The quality of the discharge planning process: the effect of a liaison nurse

Nitric oxide (NO) in brain has been implicated in neuronal regulatory processes and in neuropathologies. Previously we showed that NO modified quinpirole-induced yawning, a behavioral measure of dopamine (DA) D3 receptor activation in rats. The aim of this study was to characterize the effect of nitro-L-arginine methyl ester HCl (NAME) and L-arginine HCl on reactivity of rats to the DA D1 receptor agonist SKF 38393 and DA D1 antagonist SCH 23390 in intact and neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats (134 micrograms of base ICV at 3rd day after birth). L-arginine HCl (300 mg/kg i.p.) increased the oral activity response in 6-OHDA-lesioned rats, like SKF 38393, and induced catalepsy in intact control rats, like SCH 23390. In contrast, NAME had no effect on oral activity or catalepsy, but fully attenuated SKF 38393-induced oral activity. These findings indicate that L-arginine HCl has no apparent effect at the DA D1 receptor, but that NAME is effective in attenuating a DA D1 agonist-induced effect. Consequently NO may be an intracellular second messenger for supersensitized receptors associated with DA D1 agonist-induced oral activity.     

Partial and full dopamine D1 agonists produce comparable increases in ventral pallidal neuronal activity: contribution of endogenous dopamine

Systemic administration of the partial DA D1 agonist SKF38393 often increases the firing rate of neurons in the VP of rats. This study extended this finding by comparing responses to (+/-)SKF38393 with those produced by two D1 agonists that have greater intrinsic efficacy, (+/-)SKF82958 and (+/-)DHX. The role of endogenous DA in D1 agonist-induced effects also was examined. Extracellular recordings of single VP neurons were obtained in chloral hydrate-anesthetized male rats, to which equimolar doses of SKF38393, SKF82958 or DHX were administered i.v. Each of the agonists increased firing rate in about 45% of the neurons tested. Moreover, each agonist produced the same maximal increase in activity (161% to 178% of spontaneous rate). Acute decreases in synaptic DA, produced by either GBL or combined treatment with reserpine and AMPT, potentiated the maximal increase in activity evoked by SKF38393 or SKF82958. These DA-depleting treatments did not alter the percentage of neurons that displayed this response to D1 agonist challenge. Low doses of the selective D1 antagonists SCH23390 or SCH39166 generally attenuated the agonist-induced changes in firing rate, supporting the conclusion that D1 receptors were activated by SKF38393, SKF82958 and DHX. Thus, these three D1 agonists, which produce different maximal increases in striatal adenylyl cyclase activity, had comparable efficacy to increase VP neuronal activity. A reduction in endogenous DA enhanced the D1 agonist-induced effects, possibly through a reduction in inhibitory influences on VP neurons that are mediated by other DA receptor subtypes.     

Relationship between dopamine agonist stimulation of inositol phosphate formation and cytidine diphosphate-diacylglycerol accumulation in brain slices

Dopamine receptor-coupled stimulation of inositol phosphate formation has been characterized extensively, but little is known about the diacylglycerol arm of this dual-signaling pathway. This study examined several parameters of cytidine diphosphate-diacylglycerol (CDP-DG) accumulation as an index of agonist-stimulated DG formation. Rat brain slices pre-labeled with 5-[3H]cytidine were incubated with various test agents in the presence of LiCl and accumulated CDP-DG analyzed. Dopamine and SKF38393 significantly and dose-dependently stimulated CDP-DG accumulation. SKF38393 responses were inhibited by neomycin and reversed by myo-inositol or by exclusion of LiCl. Compared to inositol phosphate formation in 2-[3H]inositol-prelabeled slices, the CDP-DG responses were proportionately greater, while the agonist EC50 values were similar between the two assays. The D1-receptor antagonist SCH23390 inhibited SKF38393-mediated responses at 0.1-10 microM concentrations, whereas greater concentrations reversed the inhibition. SKF38393 effects were completely blocked by the DG kinase inhibitor R59022, thus precluding any role for phospholipase-D or de novo phosphatidate synthesis in the dopaminergic response. D609 which inhibits phosphatidylcholine-specific phospholipase-C (PLC), potently inhibited both CDP-DG accumulation and inositol phosphate formation. These findings demonstrate that the selective D1-receptor antagonist SCH23390 is a partial agonist at the D1-like dopamine receptor that couples to phosphoinositide signaling, that dopaminergic facilitation of phosphoinositide signaling is independent of de novo phosphatidate synthesis, and that the widely used enzyme inhibitor, D-609, is probably not selective for phosphatidylcholine-specific PLC in brain slice preparations. The greater sensitivity of the CDP-DG measurement presents this assay as a reliable and possibly superior index of dopamine receptor-coupled PLC activation in intact tissues.     

Late and prolonged post-training memory modulation in entorhinal and parietal cortex by drugs acting on the cAMP/protein kinase A signalling pathway

Rats implanted bilaterally with cannulae in the entorhinal or posterior parietal cortex or in the amygdaloid nucleus were trained in one-trial step-down inhibitory (passive) avoidance using a 0.3 mA footshock. At 0, 3, 6 or 9 h after training, they received localized 0.5 microliter infusions into these areas of a vehicle, or of 8-Br-cAMP, forskolin (adenylyl cyclase activator), KT5720 (protein kinase A inhibitor), SKF38393 (dopamine D1 receptor agonist), SCH23390 (D1 antagonist), norepinephrine hydrochloride, timolol hydrochloride (beta blocker), 8-HO-DPAT (5-HT1A receptor agonist) or NAN-190 (5-HT1A antagonist) dissolved in 20% dimethylsulfoxide (DMSO) in saline (vehicle). Rats were tested for retention 24 h after training. 8-Br-cAMP, forskolin, SKF 38393 and norepinephrine caused memory facilitation and KT5720, SCH23390, timolol and 8-HO-DPAT caused retrograde amnesia when given into the entorhinal cortex 0, 3 or 6 h but not 9 h after training. When given into the posterior parietal cortex 0, 3 or 6 but not 9 h after training, KT5720 was amnestic. When given into this structure 3 or 6 h but not 0 or 9 h after training 8-Br-cAMP, forskolin and norepinephrine caused memory facilitation and KT5720, SCH23390 and timolol caused retrograde amnesia. All treatments given into the amygdala 0, 3 or 6 h after training were ineffective except for norepinephrine given at 0 h, which caused facilitation. The data point to a role of cAMP/protein kinase A-dependent mechanisms in memory formation in the entorhinal and parietal cortex, but not the amygdala, from 0 to 6 h after training, and to a strong modulation of these mechanisms by dopaminergic D1, beta-noradrenergic and 5-HT1A receptors. The lack of effect of NAN-190 but not 8-HO-DPAT in both cortical regions suggests that 5-HT1A receptors do not play a physiological role but can be activated pharmacologically. The fact that SCH23390 was amnestic but SKF38393 had no effect when given into the parietal cortex suggests that D1 receptors may play a maintenance rather than a stimulant role in this area.     

Synergistic interaction of D1 and D2 dopamine receptors in the modulation of the reinforcing effect of brain stimulation.

Rats were trained to press a bar for hypothalamic stimulation, and a frequency-response function was plotted. Quinpirole (a selective D2 agonist) facilitated self-stimulation when injected alone but failed to show the facilitatory effect when injected either 1 hr before or 1 hr after injection of SCH 23390 (a D1 antagonist). Injection of reserpine followed by α-methyl-p-tyrosine virtually eliminated self-stimulation. Subsequent injection of either SKF 38393 (a D1 agonist) alone or quinpirole alone did not restore self-stimulation, but a combination of quinpirole and SKF 38393 did. Results suggest that a D2 dopamine agonist facilitates the reinforcing effect of brain stimulation only if D1 receptors are activated by endogenous dopamine or by an exogenous agonist. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Morphology and molecular biology: can the latter ignore the former? An imaginary dialogue

The effects of the opioid receptor antagonist naloxone on behavioural responses to the dopamine D1 receptor agonist SKF 38393 ((+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride) were assessed in the rat. SKF 38393 (5 mg/kg s.c.) induced grooming and vacuous chewing mouth movements. SKF 38393-induced grooming was dose-dependently attenuated by naloxone (0.375-1.5 mg/kg s.c), while vacuous chewing movements were unaffected. These findings suggest that dopamine D1 receptor agonist-induced grooming is dependent upon opioid systems, while vacuous chewing movements are likely to be mediated via different pathways.     

Drugs acting upon the cyclic adenosine monophosphate/protein kinase A signalling pathway modulate memory consolidation when given late after training into rat hippocampus but not amygdala

Rats implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus or in the amygdala were trained in one-trial step-down inhibitory (passive) avoidance using a 0.4 mA footshock. At various times after training (0, 1.5, 3, 6 or 9 h for animals implanted in the hippocampus; 0 or 3 h for those implanted in the amygdala), they received infusions of 8-Br-cAMP (cyclic adenosine monophosphate) (1.25 micrograms/side), SKF38393 (7.5 micrograms/side), SCH23390 (0.5 microgram/side), norepinephrine ClH (0.3 microgram/side), timolol ClH (0.3 microgram/side), 8-HO-DPAT (2.5 micrograms/side), NAN-190 (2.5 micrograms/side), forskolin (0.5 microgram/side) or KT5720 (0.5 microgram/side). Rats were tested for retention 24 h after training. SKF38393 is an agonist and SCH23390 an antagonist at dopamine D1 receptors, timolol is a beta-adrenoceptor antagonist, 8-HO-DPAT is an agonist and NAN-190 an antagonist at 5HT1A receptors, forskolin enhances adenylyl cyclase, and KT5720 inhibits protein kinase A. When given into the hippocampus 0 h post-training, norepinephrine enhanced memory and KT5720 was amnestic. When given 1.5 h after training, all treatments were ineffective. When given 3 or 6 h post-training, 8-Br-cAMP, forskolin, SKF 38393, noradrenaline and NAN-190 caused memory facilitation, and KT5720, SCH23390, timolol and 8-HO-DPAT caused retrograde amnesia. At 9 h from training, all treatments were again ineffective. When given into the amygdala 0 or 3 h post-training all treatments were ineffective, except for noradrenaline at 0 h, which caused retrograde facilitation. The data agree with the suggestion that in the hippocampus, but not the amygdala, a cAMP/protein kinase A pathway is involved in memory consolidation at 3 and 6 h from training, and that this is regulated by D1, beta, and 5HT1A receptors. This correlates with a previous report of increased cAMP levels, protein kinase A activity and P-CREB levels at 3-6 h from training in rat hippocampus in this task. This may be taken to suggest that the hippocampus, but not the amygdala, is involved in the long-term storage of step-down inhibitory avoidance in the rat.     

D? dopamine receptor involvement in the rough-and-tumble play behavior of juvenile rats.

By using dorsal contacts and pinning to quantify play behavior in juvenile rats, it was found that the D? agonist, quinpirole, reduced both measures of play at doses greater than 0.05 mg/kg. Eticlopride, a D? antagonist, also reduced both measures of play and blocked the reduction caused by quinpirole. The effect of quinpirole on play was largely unaffected by concurrent administration of either a D? agonist (SKF 38393) or a D? antagonist (SCH 23390), suggesting that D? and D? receptors are functionally independent with respect to play behavior. Quinpirole also reduced overall activity, suggesting that the effects on play may not be selective to neural circuitry responsible for play behavior. Although low doses of quinpirole (0.001–0.03 mg/kg) had a tendency to increase pinning, this effect was not very robust. These data suggest that D? dopamine receptors may not have a major role in the control of play behavior in juvenile rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of long-term haloperidol treatment on striatal neuropeptides: relation to stereotyped behavior

Behavioral and biochemical responses to D1 and D2 dopamine (DA) agonists were used to evaluate the participation of striatal peptidergic mechanisms in the motor function alterations that attend chronic neuroleptic treatment. Rats, given haloperidol (1 mg/kg, i.c.) for 21 consecutive days, were randomly allocated to one of the following treatments: the D1 agonist SKF 38393, the D2 agonist quinpirole, their combination or saline. Stereotyped behavior and neuropeptide levels were evaluated after 5 days treatment and 4 days washout. Haloperidol increased most oral behaviors including licking, chewing and biting as well as striatal enkephalin and somatostatin levels. Subsequent treatment with SKF 38393 diminished the haloperidol-induced increase in licking and chewing; quinpirole reduced chewing behavior. The administration of both agonists together decreased chewing and biting. Neither DA agonist alone, nor their combination, reduced the haloperidol-induced increase in enkephalin levels. Both SKF 38393 and quinpirole, when given alone, tended to decrease the haloperidol-induced increase in somatostatin levels; when both D1 and D2 agonists were administered together, somatostatin levels declined significantly. These results suggest that somatostatin- but not enkephalin-containing striatal neurons contribute to the expression of haloperidol-induced stereotypies.     

Opposing roles for dopamine D1 and D2 receptors in the regulation of hypothalamic tuberoinfundibular dopamine neurons

The purpose of the present study was to characterize pharmacologically dopamine D1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons in males rats, and to determine if inhibitory dopamine D1 receptors oppose stimulatory dopamine D2 receptors and account for the inability of mixed dopamine receptor agonists to alter the activity of these neurons. Tuberoinfundibular dopamine neuronal activity was estimated by measuring the concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence, the region of the hypothalamus containing terminals of these neurons. Administration of the dopamine D1 receptor agonist (+/-)-1 phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol (SKF38393) decreased median eminence DOPAC and increased plasma prolactin concentrations, whereas administration of the dopamine D1 receptor antagonist ((-)-trans,6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo[d]naphtho-[2,1 b]azepine (SCH39166) increased median eminence DOPAC concentrations but had not effect on plasma prolactin. The inhibitory effect of SKF38393 on median eminence DOPAC concentrations was blocked by SCH39166. These results demonstrate that acute activation of dopamine D1 receptors inhibits the activity of tuberoinfundibular dopamine neurons and thereby increases prolactin secretion, and that under basal conditions dopamine D1 receptor-mediated inhibition of tuberoinfundibular dopamine neurons is tonically active. Administration of the dopamine D2 receptor agonist (5aR-trans)-5,5a,6,7,8,9,9a,10-octahydro-6-propyl-pyridol[2, 3-g]quinazolin-2-amine (quinelorane) increased median eminence DOPAC concentrations, and SKF38393 caused a dose-dependent reversal of this effect. Administration of the mixed dopamine D1/D2 receptor agonist R(-)-10,11-dihydroxy-apomorphine (apomorphine) had no effect per se, but blocked quinelorane-induced increases in DOPAC concentrations in the median eminence. These results reveal that concurrent activation of dopamine D1 and D2 receptors nullifies the actions of each of these receptors on tuberoinfundibular dopamine neurons, which likely accounts for the lack of an acute effect of mixed dopamine D1/D2 receptor agonists on these hypothalamic dopamine neurons.     

Dopaminergic modulation of early signs of excitotoxicity in visualized rat neostriatal neurons

Cell swelling induced by activation of excitatory amino acid receptors is presumably the first step in a toxic cascade that may ultimately lead to cell death. Previously we showed that bath application of N-methyl-D-aspartate (NMDA) or kainate (KA) produces swelling of neostriatal cells. The present experiments examined modulation of NMDA and KA-induced cell swelling by dopamine (DA) and its receptor agonists. Nomarski optics and infra-red videomicroscopy were utilized to visualize neostriatal medium-sized neurons in thick slices from rat pups (12-18 postnatal days). Increase in somatic cross-sectional area served as the indicator of swelling induced by bath application of glutamate receptor agonists. NMDA induced cell swelling in a dose-dependent manner. Activation of DA receptors in the absence of NMDA did not produce swelling. DA and the D1 receptor agonist SKF 38393, increased the magnitude of swelling produced by NMDA. This effect was reduced in the presence of the D1 receptor antagonist, SCH 23390. In contrast, activation of D2 receptors by quinpirole decreased the magnitude of NMDA-induced cell swelling. DA slightly attenuated cell swelling induced by activation of KA receptors. Quinpirole produced a significant concentration-dependent reduction in KA-induced swelling while SKF38393 increased KA-induced swelling, but only at a low concentration of KA. Together, these results provide additional support for the hypothesis that the direction of DA modulation depends on the glutamate receptor subtype, as well as the DA receptor subtype activated. One possible consequence of these observations is that endogenous DA may be an important contributing factor in the mechanisms of cell death in Huntington's disease.     

Effects of dopaminergic drugs on innate pheromone-mediated reward in female mice: A new case of dopamine-independent "liking."

Male sexual pheromones are innately rewarding to adult female mice, but the role of dopamine in this natural reward is unknown. The authors have tackled this issue by assessing the effects of intraperitoneal injections of dopamine D? (SCH 23390, 0.02- 0.05mg/kg) and D? (sulpiride, 20.00 mg/kg) antagonists, a dopamine releasing agent (amphetamine, 0.50 -2.00 mg/kg), and D? (SKF 38393, 10.00 -20.00 mg/kg) and D? (quinpirole, 0.20 -1.00 mg/kg) agonists on the chemoinvestigation displayed by female mice in male- versus female-soiled bedding 2-choice tests. Dopamine antagonists and quinpirole failed to affect the unconditioned preference displayed by females towards male chemosignals, whereas both amphetamine and SKF 38393 abolished it. Finally, D? and D? antagonists did not block the induction of operant place conditioning by male chemosignals. As the female mice were tested in their first encounter with male sexual pheromones, their behavior can only be influenced by the "liking" component of reward. Therefore, the results suggest that dopamine mediates neither the hedonic properties of male sexual pheromones nor the acquisition of conditioned place preference. However, dopamine acting on D1 receptors might inhibit female mice attraction towards male chemosignals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Distributed memory for both short and long term

The present study examined the behavioral effects of dopamine receptor agonists, antagonists, or N-methyl-D-aspartate (NMDA) glutamate receptor antagonist in rats with a unilateral excitotoxic lesion of the globus pallidus (GP). After the unilateral GP lesions were made by injections of the ibotenic acid, drugs were systemically given and the elicited behaviors were quantitatively assessed. Systemic administration of haloperidol, but not SCH23390, dose-dependently induced contraversive dystonic posturing in unilateral GP-lesioned rats. On the other hand, systemic administration of quinpirole, but not SKF38393, induced ipsiversive circling. MK-801, only when given at a high dose, unilateral GP-lesioned rat, the D2 receptor agonist and antagonist caused ipsiversive and contraversive posturing or circling, respectively. Since the rotational behavior is induced on the basis of asymmetry of the basal ganglia output activity, there must be a marked difference between the GP ablation and the administration of D2 receptor blockade on the basal ganglia output activity, supporting a speculation that overactivity of the basal ganglia under dopamine depletion is not solely a result of the disinhibition from the inhibitory GP efferents. The present unilateral GP-lesion model appears to be a useful one for the pharmacobehavioral investigation of D2-mediated mechanisms.     

Role of dopamine D1 and D2 receptors in the nucleus accumbens in mediating reward

The objectives of this study were to examine the involvement of D1 and D2 receptors within the nucleus accumbens (ACB) in mediating reinforcement. The intracranial self-administration (ICSA) of D1 and D2 agonists was used to determine whether activating D1 and/or D2 receptors within the ACB of Wistar rats is reinforcing. At concentrations of 0.25, 0.50, and 1.0 mM (25, 50, and 100 pmol/100 nl of infusion), neither the D1 agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393 (SKF)] hydrochloride nor the D2 agonist (-)-quinpirole (Quin) hydrochloride was self-administered into the shell region of the ACB. On the other hand, equimolar mixtures of SKF and Quin (SKF+Quin), at concentrations of 0.25, 0.50, and 1.0 mM each, were significantly self-infused into the ACB shell. The core region of the ACB did not support the ICSA of SKF+Quin at any of these concentrations. Rats increased lever pressing when the response requirement was increased from a fixed ratio 1 (FR1) to FR3, and they responded significantly more on the infusion lever than they did on the control lever. Coadministration of either 0.50 mM R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine (SCH 23390) hydrochloride, a D1 antagonist, or 0.50 mM S(-)-sulpiride, a D2 antagonist, completely abolished the ICSA of the mixture of SKF+Quin (each at 0.50 mM) into the ACB shell. The present results suggest that concurrent activation of D1- and D2-type receptors in the shell of the ACB had a cooperative effect on DA-mediated reward processes.     

Dopamine D2 receptor-mediated regulation of partner preferences in female prairie voles (Microtus ochrogaster): A mechanism for pair bonding?

This study examined the role of dopamine (DA) in partner preference (PP) formation in female prairie voles (Microtus ochrogaster). The nonspecific DA antagonist haloperidol blocked mating-induced PP, whereas the nonspecific DA agonist apomorphine induced PP without mating. The D2 antagonist eticlopride, but not the D1 antagonist SCH23390, blocked PP, whereas the D2 agonist quinpirole, but not the D1 agonist SKF38393, induced PP without mating. Injections of eticlopride before or immediately after mating, but not 24 hr after mating, impaired PP, indicating that DA's effects were not due to an interference with mating or sensory recognition. Finally, intracerebroventricular (icv) injections of eticlopride diminished PP. Together, these data suggest that mating-induced PP requires activation of D2 receptors and that social experience may activate dopaminergic pathways, with enduring effects on behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amphetamine reinstates polydipsia induced by chronic exposure to quinpirole, a dopaminergic D2 agonist, in rats

The hypothesis that the combined activation of D1 and D2 dopaminergic receptors is instrumental in inducing amphetamine (AMPH)-mediated hyperdipsia was tested in rats. The D1 agonist SKF-38393 (SKF) and the D2 agonist quinpirole (QNP) were i.p. injected, alone or in combination, to male rats for 10 days. After 2 days of wash-out, a single dose of AMPH (3 mg/kg) was administered. Intake of water and food and diuresis were daily measured at 2, 5 and 24 h. In two further experiments the higher dose of QNP (0.56 mg/kg) was given with two different doses of the D1 antagonist SCH-23390 (SCH), or, respectively, of the peripheral D2 antagonist domperidone (DMP). In a fourth experiment, the possibility that QNP, given alone or in combination with SKF, produces an AMPH-like internal state was evaluated by using a drug-discrimination paradigm. Results show that chronic administration of QNP produced a significant increase of 24 h water intake that was reinstated by AMPH. This QNP effect was only partially prevented by DMP, suggesting a main central mechanism of action. By itself D1 receptor manipulation did not affect water intake, but influenced QNP polydipsia that, accordingly, was enhanced by the lower dose of SKF (0.3 mg/kg) and inhibited by the lower dose of SCH (0.01 mg/kg). In rats trained to discriminate AMPH from solvent, QNP partially generalized for the AMPH stimulus, an effect that was potentiated by SKF. In conclusion, a D1-modulated sensitization of D2 dopaminergic mechanisms is probably involved in AMPH-induced hyperdipsia.     

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.     

Enhancement of excessive lever-pressing after post-training signal attenuation in rats by repeated administration of the D? antagonist SCH 23390 or the D? agonist quinpirole, but not the D? agonist SKF 38393 or the D? antagonist haloperidol.

The authors have recently shown that attenuation of an external response feedback leads to excessive lever-pressing that is not associated with attempts to collect reward, and they have suggested that this may be an analogue to "unreasonable" excessive behavior characteristic of obsessive–compulsive disorder. The present study shows that repeated administration of SCH 23390 or quinpirole, but not SKF 38393 or haloperidol, enhances this behavioral pattern. On the basis of data regarding the enduring effects of chronic treatment with dopaminergic agents, these results suggest that overstimulation of striatal D? receptors underlies enhanced response to signal attenuation. These results may link the hypothesis that obsessions and compulsions result from a deficient response feedback mechanism with findings implicating dopaminergic abnormalities in the production of obsessions and compulsions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine D1-like receptor activation excites rat striatal large aspiny neurons in vitro

The aim of this study was to elucidate electrophysiologically the actions of dopamine and SKF38393, a D1-like dopamine receptor agonist, on the membrane excitability of striatal large aspiny neurons (cholinergic interneurons). Whole-cell and perforated patch-clamp recordings were made of striatal cholinergic neurons in rat brain slice preparations. Bath application of dopamine (1-100 microM) evoked a depolarization/inward current with an increase, a decrease, or no change in membrane conductance in a dose-dependent manner. This effect was antagonized by SCH23390, a D1-like dopamine receptor antagonist. The current-voltage relationships of the dopamine-induced current determined in 23 cells suggested two conductances. In 10 cells the current reversed at -94 mV, approximately equal to the K+ equilibrium potential (EK); in three cells the I-V curves remained parallel, whereas in 10 cells the current reversed at -42 mV, which suggested an involvement of a cation permeable channel. Change in external K+ concentration shifted the reversal potential as expected for Ek in low Na+ solution. The current observed in 2 mM Ba2+-containing solution reversed at -28 mV. These actions of dopamine were mimicked by application of SKF38393 (1-50 microM) or forskolin (10 microM), an adenylyl cyclase activator, and were blocked by SCH23390 (10 microM) or SQ22536 (300 microM), an inhibitor of adenylyl cyclase. These data indicate, first, that dopamine depolarizes the striatal large aspiny neurons by a D1-mediated suppression of resting K+ conductance and an opening of a nonselective cation channel and, second, that both mechanisms are mediated by an adenylyl cyclase-dependent pathway.     

Neurotransmitter modulation of gap junctional communication in the rat hippocampus

Increasing experimental evidence indicates that gap junctions can be modulated by neurotransmitters, in particular dopamine. To examine possible modulation of gap junctional communication in the rat hippocampus by neurotransmitters, we studied dye coupling and electrotonic transmission in the CA1 area in the presence of carbachol, a cholinergic agonist, and dopamine agonists. Carbachol markedly reduced dye coupling and the frequency of electrotonic potentials (spikelets). Spikelet amplitudes were decreased in the presence of carbachol. These effects were reversed by the cholinergic antagonist atropine, suggesting a muscarinic action of carbachol on gap junctional function. The non-specific dopamine agonist apomorphine, and the specific D1 receptor agonist SKF 38393, reduced dye coupling between pyramidal cells. Spikelet frequency was also decreased in the presence of dopamine agonists, but less than with carbachol. The specific D1 receptor antagonist, SCH 23390, reversed the effects of both dopamine agonists. These observations indicate that cholinergic and dopaminergic transmission can affect electrical and chemical (dye coupling) communication through gap junctions, and could therefore alter properties of neuronal assemblies, in addition to their effects on intrinsic membrane properties.