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.     

Differential involvement of cortical receptor mechanisms in working, short-term and long-term memory

Rats received, through bilaterally implanted indwelling cannulae, 0.5 microliter infusions of 6-cyano-7-nitroquinoxaline2,3-dione (CNQX) (0.5 microgram), D-2-amino-5-phophono pentanoic acid (AP5) (5.0 micrograms), muscimol (0.5 microgram), scopolamine (2.0 micrograms), SCH23390 (2.5 micrograms), saline or a vehicle into the CA1 region of the hippocampus, or into the antero-lateral prefrontal (PRE), posterior parietal (PP) and entorhinal cortex (EC). The infusions were given 6 min prior to one-trial step-down inhibitory avoidance training in order to measure their effect on working memory (WM), or immediately post-training in order to measure their effect on short-term (STM) and long-term memory (LTM), 1.5 and 24 h later, respectively. WM was inhibited by CNQX or muscimol given into any of the cortical areas, by SCH23390 given into CA1, PRE or PP, and by scopolamine given into PRE or EC. STM was unaffected by any of the treatments given into PRE, and was inhibited by CNQX or muscimol given into CA1, PP and EC and by scopolamine given into PP, and enhanced by SCH given into CA1. LTM was inhibited by CNQX, muscimol, scopolamine or SCH23390 given into PRE, by scopolamine given into PP, by SCH23390 given into the entorhinal cortex, and by AP5, CNQX, muscimol or scopolamine given into CA1. The results indicate a differential involvement of the various neurotransmitter systems in the three types of memory in the various brain areas, and a separation of the mechanisms and of the regions involved in each. In addition, some of the findings suggested links between WM and LTM processing in PRE, between WM and STM processing in EC and PP, and between all three types of memory in CA1.     

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.     

Electromyographical differentiation of the components of perioral movements induced by SKF 38393 and physostigmine in the rat

Facial electromyography (EMG) coupled with visual observation was used to investigate spontaneous and drug induced perioral movements in freely moving rats. Four separate perioral behaviours were identified; facial tremor, purposeless chewing, gaping and yawning. Facial tremor, yawning and gaping but not purposeless chewing produced characteristic EMG signals. Normal rats displayed a low level of purposeless chewing, occasional bursts of facial tremor but not gaping or yawning. Each burst of facial tremor was accompanied by a transient increase in purposeless chewing. Administration of the D1 agonist SKF 38393 induced a dose related increase in bursts of facial tremors and consequently an increase in the total number of purposeless chews. Gaping and yawning were not induced by SKF 38393 administration. Administration of the cholinesterase inhibitor physostigmine (0.1-0.4 mg/kg) induced a dose related increase in the total number of purposeless chews, but primarily these were not associated with facial tremor. Administration of physostigmine also increased gaping and yawning. Administration of the D1 antagonist SCH 23390 almost abolished facial tremor in normal treated rats but only partially reduced that induced by SKF 38393 and physostigmine. SCH 23390 reduced purposeless chewing in SKF 38393 treated rats but not in normal or physostigmine treated animals. Administration of the cholinergic antagonist atropine almost abolished facial tremor in normal and physostigmine treated rats, but only reduced by 46% that induced by SKF 38393. Atropine reduced purposeless chewing in normal, physostigmine and SKF 38393 treated animals. Physostigmine induced gaping and yawning were abolished by atropine administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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)     

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.     

Synaptic density of the prefrontal cortex regulated by dopamine instead of serotonin in rats

Recent findings indicate that monoamine contributes to synaptic plasticity. We examined the synaptic density of the prefrontal cortex and parietal cortex of rats using dopamine (DA) antagonists and agonists, as well as serotonin (5-HT) depleters and found a reduction in synaptic density in the prefrontal cortex lamina V-VI at a maximum of 20% with administration of a D1 antagonist (SCH23390) and at a maximum of 30% with a D2 antagonist (YM09151). Further, with the administration of D1+D2 antagonists there was a 27% decrease in synaptic density, which was a larger reduction than the total of the single dosages of each DA antagonist at equal levels. Increase in synaptic density was seen at a maximum of 8.5% with dosage of a D1 agonist (SKF38390) and 14.5% with dosage of a D2 agonist (PPHT). The dosage of D1+D2 agonists showed a 27.1% increase in synaptic density. There was no change in synaptic density of the parietal cortex with either DA antagonist or agonist administration. Administration of 5-HT depleter pCPA resulted in a 13.8% reduction of synaptic density in the parietal cortex, though there was no change identified in the synaptic density in the prefrontal cortex. Based on these results, it was suggested that the area of the brain with affected synaptic plasticity could differ, depending on the type of monoamine.     

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.     

Fencamfamine modulates sodium, potassium-ATPase through cyclic AMP and cyclic AMP-dependent protein kinase in rat striatum

Dopamine (DA) and fencamfamine (FCF) modulatory action on Na,K-ATPase and Mg-ATPase activity were evaluated in rat striatum. DA and FCF induced a decrease in Na,K-ATPase, without affecting Mg-ATPase activity. The effect of FCF was dose-dependent from 10 to 100 microM, with an IC50 of 4.7 x 10(-5) M. Furthermore, the effect of FCF (100 microM) increasing AMPc levels, but not GMPc, was nonadditive with that of DA (10 microM), which is consistent to a common site of action. The 8-bromo-cyclic AMP also induced a specific reduction in the Na,K-ATPase activity. The reduction of Na,K-ATPase induced by FCF (100 microM) was blocked by either SCH 23390 or sulpiride, which are D1 and D2 receptor antagonists. The decrease in striatal NA,K-ATPase activity induced by FCF was blocked by KT 5720, a selective inhibitor of cyclic AMP-dependent protein kinase (PKA), but not by KT 5823, a selective inhibitor of cyclic GMP-dependent protein kinase (PKG). Otherwise, KT 5720 or KT 5823 did not produce any change in Na,K-ATPase or Mg-ATPase activity. These data suggest that FCF reduces Na,K-ATPase activity through cyclic AMP-dependent changes in protein phosphorylation via a PKA mechanism.     

Dopamine-induced relaxation in isolated intrarenal arteries from adult stroke-prone spontaneously hypertensive rats

1. The relaxant effects of dopamine (DA) on the intrarenal arteries obtained from 6 month old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar-Kyoto (WKY) rats were pharmacologically investigated in vitro. 2. DA (10(-7)-3 x 10(-5) mol/L) produced endothelium-independent relaxation on the arterial rings which had been incubated with phenoxybenzamine (2 x 10(-6) mol/L) and precontracted with KCl. 3. DA-induced relaxation was greater in the arterial rings from SHRSP than in those from WKY. SKF 38393 (10(-8)-10(-6) mol/L) partially mimicked DA-produced relaxation in both groups. SCH 23390 dose-dependently inhibited DA-induced relaxation with pD'2 value of 9.33 for SHRSP and of 9.26 for WKY. 4. There were no significant differences between SHRSP and WKY in the relaxation caused by forskolin, dibutyryl cyclic AMP, or 3-isobutyl-1-methylxanthine. 5. These results suggested that DA1 receptor-mediated relaxation was increased in the intrarenal arteries from SHRSP, and this increase might not be associated with altered vasodilation mediated by cyclic AMP.     

Agonist-induced desensitization of adenylyl cyclase activity mediated by 5-hydroxytryptamine7 receptors in rat frontocortical astrocytes

A reward-relevant relationship between dopamine projection regions of the ventral tegmental area (VTA) was investigated through the use of brain stimulation reward (BSR) thresholds. Using a rate-free method, changes in VTA BSR thresholds were determined after intracranial injections of the dopamine D1 antagonist, SCH 23390 into the prefrontal cortex (PFC), or the nucleus accumbens (NAcc). Reward thresholds assessed immediately after the infusion of SCH 23390 into the NAcc (0.5 microgram/0.5 microliter/side) were significantly higher than those assessed just after saline infusions, indicating a drug-induced attenuation of the rewarding effects of the brain stimulation. The effects of this dose subsided when tested 24 h later. Conversely, intra-PFC infusions of SCH 23390 at the same dose (0.5 microgram/0.5 microliter/side) resulted in lowered BSR thresholds when rats were tested immediately after infusion. In addition, animals tested 24 h after receiving the lowest dose (0.125 microgram/0.5 microliter/side) demonstrated a robust delayed threshold-lowering effect. These immediate and delayed effects of the intra-PFC dopamine antagonist demonstrate a facilitation of VTA BSR and are consistent with the view that PFC dopamine serves a modulatory role over important reward elements within the NAcc. The deferred effects of intra-prefrontal cortex DA receptor blockade on brain stimulation reward thresholds may reflect adaptive responses of subcortical structures to changes in PFC dopamine neurotransmission. It has been suggested that neural adjustments of this type may underlie long term changes in central nervous system functioning brought about by disease, drug use or behavioral conditioning.     

Dopamine decreases the excitability of layer V pyramidal cells in the rat prefrontal cortex

In both primates and rodents, the prefrontal cortex (PFC) is highly innervated by dopaminergic fibers originating from the ventral tegmental area, and activation of this mesocortical dopaminergic system decreases spontaneous and evoked activity in the PFC in vivo. We have examined the effects of dopamine (DA), over a range of concentrations, on the passive and active membrane properties of layer V pyramidal cells from the rat medial PFC (mPFC). Whole-cell and perforated-patch recordings were made from neurons in rat mPFC. As a measure of cell excitability, trains of action potentials were evoked with 1-sec-long depolarizing current steps. Bath application of DA (0.05-30 microM) produced a reversible decrease in the number of action potentials evoked by a given current step. In addition, DA reversibly decreased the input resistance (RN) of these cells. In a subset of experiments, a transient increase in excitability was observed after the washout of DA. Control experiments suggest that these results are not attributable to changes in spontaneous synaptic activity, age-dependent processes, or strain-specific differences in dopaminergic innervation and physiology. Pharmacological analyses, using D1 agonists (SKF 38393 and SKF 81297), a D1 antagonist (SCH 23390), a D2 receptor agonist (quinpirole), and a D2 antagonist (sulpiride) suggest that decreases in spiking and RN are mediated by D2 receptor activation. Together, these results demonstrate that DA, over a range of concentrations, has an inhibitory effect on layer V pyramidal neurons in the rat mPFC, possibly through D2 receptor activation.     

Homologous desensitization of the D1A dopamine receptor: efficacy in causing desensitization dissociates from both receptor occupancy and functional potency

The role of drug efficacy in agonist-induced desensitization was studied in C-6 glioma cells transfected with the monkey dopamine D1A (mD1A) receptor. Dopamine pretreatment for 2 hr produced greater than 80% loss of responsiveness in the stimulation of cAMP accumulation that was blocked by the D1 antagonist SCH23390. A series of full and partial D1 agonists from structurally dissimilar classes were then examined. Three full agonists (dihydrexidine, SKF82958, A77636) desensitized the receptor to the same extent as dopamine, whereas two other full agonists (dinapsoline and A68930) and all the partial agonists tested (SKF38393, pergolide and d-lysergic acid diethylamide tartrate) produced only partial desensitization (i.e., 50% that of dopamine). Whereas partial agonists (i.e., SKF38393, pergolide and d-lysergic acid diethylamide tartrate) caused no alteration in ligand-accessible mD1A receptors, four of the full agonists (dopamine, dihydrexidine, dinapsoline, A68930) caused a 30 to 40% reduction in receptor number. One full agonist, A77636, caused nearly an 80% decrease in receptor number, despite the fact that the degree of functional desensitization was similar to the other full agonists. The desensitization of the D1 receptor was homologous, not affecting beta-2 adrenergic receptors endogenous to C-6 cells. Neither incubation with cAMP analogs, nor inhibition of protein kinase A, affected dopamine-induced desensitization, suggesting a cAMP-independent mechanism in this cell line. Together, these data suggest that functional desensitization of the mD1A receptor expressed in C-6 glioma cells is a cAMP-independent mechanism, cannot be predicted reliably from agonist efficacy for stimulating adenylate cyclase and can occur in the absence of changes in receptor number.     

Factors affecting the efficiency of peripheral blood stem cell collection in children treated with chemotherapy and G-CSF

Post-training administration of morphine (0.25, 0.5, or 1 mg/kg) dose-dependently impairs retention of an inhibitory avoidance response in mice. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation. In fact, they were observed when drugs were given at short, but not long, periods of time after training, i.e., when the memory trace was susceptible to modulation. Moreover, these effects are not to be ascribed to an aversive or a rewarding or nonspecific action of the drugs on retention performance, because the latencies during the retention test of those mice that had not received a footshock during the training were not affected by post-training drug administration. Pretreatment with either selective D1 or D2 dopamine (DA) receptor antagonists SCH 23390 and (-)-sulpiride administered at per se noneffective doses (0.025 and 6 mg/kg, respectively) potentiated the effects of morphine, while either selective D1 or D2 receptor agonists SKF 38393 and LY 171555 at per se noneffective doses (5 and 0.25 mg/kg, respectively) antagonized the effects of the opiate on memory consolidation. No significant differences were evident between the effects of D1 and D2 receptor active compounds, thus suggesting that D1 and D2 receptor types are similarly involved in the effects of morphine on memory consolidation, in agreement with previously reported results. These results are discussed in terms of a possible inverse relationship of endogenous opioid and DA systems in the brain that are involved in memory processes.     

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.     

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)     

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.     

Inhibition of the mesoamygdala dopaminergic pathway impairs the retrieval of conditioned fear associations.

Previous findings have demonstrated that systemic dopaminergic manipulations impair the retrieval of Pavlovian conditioned fear. A second-order fear-conditioning paradigm was used to test whether the dopaminergic projection from the ventral tegmental area (VTA) to the lateral and basal amygdala (LBA) can affect conditioned fear. Phase 1 entailed conditioned stimulus-unconditioned stimulus (CS1-US) pairings. In Phase 2, drugs were infused in either the LBA or VTA prior to pairings of CS2 (a second cue) with CS1. In Phase 3, freezing behavior elicited by CS2 was tested without drugs. Infusions of the D2 agonist quinpirole into the VTA or of the D1 antagonist SCH 23390 into the LBA caused a decrease in freezing to CS2. Both manipulations decrease D1 receptor activation in the LBA. Infusions of the D1 agonist SKF 38393 into the LBA had no effect. This pattern of results is consistent with the hypothesis that the VTA-LBA dopaminergic projection modulates the retrieval of an association between a CS and footshock US. (PsycINFO Database Record (c) 2010 APA, all rights reserved)