Effects of different substance misuse in genital reflexes of paradoxical sleep deprived male rats

As psychostimulants are widely abused, their neurochemical and behavioral effects have been extensively studied for many years. Our previous data demonstrate that paradoxical sleep deprivation (PSD) enhances drug-induced penile erection and ejaculation. PSD in association to drugs of abuse like cocaine potentiated genital reflexes in male rats. In this sense, the present study investigated if three substances abused by young people--such as Delta(9)-tetrahydrocannabinol (Delta(9)THC), alcohol and caffeine--had any significant effect on the genital reflexes in PSD rats. The results indicated that PSD induced erection in 50% of the rats and 20% ejaculated. In addition, there was no significant alteration in the number of animals exhibiting genital reflexes neither on the frequency of these behaviors when challenged with Delta(9)-THC or alcohol or caffeine after 96 h of PSD. These findings show that Delta(9)THC, alcohol and caffeine when administrated isolated did not produce alterations in genital reflexes in the PSD male rats.     

Behavioral profile of L–741,741, a selective D4 dopamine receptor antagonist,in social encounters between male mice

Although the role of dopamine D1–D2–D3 receptors in the modulation of aggression has been extensively documented, there is not information with respect to the implication of D4 receptor. The aim of this study was to examine the acute effects of L–741,741 (0.75, 1.5 and 3 mg/kg, i.p), a selective D4 receptor antagonist, on social encounters between male mice using an ethopharmacological approach. Ten min of diadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. These encounters were videotaped and the accumulated time allocated by subjects to ten broad behavioral categories was estimated. Besides other behaviors, the aggressive and motor behaviors were evaluated 30 min after injection using an ethologically based analysis. L–741,741 did not affect significantly offensive behaviors (threat and attack), as compared with the control group. Likewise, motor and anxiety‐related behaviors (such as social investigation, avoidance/flee or defense submission) were not altered after drug administration. These results suggest that dopamine D4 receptor is not involved in the modulation of aggressive behavior. Aggr. Behav. 29:552–557, 2003. © 2003 Wiley‐Liss, Inc.     

Glucocorticoid-induced impairment of long-term memory retrieval in rats: an interaction with dopamine D2 receptors

This study investigated glucocorticoid-dopaminergic interactions in modulating retrieval of long-term memory in an inhibitory avoidance task. Young adult male rats were trained in one trial inhibitory avoidance task (0.5 mA, 3 s footshock). On the retention test given 48 h after training, the latency to re-enter the dark compartment of the apparatus was recorded. Systemically administered corticosterone (1 or 3 mg/kg) given to rats 30 min before retention testing impaired their memory retrieval, but the lower dose was more effective than the higher one. Administration of the dopamine (DA) D2 receptor antagonist sulpiride (6 or 20 mg/kg) 30 min before corticosterone attenuated the impairing effects of corticosterone (1 mg/kg) on memory retrieval. Administration of the DA D1 receptor antagonist SCH23390 (25 or 50 microg/kg) had no effect on corticosterone-induced impairment of memory retrieval. Further, applied doses of sulpiride or SCH23390 alone were ineffective in modulating memory retrieval. These findings provide evidence for the existence of an interaction between glucocorticoids and DA D2 receptor on memory retrieval process.     

Modulatory influence of dopamine receptors on consolidation of object recognition memory

The role of dopamine receptors in regulating the formation of recognition memory remains poorly understood. Here we show the effects of systemic administration of dopamine receptor agonists and antagonists on the formation of memory for novel object recognition in rats. In Experiment I, rats received an intraperitoneal (i.p.) injection of vehicle, the selective D1 receptor agonist SKF38393 (1.0 and 5.0mg/kg), or the D2 receptor agonist quinpirole (1.0 and 5.0mg/kg) immediately after training. In Experiment II, rats received an injection of vehicle, the dopamine receptor antagonist SCH23390 (0.1 and 0.05 mg/kg), or the D2 receptor antagonist raclopride (0.5 and 0.1mg/kg) before training, followed by an injection of vehicle or the nonselective dopamine receptor agonist apomorphine (0.05 mg/kg) immediately after training. SKF38393 at 5mg/kg produced an enhancement of novel object recognition memory measured at both 24 and 72 h after training, whereas the dose of 10mg/kg impaired 24-h retention. Posttraining administration of quinpirole did not affect 24-h retention. Apomorphine enhanced memory in rats given pretraining raclopride, suggesting that the effect was mediated by selective activation of D1 receptors. The results indicate that activation of D1 receptors can enhance recognition memory consolidation. Importantly, pharmacological activation of D1 receptors enhanced novel object recognition memory even under conditions in which control rats showed significant retention.     

Evaluation of the interaction between D1 and D2 receptors in a drug discrimination paradigm

Recent research has suggested that there is a synergistic interaction between D1 and D2 dopamine (DA) receptors and that D1 stimulation by endogenous DA is necessary for the expression of some D2-mediated behavioral effects. The purpose of the present experiment was to examine further the interactions between D1 and D2 receptors using drug discrimination (DD), a behavioral paradigm that is sensitive and selective for D1 and D2 agonist and antagonist activity. Two groups of male Sprague-Dawley rats (N = 8/group) were trained to discriminate the D2 agonist quinpirole (QUIN; either 0.05 or 0.012 mg/kg, ip, 10 min pre-session) from saline (1.0 ml/kg, ip, 10 min pre-session) in a two-lever, food-reinforced DD paradigm. QUIN (0.0015-0.1 mg/kg) produced a dose-related increase in QUIN-appropriate responding in both groups of rats. The D1 agonist SKF 38393 (SKF; 6.4-12.8 mg/kg, ip) given alone did not substitute for QUIN in either of the two training dose groups. The administration of SKF 30 min before QUIN had no effect on the QUIN dose-response function in either group of rats. These results indicate that stimulation of D1 receptors failed to potentiate a behavioral effect mediated by D2 receptors. The D1 antagonist SCH 23390 (SCH; 0.0015-0.05 mg/kg, ip) partially substituted for QUIN in the group trained with the 0.05 dose of QUIN, and to a larger extent in the group trained with the 0.012 dose of QUIN. SCH did not alter the effect of the training dose of QUIN except at a dose high enough to virtually eliminate lever pressing in the group trained to discriminate the high dose of QUIN. The failure of SCH to block QUIN suggests that D1 receptor stimulation by endogenous DA is not necessary for this D2 effect to be expressed. These results may be accounted for by assuming a presynaptic site of action for QUIN in the QUIN discrimination. Further, they demonstrate that the interaction between D1 and D2 receptors cannot be simply characterized as synergistic.     

Microinjections of the dopamine D2 receptor antagonist sulpiride into the medial prefrontal cortex attenuate glucocorticoid-induced impairment of long-term memory retrieval in rats

We recently reported that blockade of dopamine (DA) D2 receptors attenuated deficits in long-term memory retrieval induced by a systemic injection of corticosterone, but the anatomical sites of such interaction were not known. In this study, we investigated whether the DA D2 receptors located in the medial prefrontal cortex (mPFC) may play a role in the impairing effects of glucocorticoids on the memory retrieval process. Young adult male rats were trained in a one trial inhibitory avoidance task (0.5 mA, 3s footshock). On the retention test given 48 h after training, the latency to re-enter the dark compartment and the time spent in light compartment of the apparatus were recorded. Systemically administered corticosterone (1mg/kg) given to rats 30 min before retention testing impaired their memory retrieval. Bilateral microinjections of the DA D2 receptor antagonist sulpiride (10 or 100 ng/0.5 microl per side) into the mPFC 30 min before corticosterone administration attenuated the glucocorticoid-induced impairment of memory retrieval. Furthermore, applied doses of sulpiride alone were ineffective in modulating memory retrieval. These findings indicate that D2 receptors located in the mPFC play an important role in mediating the impairing effects of glucocorticoids on memory retrieval.     

The role of dopamine in reinforcement: changes in reinforcement sensitivity induced by D1-type, D2-type, and nonselective dopamine receptor agonists

Dose-dependent changes in sensitivity to reinforcement were found when rats were treated with low, moderate, and high doses of the partial dopamine D1-type receptor agonist SKF38393 and with the nonselective dopamine agonist apomorphine, but did not change when rats were treated with similar doses of the selective dopamine D2-type receptor agonist quinpirole. Estimates of bias did not differ significantly across exposure to SKF38393 or quinpirole, but did change significantly at the high dose of apomorphine. Estimates of goodness of fit (r2) did not change significantly during quinpirole exposure. Poor goodness of fit was obtained for the high doses of SKF38393 and apomorphine. Decrements in absolute rates of responding were observed at the high dose of quinpirole and at the moderate and high doses of SKF38393 and apomorphine. Changes in r2 and absolute responding may be due to increases in stereotyped behavior during SKF38393 and apomorphine exposure that, in contrast to quinpirole, were distant from the response lever. The present data provide evidence that sensitivity to reward is affected more strongly by dopamine D1-like receptors rather than D2-like receptors, consistent with evidence from other studies investigating consummatory dopamine behavior and the tonic/phasic dopamine hypothesis.     

Effects of NMDA receptor channel blockade on aggression in isolated male mice

N‐Methyl‐D ‐aspartate (NMDA) receptor antagonists are perspective candidates for medication development for a number of diseases/states that are associated with increased aggressiveness (e.g., opioid withdrawal). The prototypic NMDA receptor antagonist phencyclidine (PCP) itself is a widely abused substance and is known to elevate levels of aggression in drug users. The present study was aimed at testing several drugs that share with PCP the ability to block NMDA receptor–associated channel. The resident‐intruder procedure was used to assess drug effects on aggressive behavior in isolated male mice. Resident aggressive mice were administered NMDA channel blockers (PCP; 0.3–10 mg/kg), dizocilpine (MK‐801; 0.01–0.3 mg/kg), memantine (1–30 mg/kg), and MRZ 2/579 (0.1–5.6 mg/kg). The competitive NMDA receptor antagonist D CPPene (0.1–5.6 mg/kg) was also tested as a compound representing an alternative approach to reduce activity of NMDA receptor complex. PCP, dizocilpine, and memantine inhibited expression of aggressive behaviors only at doses that produced ataxia. The novel channel blocker MRZ 2/579 also produced ataxia at the highest dose level but failed to affect aggressiveness. Reduction in aggression with a corresponding increase in sociability was observed after administration of D ‐CPPene. Overall, the present results suggest that NMDA receptor channel blockers do not exert selective effects on aggressive behavior. Aggr. Behav. 25:381–396, 1999. © 1999 Wiley‐Liss, Inc.     

Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats

The 5-hydroxytryptamine₆ (5-HT₆) receptor has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the novel, selective 5-HT₆ antagonists compound (CMP) X and CMP Y and the reference 5-HT₆ antagonist GSK-742457 could ameliorate impairments in episodic memory in 3-months-old male Wistar rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer’s disease, AD) was used as a positive reference compound. First, effects of the 5-HT₆ antagonists CMP X, CMP Y and GSK-742457 were investigated on object recognition task (ORT) performance in rats treated with the muscarinic antagonist scopolamine (0.1 mg/kg, administered intraperitoneally, i.p., 30 min before trial 1). Second, effects of the combination of suboptimal doses of 5-HT₆ antagonists CMP X and CMP Y with the AChEI donepezil were studied, to determine whether the 5-HT₆ antagonists show additive synergism with donepezil in the ORT. Finally, effects of CMP Y, GSK-742457 and donepezil were investigated on object location task (OLT) performance in rats treated with scopolamine.Donepezil (1 mg/kg, oral administration, p.o.), GSK-742457 (3 mg/kg, i.p.), CMP X (3 mg/kg, i.p.) and CMP Y (30 mg/kg, p.o.), all ameliorated the scopolamine-induced deficits in object recognition. In the ORT, we have found that combined administration of subthreshold doses of CMP X (1 mg/kg, i.p.) and CMP Y (10 mg/kg, p.o.) with the AChEI donepezil (0.1 mg/kg, p.o.), enhanced memory performance in Wistar rats with deficits induced by scopolamine. Donepezil (0.1 mg/kg, p.o.) alone had no discernable effects on performance. This suggests additive synergistic effects of the 5-HT₆ antagonists (CMP X and CMP Y) with donepezil on cognitive impairment. Finally, donepezil (1 mg/kg, p.o.), GSK-742457 (10 mg/kg, p.o.) and CMP Y (30 mg/kg, p.o.) also reduced scopolamine-induced deficits in the OLT.In conclusion, the 5-HT₆ antagonists were found to clearly improve episodic memory deficits induced by scopolamine. In addition, co-administration of the 5-HT₆ receptor antagonists CMP X and CMP Y with the AChEI donepezil to cognitively impaired rats also resulted in potentially additive enhancing effects on cognition. This suggests that these compounds could have potential as monotherapy, but also as adjunctive therapy in patients with AD treated with common treatments such as donepezil.     

Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning processes and is important for inhibitory avoidance and conditioned taste aversion learning. MGlu5 receptors are physically connected with NMDA receptors and they interact with, and modulate, the function of one another in several brain regions. The present studies used systemic co-administration of an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and an NMDA receptor antagonist dizocilpine maleate (MK-801) to characterize the interactions of these receptors in two aversive learning tasks. Male Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance or conditioned taste aversion task. CDPPB (3 or 10mg/kg, s.c.), delivered by itself prior to the conditioning trial, did not have any effect on performance in either task 48 h after training. However, CDPPB (at 3mg/kg) attenuated the MK-801 (0.2mg/kg, i.p.) induced learning deficit in both tasks. CDPPB also reduced MK-801-induced hyperactivity. These results underlie the importance of mGlu5 and NMDA receptor interactions in modulating memory processing, and are consistent with findings showing the efficacy of positive allosteric modulators of mGlu5 receptors in reversing the negative effects of NMDA receptor antagonists on other behaviors such as stereotypy, sensorimotor gating, or working, spatial and recognition memory.     

Modulation of baseline behavior in rats by putative serotonergic agents in three ethoexperimental paradigms

The present study adopts an ethoexperimental approach to examine the deportment subsequent to alteration in serotonin (5-HT) neurotransmission following treatment with site-specific neuropharmacological probes. The impact of perturbation in (5-HT) neurotransmission on baseline behavior was analyzed employing three animal models of anxiety, i.e., hole-board, elevated plus maze, and bright/dark arena. Inbred male rats (Wistar strain, weighing between 150 and 200 g) were used in this study. The vivarium and the behavioral laboratory were specially designed to permit operation of reversed light-dark cycle and all experiments were performed during the dark period. Pharmacological tools selected to influence 5-HT levels include (1) a combination of tranylcypromine and tryptophan (TCP + TRYPT) (0.75 mg/kg + 40 mg/kg) which augments 5-HT biosynthesis; (2) p-chlorophenylalanine (PCPA: 200 mg/kg), an inhibitor of 5-HT biosynthesis; and (3) 5-HT reuptake blockers, namely zimelidine (ZIM) (40 mg/kg) and fluoxetine (FLU) (10 mg/kg). Rats under the influence of PCPA exhibited anxiolytic response, whereas those under treatments to raise 5-HT levels, viz., TCP + TRYPT, ZIM and FLU, displayed anxiogenic-like reactions. Several other agents known to specifically interact with 5-HT receptor subtypes were also tested. 5-HT2 receptor stimulants, such as quipazine (5 mg/kg) and MK 212 (0.5 mg/kg), were found to be anxiogenic. Buspirone (2 mg/kg), a 5-HT1 agonist, surmounted normal behavioral inhibition. However, another 5-HT1 stimulant, 8-OH-DPAT (0.025 mg/kg), had anxiogenic action. Pretreatment with 5-HT3 antagonists [zacopride (2 mg/kg) and GR 38032F (0.1 mg/kg)] and putative 5-HT1 antagonist [propranolol (10 mg/kg)] resulted in borderline disinhibition of normal behavioral inhibition to novel environments. In contrast, cyproheptadine (0.5 mg/kg), a 5-HT2 antagonist, provoked anxiogenic-like behavior. Altogether, uniform results were obtained for each probe in all the three models, suggesting that the battery of anxiety tests chosen in this study is reliable and sensitive to detect unknown pharmacological responses. The results support the hypothesis that stimulation of serotonergic neurotransmission heightens normal anxiety, whereas its blockade releases normal behavioral inhibition. Furthermore, this work establishes the validity of using the three paradigms in evaluating the involvement of multiple neurotransmitter receptors in the control of behavior of rodents under natural circumstances and also detects any aberration following exposure to novelty and stress.     

Long-lasting teratogenic effects of nicotine on cognition: gender specificity and role of AMPA receptor function

Nicotine, the main psychoactive ingredient in tobacco, readily crosses the placental barrier to cause growth and neurobehavioral abnormalities in the offspring. The current study was designed to assess whether nicotinic action causes long lasting teratogenic effects and synaptic dysfunctions. Pregnant Sprague-Dawley rats were infused with nicotine via osmotic minipumps at a dose of 6 mg/kg/day corresponding to the dose receiving during heavy smoking. A battery of behavioral tests and electrophysiological experiments were performed during specific postnatal periods. A spectrum of developmental and behavioral modifications in adolescent, young-adult and aged animals resulted after prenatal nicotine exposure. The potentially teratogenic effect of nicotine was clearly demonstrated in both genders by changes in developmental reflexes, exploratory and novelty seeking behavior, as well as a higher level of anxiety, and changes in individual and group responses in learning and memory. Most of the behavioral abnormalities were transitional with advancing age (6 months), although cognitive deficits measured by a two-way active avoidance task were long-lasting for male rats. Electrophysiological studies show decreased excitatory postsynaptic responses (mEPSCs) mediated by AMPA receptors in the hippocampus. These results suggest that teratogenic effect of nicotine on cognition is age and gender-specific, long-lasting and associated with AMPA receptor function.     

Selection for reduced aggressiveness towards man and dopaminergic activity in Norway rats

The brain dopaminergic system is involved in the process of long-term selection for reduced aggressive reaction towards man in Norway rats. The dopamine levels in the striatum as well as the nucleus accumbens with the tuberculum olfactorium were significantly lower in domesticated rats than in their wild counterparts. A substantial decrease was found in homovanillic acid level in the n. accumbens and tuberculum olfactorium. Specific binding of [³H]spiperone which labels D-2 dopamine receptors was higher in the mesolimbic structure of tame rats, whereas binding of [³H]SCH 23390 (D-1 receptors) was unchanged in this area. No substantial differences were detected in D-1 and D-2 binding in striatum. Apomorphine (0.3 mg/kg) elicited less locomotion in tame animals, reflecting a decrease of sensitivity of postsynaptic dopamine receptors. Tame rats showed fewer aggressive contacts in a foot-shock test than wild rats and the D-2 receptor antagonist sulpiride (25 mg/kg) significantly decreased the foot-shock aggression only in wild rats. Therefore, domestication, which diminishes defensive behavior and emotional reactivity of animals, is associated with decreases of dopamine level in the striatum, changed metabolism of dopamine in mesolimbic system, and an alteration in density and senstivity of D-2 receptors.     

Social factors influence haloperidol-induced catalepsy in rat

This study employed manipulations which presumably influence social interactions in rats: (1) paired housing with a heavier conspecific and (2) exposure to the odors of other rats. The dependent variable was the akinetic state induced by haloperidol, a neuroleptic and dopamine antagonist. In Experiment 1, adult male Long-Evans hooded rats were matched by weight and caged alone or in pairs with one rat 30 g heavier than its cagemate. All rats received haloperidol (1.5 mg/kg) and catalepsy testing. Heavy rats showed more catalepsy than the lighter member of pairs or weight-matched, singly housed controls. In Experiment 2, adult male rats were left unrecaged or were recaged into cages with bedding recently soiled by females or other adult males. After haloperidol (1.0 mg/kg), the rats exposed to bedding soiled by other adult males showed more catalepsy than did the control groups. Thus, the results of both experiments indicated that social factors can influence the akinesia induced by dopamine antagonists.     

Antiaggressive Effects of Zolpidem and Zopiclone in Agonistic Encounters Between Male Mice

The effects of benzodiazepines on various types of aggression have been extensively studied. These substances produce their pharmacological effects by allosterically modulating the action of GABA via specific recognition sites on the GABA_A receptor called omega 1 and omega 2. The antiaggressive profile of non‐benzodiazepine compounds that also act at omega sites, such as zopiclone (a non‐selective omega 1 and 2 ligand) and zolpidem (a selective omega 1 ligand) has been scarcely explored. In this study, we examined the action of zolpidem (0.75‐3 mg/kg, intraperitoneally) and zopiclone (1.5‐6 mg/kg), administered acutely or subchronically for 10 days, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to anosmic “standard opponents” 30 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. Acute treatment with zopiclone produced a marked antiaggressive effect, reducing offensive behaviors (threat and attack) at all doses used (1.5, 3, and 6 mg/kg) without affecting immobility. Likewise, the intermediate dose of zolpidem (1.5 mg/kg) significantly decreased aggression in a specific manner, without altering immobility, whereas the highest dose (3 mg/kg) provoked a reduction of aggression accompanied by a weak (but significant) increase of immobility. With repeated treatment, no tolerance to the antiaggressive effects of zopiclone and zolpidem was developed. It is concluded that omega sites at the GABA_A receptor could be involved in the control of aggression. Aggr. Behav. 28:416–425, 2002. © 2002 Wiley‐Liss, Inc.     

Modulation of recognition and temporal order memory retrieval by dopamine D1 receptor in rats

The present study examines the effects of SKF 81297, a selective D1 agonist, on information retrieval in recognition and temporal order memory for objects, using three different tasks. Separate groups of rats were trained in each task and then given an intraperitoneal injection of saline or the D1 agonist (0.03, 0.3 mg/kg), before the memory testing trial in an object recognition, object location, and object temporal order memory tasks. We show that SKF 81297, at high dose (0.3 mg/kg), facilitates information retrieval after a long delay (4 h) in the three memory tasks whereas both high and low doses of D1 agonist impair recognition memory after a short delay (15 min). These results indicate a significant role of dopamine D1 receptors in recognition memory for both familiarity and place of objects in addition to object temporal order memory.     

Roles of dopamine D1 and D2 receptors in the acquisition and expression of fat-conditioned flavor preferences in rats

Sugars and fats elicit innate and learned flavor preferences with the latter mediated by flavor-flavor (orosensory) and flavor-nutrient (post-ingestive) processes. Systemic dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC), but not opioid antagonists blocked the acquisition and expression of flavor-flavor preferences conditioned by sugars. In addition, systemic D1, but not D2 or opioid antagonists blocked the acquisition of flavor-nutrient preferences conditioned by intragastric (IG) sugar infusions. Given that DA antagonists reduce fat intake, the present study examined whether systemic D1 or D2 antagonists altered the acquisition and/or expression of conditioned flavor preferences (CFP) produced by pairing one novel flavor (CS+, e.g., cherry) with a 3.5% corn oil (CO: fat) solution relative to another flavor (CS-, e.g., grape) paired with a 0.9% CO solution. In an expression study, food-restricted rats were trained to drink either flavored 3.5% or 0.9% CO solutions on alternate days. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 0.9% CO solutions occurred 0.5h after systemic administration of vehicle (VEH), SCH (50-800 nmol/kg) or RAC (50-800 nmol/kg). The rats displayed a robust CS+ preference following VEH treatment (87-88%) the expression of which was attenuated by treatment with moderate doses of RAC, and to a lesser degree, SCH. In an acquisition study, six groups of rats received VEH, SCH (25, 50, 200 nmol/kg) or RAC (50, 200 nmol/kg) 0.5 h prior to 1-bottle training trials with CS+ flavored 3.5% and CS- flavored 0.9% (CS-) CO solutions. A seventh Limited VEH group was trained with its training intakes limited to that of the SCH and RAC groups. Subsequent two-bottle tests were conducted with the CS+ and CS- flavors presented in 0.9% CO without injections. Significant and persistent CS+ preferences were observed in VEH (75-82%), Limited VEH (70-88%), SCH25 (75-84%), SCH50 (64-87%), SCH200 (78-91%) and RAC200 (74-91%) groups. In contrast, the group trained with RAC50 displayed a significant initial CS+ preference (76%) which declined over testing to 61%. These data indicate limited DA D1 and D2 receptor signaling involvement in the expression and acquisition of a fat-CFP relative to previous robust effects for sugar-CFP.     

The role of nucleus accumbens and dorsolateral striatal D2 receptors in active avoidance conditioning

The role of dopamine (DA) in rewarding motivated actions is well established but its role in learning how to avoid aversive events is still controversial. Here we tested the role of D2-like DA receptors in the nucleus accumbens (NAc) and the dorsolateral striatum (DLS) of rats in the learning and performance of conditioned avoidance responses (CAR). Adult male Wistar rats received systemic, intra-NAc or intra-DLS (pre- or post-training) administration of a D2-like receptor agonist (quinpirole) or antagonist ((−)sulpiride) and were given two sessions in the two-way active avoidance task. The main effects observed were: (i) sulpiride and lower (likely pre-synaptic) doses of quinpirole decreased the number of CARs and increased the number of escape failures; (ii) higher doses of quinpirole (likely post-synaptic) increased inter-trial crossings and failures; (iii) pre-training administration of sulpiride decreased the number of CARs in both training and test sessions when infused into the NAc, but this effect was observed only in the test session when it was infused into the DLS; (iv) post-training administration of sulpiride decreased CARs in the test session when infused into the NAc but not DLS. These findings suggest that activation of D2 receptors in the NAc is critical for fast adaptation to responding to unconditioned and conditioned aversive stimuli while activation of these receptors in the DLS is needed for a slower learning of how to respond to the same stimuli based on previous experiences.     

慢性应激性抑郁发生中大鼠眶额叶多巴胺D1受体对谷氨酸及其NMDA受体的调节

本文旨在探讨慢性应激性抑郁发生过程中眶额叶多巴胺D1受体对谷氨酸(glutamic acid, Glu)及其N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体的NR2B亚基的影响。实验通过建立慢性不可预见性温和应激(chronic unpredictable mild stress, CUMS)抑郁模型, 结合眶额叶微量注射多巴胺D1受体激动剂SKF38393和多巴胺D1受体拮抗剂SCH23390, 运用糖水偏爱测试、悬尾实验和敞箱实验等方法检测动物的行为表现, 采用高效液相色谱法(high-performance liquid chromatography, HPLC)和蛋白质免疫印迹法(Western blot, WB)来检测眶额叶内谷氨酸、多巴胺含量及NR2B和多巴胺D1受体的表达。结果显示, 与对照组相比, CUMS组大鼠表现出明显的抑郁样行为变化, 且眶额叶多巴胺含量降低, 其D1型受体表达降低, 谷氨酸含量升高, 其NMDA受体的NR2B亚基也明显上调; 注射SKF38393后可明显改善应激引起的抑郁样行为, 且眶额叶谷氨酸含量显著下降, NMDA受体的NR2B亚基表达也有所降低; 正常大鼠注射多巴胺D1受体拮抗剂SCH23390, 大鼠表现出和CUMS模型组相似的抑郁样行为, 且眶额叶谷氨酸含量升高, 其NMDA受体的NR2B亚基也明显上调。以上结果表明, 慢性不可预见性应激可能使眶额叶多巴胺释放减少, 从而使谷氨酸过量释放, NMDA受体过度激活, 导致抑郁发生。多巴胺抗抑郁作用是通过D1型受体抑制谷氨酸及其NMDA受体NR2B亚基表达来实现。     

Differential effects of competitive benzodiazepine receptor antagonists on the anticonflict activity of G? 4962

The anticonflict activity of the triazolobenzothiadiazine G? 4962 (40 mg/kg po) in the four-plate test using male NMRI mice was selectively antagonized by beta CCE (10 mg/kg iv), but not by Ro 15-1788 (20 mg/kg ip) or CGS 8216 (20 mg/kg ip), although G? 4962 has affinity for the benzodiazepine receptor. In contrast, the anticonflict activity of diazepam (4 mg/kg po) was antagonized by all three BZ antagonists. Relative to known putative anxiolytics, this profile of G? 4962 is unexpected and unique.