The effects of cocaine, amphetamine, and the dopamine D? receptor agonist SKF 38393 on fear extinction as measured with potentiated startle: Implications for psychomotor stimulant psychosis.

Using Pavlovian conditioned increases in the amplitude of the acoustic startle reflex as a behavioral indicator of fear motivation, the authors previously showed a resistance to extinction after repeated associations of cocaine with the fear-evoking conditioned stimulus (CS). In Experiment 1, acute administration of cocaine, amphetamine, and the dopamine (DA) D? receptor agonist SKF 38393 produced a similar fear enhancement. In Experiment 2, a noncontingent injection of cocaine and SKF 38393 provoked a CS potentiation of acoustic startle in fear-extinguished laboratory rats. Potential behavioral, neurochemical, and neuroendocrine explanations for the effects of psychomotor stimulants on conditional fear were discussed. It was suggested that DA agonist drugs increase fear expression possibly by activating mesoamygdaloid associative neurocircuitry involved in excitatory conditioned fear reactions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Biphasic locomotor effects of the dopamine D1 agonist SKF 38393 and their attenuation in non-habituated mice

The locomotor stimulatory effects of the dopamine D1 receptor partial agonist SKF 38393 were examined in male C57B1/6J mice. Non-habituated mice showed marked dose-related (3-300 mg/kg, SC) locomotor stimulation. The time-course effect was biphasic at very high doses (100-300 mg/kg), with dose-related locomotor depression followed by dose-related long-term hyperlocomotion. For all doses, locomotor effects were detectable throughout the 4-h test period. To determine whether these effects were mediated by D1 receptor stimulation, effects of SKF 38393 were assessed in combination with behaviorally inactive and active doses (0.1 and 0.2 mg/kg, respectively) of the selective D1 receptor antagonist SCH 39166. Both doses of SCH 39166 attenuated the hyperlocomotion induced by 30 mg/kg of the agonist to a similar degree. However, neither dose was able to reverse either the depressant or the stimulatory effects of 300 mg/kg SKF 38393. These results demonstrate effects of the prototypical D1 agonist previously unobserved, and raise questions concerning the nature of agonist/antagonist interactions at the D1 receptor subtype.     

Place conditioning with the dopamine D1-like receptor agonist SKF 82958 but not SKF 81297 or SKF 77434

While self-administration and place conditioning studies have shown that dopamine D2-like receptor agonists produce reward-related learning, the effects of dopamine D1-like receptor agonists remain equivocal. The present study tested three dopamine D1-like receptor agonists for their ability to induce a place preference. Like control rats treated with amphetamine (2.0 mg/kg i.p.), rats treated with SKF 82958 (+/- -6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1-phenyl-1H- 3-benzazepine hydrobromide; 0.05 but not 0.01, 0.025, 0.075, or 0.10 mg/kg s.c. and/or i.p.) during conditioning showed a significant increase in the amount of time spent on the drug-paired side during the drug free test. Neither SKF 81297 (+/- -6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; 0.25, 0.50, 1.0, 2.0, and 4.0 mg/kg i.p.) nor SKF 77434 (+/- -7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride; 0.20, 1.0, 5.0, and 10.0 mg/kg i.p.) produced place conditioning. Significant increases in locomotion were seen at some doses of all drugs. Results show for the first time that systemic administration of a dopamine D1-like receptor agonist produces a place preference and are consistent with previous findings showing that dopamine D1-like receptor activation produces reward-related learning.     

Infusion of the dopamine D1 receptor antagonist SCH 23390 into the amygdala blocks fear expression in a potentiated startle paradigm

Peptide 161-180 of human interphotoreceptor retinoid-binding protein (IRBP) contains a major uveitogenic epitope for mice of the H-2r haplotype. The human and bovine homologs differ from the autologous murine homolog by three and four amino acid residues, respectively. We compare the immunogenicity and pathogenicity of the three homologs, and investigate their ability to induce oral tolerance to experimental autoimmune uveoretinitis (EAU) induced by the autologous peptide. All three 161-180 homologs were pathogenic, with a hierarchy: human > murine > bovine. All crossreacted with each other and with IRBP. Feeding any of the three homologs (6 x 200 microg over 2 weeks) lowered antigen-specific responses and protected from EAU induced by the autologous homolog, and reduced EAU induced with whole IRBP. Peptide-fed mice had a reduced frequency of peptide-reactive T cells, suggesting a mechanism involving anergy and/or deletion. The results indicate that non-identical, but crossreactive, heterologous epitopes can protect against EAU induced by the corresponding autologous epitope, and even by the whole multi-epitope protein. These findings may impact on clinical trials in which uveitis patients are undergoing oral immunotherapy with bovine retinal antigens.     

Effects of full D1 dopamine receptor agonists on firing rates in the globus pallidus and substantia nigra pars compacta in vivo: tests for D1 receptor selectivity and comparisons to the partial agonist SKF 38393

Many studies have used the D1 agonist SKF 38393 to characterize D1 receptor influences on firing rates in basal ganglia nuclei in vivo. However, SKF 38393 is a partial agonist and so may not be ideal for delineating D1 receptor effects. This study characterizes the effects of four full D1 agonists, SKF 82958 (chloro-APB), SKF 81297 (6-chloro-PB), dihydrexidine and A-77636, on the firing rates of midbrain dopamine and globus pallidus neurons. Recordings were done in fully anesthetized or paralyzed, locally anesthetized rats, and drugs were given systemically intravenously. Dihydrexidine, SKF 81297 and A-77636 were free of rate effects on midbrain dopamine neurons (up to 10.2 mg/kg) and also did not antagonize the inhibitory effects of quinpirole. In contrast, SKF 82958 strongly inhibited dopamine cells through activation of D2 autoreceptors (ED50 = 0.70 mg/kg). Of these drugs, SKF 82958 also was the only one to increase pallidal unit firing rates when given alone (at 5.0 but not 1.0 mg/kg); the other compounds appeared to be selective for postsynaptic D1 receptors. The results suggest that SKF 82958 may be more properly classified as a mixed D1/D2 agonist. In addition, all four agonists strongly potentiated the pallidal response to quinpirole, demonstrating a D1 receptor potentiation of D2 receptor effects. The results support the role of D1 receptors in the midbrain and globus pallidus as previously characterized with SKF 38393. The similar actions of partial and full D1 agonists in these systems support evidence for a D1 receptor reserve and possibly an effector system other than adenylate cyclase.     

Lesions of the amygdala, but not of the cerebellum or red nucleus, block conditioned fear as measured with the potentiated startle paradigm.

In Exp I, 97 male Sprague-Dawley albino rats were given 10 light–shock pairings on 2 successive days. At 24–48 hrs following training, groups of Ss received bilateral transection of the cerebellar peduncles, bilateral lesions of the red nucleus (which receives most of the cerebellar efferents), or bilateral lesions of the central nucleus of the amygdala. Controls were sham operated. At 3–4 days after surgery, Ss were tested for potentiated startle (PS [increased acoustic startle in the presence of the light previously paired with shock]). PS was blocked by lesions of the central nucleus of the amygdala but not by transection of the cerebellar peduncles or lesions of the red nucleus. Exp II, in which a visual prepulse test was used with 14 Ss, indicated that the blockade of PS observed in Ss with amygdala lesions could not be attributed to optic tract damage. Exp III, with 20 Ss, demonstrated that the absence of potentiation in Ss with amygdala lesions was not simply due to a lowered startle level ceiling, because these Ss could show increased startle with increased stimulus intensity and with administration of intraperitoneal strychnine, (0.75 mg/kg), a drug that increases startle. Results are consistent with the hypothesis that the amygdala is involved in fear conditioning. (64 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The antisecretory effects of clozapine, a dopamine D4 receptor antagonist, are blocked by the dopamine D1 receptor antagonist, SCH23390

Dopaminergic compounds affect gastric secretion and response to experimental gastric mucosal injury. We showed previously that the novel dopamine D4 receptor antagonist, clozapine, significantly reduces gastric acid secretion and restraint stress-induced gastric lesions. Because the selectivity of clozapine for D4 receptors has recently been questioned, we tested the ability of a known D1 receptor blocker, SCH23390, to affect clozapine-induced reduction in gastric acid secretion. SCH23390 given i.p. or i.c.v., at doses that did not affect gastric acid secretion, significantly blocked the anti-secretory effect of clozapine, administered either peripherally or centrally. These data suggest that neither clozapine nor SCH23390 exhibit as high a degree of selectivity for the dopamine D4 and D1 receptor, respectively, as previously believed.     

Behavioral effects of psychomotor stimulants in rats with dorsal or ventral subiculum lesions: Locomotion, cocaine self-administration, and prepulse inhibition of startle.

Compelling evidence suggests a primary role for the mesoaccumbens dopaminergic pathway in the behavioral effects of amphetamine and cocaine, but the roles of other projections to the accumbens, including those arising in the hippocampal formation, are less clear. The authors evaluated the effects of discrete excitotoxic lesions of either the dorsal or ventral subiculum on the locomotor activating, reinforcing, and sensorimotor gating-disruptive effects of psychomotor stimulant drugs. Whereas dorsal subiculum-lesioned rats were hyperactive in tests of exploratory locomotion and startle reactivity, ventral subiculum-lesioned rats exhibited an attenuated locomotor response to amphetamine, moderately impaired acquisition of cocaine self-administration, and reduced levels of prepulse inhibition of startle. These 2 behavioral profiles overlap considerably with those previously observed in rats with lesions of the rostrodorsal and caudomedial accumbens, respectively, and suggest that projections from dorsal subiculum to accumbens core and ventral subiculum to accumbens shell exert distinct influences on behavioral responses that are amplified by psychomotor stimulant drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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

Two experiments showed that having two incongruent words present on a single Stroop trial (e.g., both red and green in blue, say "blue") did not alter interference relative to having only one incongruent word. This was true whether the two incongruent words were presented successively at several stimulus onset asynchronies (Experiment 1) or simultaneously in adjacent positions (Experiment 2). We argue that the first word captures attention and "locks out" others, preventing additional interference.     

The push-pull action of dopamine on spatial tuning of the monkey retina: the effects of dopaminergic deficiency and selective D1 and D2 receptor ligands on the pattern electroretinogram

Retinal dopamine depletion in monkeys using either systemic MPTP or 6-OHDA results in attenuated electroretinographic (ERG) responses to peak spatial frequency stimuli. Diverse dopamine receptors have been identified in the primate retina. ERG studies performed using Haloperidol (a mixed antagonist), L-Sulpiride (D2 antagonist) and CY 208-243 (a D1 agonist) cause spatial frequency dependent diverse effects. 'Tuning' of the normal spatial contrast response PERG, was quantified by dividing the amplitude of the response at the peak spatial frequency with the amplitude to the low spatial frequency response yielding a number greater than one. Tuning for the pharmacological experiments was defined by dividing the actual amplitude obtained at the normal peak response with the actual amplitude at the low spatial frequency response. The PERG spatial contrast response function is discussed as the envelope output of retinal ganglion cells or the average or 'equivalent' retinal ganglion cell. However, we postulate the existence of two dopamine sensitive pathways with different weights for two classes of ganglion cells. It is inferred that D1 receptors are primarily affecting the 'surround' organization of ganglion cells with large centers, while D2 post-synaptic receptors contribute to 'center' response amplification of ganglion cells with smaller centers. These inferences are consistent with some lower vertebrate data. It is also inferred that low affinity D2 autoreceptors may be involved in the D1 'surround' pathway. An understanding of the logic performed by retinal D1 and D2 receptors may be useful to discern the functional role of diverse dopamine receptors in DA circuits elsewhere in the CNS.     

2-aminotetralin-derived substituted benzamides with mixed dopamine D2, D3, and serotonin 5-HT1A receptor binding properties: a novel class of potential atypical antipsychotic agents

A new chemical class of potential atypical antipsychotic agents, based on the pharmacological concept of mixed dopamine D2 receptor antagonism and serotonin 5-HT1A receptor agonism, was designed by combining the structural features of the 2-(N,N-di-n-propylamino)tetralins (DPATs) and the 2-pyrrolidinylmethyl-derived substituted benzamides in a structural hybrid. Thus, a series of 35 differently substituted 2-aminotetralin-derived substituted benzamides was synthesized and the compounds were evaluated for their ability to compete for [3H]-raclopride binding to cloned human dopamine D2A and D3 receptors, and for [3H]-8-OH-DPAT binding to rat serotonin 5-HT1A receptors in vitro. The lead compound of the series, 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (12a), displayed high affinities for the dopamine D2A receptor (Ki = 3.2 nM), the dopamine D3 receptor (Ki = 0.58 nM) as well as the serotonin 5-HT1A receptor (Ki = 0.82 nM). The structure-affinity relationships of the series suggest that the 2-aminotetralin moieties of the compounds occupy the same binding sites as the DPATs in all three receptor subtypes. The benzamidoethyl side chain enhances the affinities of the compounds for all three receptor subtypes, presumably by occupying an accessory binding site. For the dopamine D2 and D3 receptors, this accessory binding site may be identical to the binding site of the 2-pyrrolidinylmethyl-derived substituted benzamides.     

The effects of D1 or D2 dopamine receptor antagonism in the medial preoptic area, ventral pallidum, or nucleus accumbens on the maternal retrieval response and other aspects of maternal behavior in rats.

The medial preoptic area (MPOA), ventral pallidum (VP), and nucleus accumbens (NA) receive dopaminergic afferents and are involved in maternal behavior. Experiments investigated whether dopamine (DA) receptor antagonism in NA disrupts maternal behavior, determined the type of DA receptor involved, and investigated the involvement of drug spread to VP or MPOA. Injection of SCH 23390 (D1 DA receptor antagonist) into NA of postpartum rats disrupted retrieving at dosage levels that were ineffective when injected into MPOA or VP. Motor impairment was not the cause of the deficit. Injection of eticlopride (D2 DA receptor antagonist) into NA or VP was without effect. Results emphasize the importance of DA action on D1 receptors in NA for retrieval behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interaction with the aromatic hydrocarbon receptor, CYP1A induction, and mutagenicity of a series of diaminotoluenes: implications for their carcinogenicity

The present study was undertaken to provide a rationale for the marked difference in carcinogenic potential among isomeric diaminotoluenes, in relation to their ability to induce their own bioactivation through CYP1A induction, their genotoxic potential, and their ability to bind to the cytosolic aromatic hydrocarbon (Ah) receptor. Of the four possible diaminotoluenes only the 2,3- and, to a lesser extent, the 2,4-isomer induced CYP1A activity. Similarly, only these two isomers could displace [3H]T-CDD from the hepatic cytosolic Ah receptor. In the presence of Aroclor 1254- induced microsomes, 2,4- and 2,6-diaminotoluene were potent mutagens in the Ames test. Only 2,4-diaminotoluene could autoinduce its activation. Of the four isomers only 2,4-diaminotoluene is an established carcinogen and this is compatible with the present observations that it is the only isomer that stimulates its own activation through CYP1A induction, is metabolically converted to genotoxic intermediates, and binds to the Ah receptor. 2,6-Diaminotoluene is recognized as a mutagenic noncarcinogen and in the present studies it elicited a positive mutagenic response in the Ames test but failed to induce CYP1A activity and its own activation, and could not bind to the Ah receptor even at concentrations as high as 5 x 10(-4) M. The present findings demonstrate that in vitro studies are very useful tools in predicting the carcinogenic potency of isomeric chemicals.     

Exendin-(9-39) is an inverse agonist of the murine glucagon-like peptide-1 receptor: implications for basal intracellular cyclic adenosine 3',5'-monophosphate levels and beta-cell glucose competence

The effect of exendin-(9-39), a described antagonist of the glucagon-like peptide-1 (GLP-1) receptor, was evaluated on the formation of cAMP- and glucose-stimulated insulin secretion (GSIS) by the conditionally immortalized murine betaTC-Tet cells. These cells have a basal intracellular cAMP level that can be increased by GLP-1 with an EC50 of approximately 1 nM and can be decreased dose dependently by exendin-(9-39). This latter effect was receptor dependent, as a beta-cell line not expressing the GLP-1 receptor was not affected by exendin-(9-39). It was also not due to the endogenous production of GLP-1, because this effect was observed in the absence of detectable preproglucagon messenger RNA levels and radioimmunoassayable GLP-1. Importantly, GSIS was shown to be sensitive to this basal level of cAMP, as perifusion of betaTC-Tet cells in the presence of exendin-(9-39) strongly reduced insulin secretion. This reduction of GSIS, however, was observed only with growth-arrested, not proliferating, betaTC-Tet cells; it was also seen with nontransformed mouse beta-cells perifused in similar conditions. These data therefore demonstrated that 1) exendin-(9-39) is an inverse agonist of the murine GLP-1 receptor; 2) the decreased basal cAMP levels induced by this peptide inhibit the secretory response of betaTC-Tet cells and mouse pancreatic islets to glucose; 3) as this effect was observed only with growth-arrested cells, this indicates that the mechanism by which cAMP leads to potentiation of insulin secretion is different in proliferating and growth-arrested cells; and 4) the presence of the GLP-1 receptor, even in the absence of bound peptide, is important for maintaining elevated intracellular cAMP levels and, therefore, the glucose competence of the beta-cells.