[(35)S]thio)-triphosphate), Galpha(i3) (antibody capture/scintillation proximity), and mitogen-activated protein kinase (immunoblot) activation procedures, it behaved as an agonist: pEC(50) values, 8.7, 8.6, and 8.5, respectively. These actions were blocked by haloperidol and the selective D(3) receptor antagonist S33084 [(3aR,9bS)-N-[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl]-(4-phenyl) benzamide)]. S32504 showed lower potency at hD(2S) and hD(2L) receptors in [(35)S]GTPgammaS binding (pEC(50) values, 6.4 and 6.7) and antibody capture/scintillation proximity (hD(2L), pEC(50), 6.6) procedures. However, reflecting signal amplification, it potently stimulated hD(2L) receptor-coupled mitogen-activated protein kinase (pEC(50), 8.6). These actions were blocked by haloperidol and the selective D(2) receptor antagonist L741,626 [4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol]. The affinity of S32504 for hD(4) receptors was low (5.3) and negligible for hD(1) and hD(5) receptors (pK(i), <5.0). S32504 showed weak agonist properties at serotonin(1A) ([(35)S]GTPgammaS binding, pEC(50), 5.0) and serotonin(2A) (G(q), pEC(50), 5.2) receptors and low affinity for other (>50) sites. In anesthetized rats, S32504 (0.0025-0.01 mg/kg, i.v.) suppressed electrical activity of ventrotegmental dopaminergic neurons. Correspondingly, S32504 (0.0025-0.63 mg/kg, s.c.) potently reduced dialysis levels (and synthesis) of dopamine in striatum, nucleus accumbens, and frontal cortex of freely moving rats, actions blocked by haloperidol and L741,626 but not by S33084. In contrast, S32504 only weakly inhibited serotonergic transmission and failed to affect noradrenergic transmission. Actions of S32504 were expressed stereospecifically versus its less active enantiomer S32601 [(-)-trans-3,4,4a,5,6,10b-hexahydro-9-carbomoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine]. Although the D(3)/D(2) agonist and antiparkinsonian agent ropinirole mimicked the profile of S32504, it was less potent. In conclusion, S32504 is a potent and selective agonist at dopamine D(3) and D(2) receptors.     

Aripiprazole,a novel antipsychotic,is a high-affinity partial agonist at human dopamine D2 receptors

Aripiprazole is the first next-generation atypical antipsychotic with a mechanism of action that differs from currently marketed typical and atypical antipsychotics. Aripiprazole displays properties of an agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively. This study examined the interactions of aripiprazole with a single population of human D2 receptors to clarify further its pharmacologic properties. In membranes prepared from Chinese hamster ovary cells that express recombinant D2L receptors, aripiprazole bound with high affinity to both the G protein-coupled and uncoupled states of receptors. Aripiprazole potently activated D2 receptor-mediated inhibition of cAMP accumulation. Partial receptor inactivation using the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) significantly reduced the maximum effect of aripiprazole on inhibition of cAMP accumulation. This effect was seen with concentrations of EEDQ that did not alter the maximal inhibitory effect of dopamine. Consistent with the expected effects of a partial agonist, increasing concentrations of aripiprazole blocked the action of dopamine with maximal blockade equal to the agonist effect of aripiprazole alone. The efficacy of aripiprazole relative to that of dopamine varied from 25% in cells that lacked spare receptors for dopamine to 90% in cells with receptor reserve. These results, together with previous studies demonstrating partial agonist activity at serotonin 5-hydroxytryptamine (5-HT)1A receptors and antagonist activity at 5-HT2A receptors, support the identification of aripiprazole as a dopamine-serotonin system stabilizer. The receptor activity profile may underlie the unique activity of aripiprazole in animals and its antipsychotic activity in humans.     

Aspartate-releasing nerve terminals in rat striatum possess D-2 dopamine receptors mediating inhibition of release

The release of endogenous aspartic acid has been investigated using synaptosomes from rat corpus striatum. Exposure in superfusion to a depolarizing concentration of KCl (15 mM) evoked an overflow of aspartate which was almost entirely calcium-dependent. When added to the superfusion medium, dopamine (DA) and the selective DA D-2 receptor agonists quinpirole (LY-171555) and pergolide inhibited the K+ -evoked aspartate release in a concentration-dependent manner. The natural agonist DA was very potent (IC50 = 1 nM). The selective D-1 receptor agonist SK&F 38393 had no effect on the release of aspartate. The selective D-2 receptor antagonist S-sulpiride, but not the R-enantiomer, antagonized the DA-induced inhibition of aspartate release. The DA effect was unaltered by SCH 23390, a selective dopamine D-1 receptor antagonist. The findings that 1) the release of endogenous aspartate evoked by depolarization was calcium-dependent and 2) the release of aspartate was potently modulated through D-2 receptors are compatible with the idea that aspartate is released as a transmitter from striatal axon terminals. The possibility that aspartate and glutamate are coreleased from these terminals is discussed.     

Discriminative stimulus properties of lisuride revisited: involvement of dopamine D2 receptors

Although the discriminative stimulus effects of the clinically useful ergot derivative lisuride have previously been related to dopamine (DA) neuronal systems, the involvement of DA D1 and D2 receptor subtypes in the lisuride cue has been characterized for the first time in the present experiment. In rats trained to discriminate lisuride (0.04 mg/kg) from saline, appropriate doses of the putative D2 agonist LY 171555 (0.008-0.063 mg/kg) substituted completely whereas the D1 agonist SKF 38393 (2.0-16.0 mg/kg) evoked primarily saline-lever responding. When given in combination with lisuride (0.04 mg/kg), the D2 antagonist (-)-sulpiride (5-30 mg/kg), but not the D1 antagonist SCH 23390 (0.125-0.5 mg/kg), blocked the lisuride cue. Combination tests also suggested that bromuride and pirenperone have DA antagonist properties. Although the specificity of these agents is not fully known, these results support the conclusion that D2 but not D1 receptors play an important role in the stimulus effects of lisuride. Although a role for serotonin in the similar stimulus properties of lisuride and SCH 23390 cannot be ruled out, partial substitution of SCH 23390 (0.0625-0.35 mg/kg; administered alone) for lisuride complements previous observations which suggest that the two DA subtypes may be functionally linked in vivo.     

Behavioral effects of selective dopaminergic compounds in rats discriminating cocaine injections.

The involvement of dopamine receptor subtypes in the discriminative stimulus effects of cocaine was evaluated by the ability of a series of compounds selective for D1 or D2 dopamine receptors to produce discriminative stimulus effects comparable to cocaine. Male, Sprague-Dawley rats were trained to discriminate 10 mg/kg of cocaine HCI from saline in a two-lever discrimination procedure. Inhibitors of catecholamine and serotonin reuptake (GBR 12909, WIN 35,428 and mazindol), d-amphetamine, and the nonselective dopamine agonist, apomorphine, produced dose-dependent increases in cocaine-appropriate responding and fully substituted for cocaine. Cocaine methiodide, a charged, quaternary cocaine analog, did not substitute for cocaine. Neither pentobarbital, haloperidol nor SCH 23390 produced cocaine-like behavioral activity. Both D1- and D2-selective agonists with diverse structures partially substituted for cocaine, producing from 40 to 80% cocaine-appropriate responses. The D1 agonists studied were SKF 38393 and stereoisomers, SKF 75670 and CY 208-243. Dihydrexidine, a full D1 agonist for induction of adenylate cyclase activity, also only partially substituted for cocaine. The peripherally acting D1 agonist, fenoldopam, produced predominantly saline-appropriate responding that was unrelated to dose. The D2 agonists tested were pergolide, quinpirole, (-)-NPA, RU 24213, N-0434 and N-0437. The D2 antagonist haloperidol did not block the discriminative stimulus effects of cocaine. In contrast, the D1 antagonist SCH 23390 reduced the discriminative stimulus effects of cocaine by a maximum of 50%. These results suggest that both D1 and D2 receptors may play a role in the discriminative stimulus effects of cocaine but that stimulation of either dopamine receptor subtype alone is not sufficient.     

Systemic injections of alpha-1 adrenergic agonists produce antinociception in the formalin test.

The role of alpha 1 receptors in antinociception was investigated in the formalin test, a well established test of tonic pain. The effect of systemic injections of selective alpha 1-adrenergic agonists (phenylephrine and methoxamine), a mixed alpha agonist selective for alpha 2 receptors (ST-91), and 2 adrenergic antagonists (prazosin and idazoxan) was measured in groups of Long-Evans rats. All agonists tested produced significant antinociception in this test. Dose-response curves for each agonist were statistically parallel and equally efficacious (100% antinociception). Prior injection of 0.15 mg/kg prazosin (an alpha 1 antagonist) completely antagonized the antinociception produced by either an ED50 or a maximally effective dose of each agonist tested. Idazoxan (0.5 mg/kg), an alpha 2 antagonist, was without effect on the antinociception produced by phenylephrine or methoxamine. ST-91 produced significant antinociception in the presence of idazoxan although the response was different from that obtained with ST-91 alone. The observed antinociception in the formalin test was not due to drug-induced changes in peripheral inflammation as measured using plethysmometry. Moreover, none of the drugs tested produced significant changes in coordinated motor behavior (accelerated rotarod test) at doses that produced significant analgesia (ED50). We conclude that alpha 1 receptors contribute significantly to adrenergic analgesia in the formalin test by an undefined action on sensory processing mechanisms.     

Acute extrapyramidal syndrome in Cebus monkeys: development mediated by dopamine D2 but not D1 receptors

The present study assessed the role of dopamine D1 and D2 receptors in the production of an extrapyramidal syndrome (EPS) in Cebus apella monkeys. Previous studies have shown the development of EPS in both old and new world monkeys with haloperidol administration. We now report that repeated weekly administration of a selective D1 antagonist, SCH 23390, does not produce this syndrome in cebus monkeys. Cebus monkeys were treated with either vehicle (n = 6), the specific D2 antagonist haloperidol (0.3 mg/kg p.o., n = 9) or the specific D1 antagonist SCH 23390 (10.0 mg/kg p.o., n = 9) once a week for approximately 1 year and behavioral effects were observed and scored. The drug doses used in this study produced similar sedative scores when given acutely and sedation increased over the first 12 weeks of the study for both treatment groups. However, by the 12th week of dosing with haloperidol all the monkeys showed a profound EPS characterized by limb extensions, head pushing, tongue protrusions and sometimes severe biting movements. In contrast, none of the SCH 23390-treated monkeys showed any abnormal movements, suggesting D1 antagonists have a low EPS side-effect liability. The profile of the incidence of EPS seen with classical neuroleptic drugs in cebus monkeys and their blockade of EPS by anticholinergic drugs mimics the profile seen in humans. The models presented appear to be predictive of the production of the EPS in humans and could be used to screen neuroleptics for EPS liability. Furthermore, the EPS is probably due to the selective blockade of dopamine D2 receptors with its associated enhancement of cholinergic neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)     

D2 dopamine receptors modulate calcium channel currents and catecholamine secretion in bovine adrenal chromaffin cells

Although dopamine is known to be present in sympathetic ganglia, its role and mode of action as a peripheral neurotransmitter are still poorly understood. Dopaminergic agonists have been shown to inhibit adrenal catecholamine release and calcium uptake. However, the specific dopamine receptor subtype mediating these effects and the receptor transduction mechanism remain unknown. We now provide evidence demonstrating 1) that slowly inactivating, voltage-gated calcium channels serve as a target site for dopaminergic modulation of chromaffin cell function and 2) that it is the D2 receptor subtype which mediates dopaminergic inhibitory effects on catecholamine secretion, 45Ca uptake and voltage-gated calcium currents. Whole cell patch clamp electrophysiological techniques were used to monitor directly voltage-gated Ca++ channels. The D2 agonist apomorphine but not the D1 agonist SKF 38393 reduced reversibly a slowly inactivating, voltage-gated calcium current in cultured chromaffin cells and this effect was blocked by the D2 receptor antagonist haloperidol. The presence of D2 but not D1 dopamine receptors on chromaffin cell membranes was demonstrated by radioligand binding methods, using the specific D1 and D2 receptor radioligands, [3H]SCH23390 and [3H]N-methylspiperone, respectively. Nicotine- and KCl (60 mM)-evoked catecholamine secretion and 45Ca uptake were inhibited by the D2 agonist, apomorphine, but not by the D1 agonist, SKF 38393. These inhibitory effects were prevented by the D2 antagonist, sulpiride, but not by the D1 antagonist, SCH 23390. D2 dopamine receptors appear to function as inhibitory modulators of adrenal catecholamine secretion with a mode of action involving inhibition of calcium channel currents.     

Behavioral differentiation of the stimulus properties of a dopaminergic D1 agonist from a D2 agonist

This study examined the hypothesis that the stimulus properties of a dopaminergic D1 agonist should be functionally discriminable from those of a D2 agonist. Rats were trained in a two-lever food-reinforced drug discrimination paradigm to discriminate either the D1 agonist SKF 38393 from apomorphine (SKF/APO), SKF from saline (SKF/SAL) or apomorphine from saline (APO/SAL), at an APO dose previously established to have D2-mediated stimulus properties. Results showed the SKF/APO discrimination to be readily acquired. The SKF cue showed similar stimulus properties under both the SKF/APO and SKF/SAL training conditions which were mediated by the D1 receptor: the SKF response was blocked by the D1 antagonist SCH 23390, but not by the D2 antagonist haloperidol. Run length data suggested a graded rather than quantal effect of SKF dose on responding during SKF generalization tests. In APO/SAL-trained animals, the APO cue was D2 mediated; responding was blocked by haloperidol, but not by SCH 23390 and APO responding generalized to the selective D2 agonist LY 171555 (quinpirole), but not to SKF. In the SKF/APO condition, APO responding did not decrease with APO dose, nor were antagonists effective in blocking responding, reflecting the lack of an alternative no-drug response option. Higher doses of APO appear to have D1 properties; doses above the training dose engendered SKF responding in both the SKF/SAL and SKF/APO groups, a response which could be blocked by the D1 antagonist SCH 23390, but not by the D2 antagonist, haloperidol. In all three training conditions, generalization test outcomes could be influenced by the conditions of the previous test session.(ABSTRACT TRUNCATED AT 250 WORDS)