Characterization of the discriminative stimulus effects of lorcaserin in rats

Lorcaserin is approved by the Food and Drug Administration for treating obesity and is under consideration for treating substance use disorders; it has agonist properties at serotonin (5‐HT)_2C receptors and might also have agonist properties at other 5‐HT receptor subtypes. This study used drug discrimination to investigate the mechanism(s) of action of lorcaserin. Male Sprague–Dawley rats discriminated 0.56 mg/kg i.p. lorcaserin from saline while responding under a fixed‐ratio 5 schedule for food. Lorcaserin (0.178‐1.0 mg/kg) dose‐dependently increased lorcaserin‐lever responding. The 5‐HT_2C receptor agonist mCPP and the 5‐HT_2A receptor agonist DOM each occasioned greater than 90% lorcaserin‐lever responding in seven of eight rats. The 5‐HT_1A receptor agonist 8‐OH‐DPAT occasioned greater than 90% lorcaserin‐lever responding in four of seven rats. The 5‐HT_2C receptor selective antagonist SB 242084 attenuated lorcaserin‐lever responding in all eight rats and the 5‐HT_2A receptor selective antagonist MDL 100907 attenuated lorcaserin‐lever responding in six of seven rats. These results suggest that, in addition to agonist properties at 5‐HT_2C receptors, lorcaserin also has agonist properties at 5‐HT_2A and 5‐HT_1A receptors. Because some drugs with 5‐HT_2A receptor agonist properties are abused, it is important to fully characterize the behavioral effects of lorcaserin while considering its potential for treating substance use disorders.     

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.     

Depression

Abstract— The theory of clinical depression presented here integrates etiological factors, changes in specific structural and cellular substrates, ensuing symptomatology, and treatment and prevention. According to this theory, important etiological factors, such as stress, can suppress the production of new neurons in the adult human brain, thereby precipitating or maintaining a depressive episode. Most current treatments for depression are known to elevate brain serotonin neurotransmission, and such increases in serotonin have been shown to significantly augment the ongoing rate of neurogenesis, providing the neural substrate for new cognitions to be formed, and thereby facilitating recovery from the depressive episode. This theory also points to treatments that augment neurogenesis as new therapeutic opportunities.     

NMDA受体的结构与药理学特性

NMDA受体是一类离子型谷氨酸受体,其功能主要参与发育过程中神经回路的细化及触发多种形式的突触可塑性。近年来的证据表明,组成NMDA受体的亚单位有着复杂的生理学和药理学特性;NMDA受体的数量、分布和亚单位组成并非一成不变,而是在发育过程中、神经元活动时,以一种细胞特异性和突触特异性的方式变化着。这种NMDA受体的双向变化是突触可塑性重塑的基础,而其调节的异常又可导致神经-精神疾病的发生,如可卡因成瘾、精神分裂症等     

β-受体阻滞剂治疗慢性心力衰竭的哲学发展观

随着科学技术的快速发展和人们认识的不断深入,慢性心力衰竭（CHF）的发病机制处于不断嬗变的过程,CHF的药物治疗概念也发生了根本性的变化。β-受体阻滞剂在CHF的治疗策略中,经历了从禁用到必用的过程,成为了CHF药物治疗的重大突破。大量临床试验表明,β-受体阻滞剂不仅能改善患者预后,而且能明显改善左室的舒张和收缩功能,全面改善患者的血流动力学,提高患者的运动耐量和生活质量,延长生存时间。β-受体阻滞剂在CHF治疗中地位的变化,体现了哲学发展观与疾病的治疗以及药物应用的紧密联系,指导着我们的临床实践,也体现了哲学与自然科学的密切联系。本文将β-受体阻滞剂治疗CHF的新旧观念进行阐述、比较,对其作用机制以及临床用药进行介绍,并对其发展空间进行展望。随着科学的进步,人类有能力从长远的角度控制疾病。     

Treadmill exercise enhances passive avoidance learning in rats: the role of down-regulated serotonin system in the limbic system

While serotonin (5-HT) may impair learning and memory, exercise has been reported to improve them. Whether chronic exercise can facilitate fear memory via regulating the serotonin system is unknown. We examined the effects of 4-week treadmill exercise training on levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), the protein expression of its receptor 5-HT_1A and transporter in the amygdala, hippocampus and prefrontal cortex of male Sprague–Dawley rats. Our results demonstrated that treadmill exercise (1) improved the passive avoidance learning performance; (2) decreased the 5-HT level in the hippocampus; (3) decreased the expression of 5-HT_1A receptor in the amygdala without altering the transporter expression. Moreover, pretreatment with 0.1 mg/kg 8-hydroxy-di-n-propylamino tetralin, a selective 5-HT_1A receptor agonist, impaired the passive avoidance performance and completely abolished the exercise-enhanced fear memory. Our results suggest that down-regulation of the 5-HT system in the limbic system, i.e., the reduction of the hippocampus 5-HT content and the amygdala 5-HT_1A receptor expression, may be involved in the exercise-enhanced fear memory.     

The effects of acute plasma tryptophan manipulation on hostile mood: The influence of trait hostility

The effects of acute plasma tryptophan manipulation on changes in hostile, anxious, and depressive mood were studied in 48 males. Subjects consumed tryptophan-free or nutritionally balanced amino acid mixtures as a means of manipulating brain serotonin levels. Mood (hostility, anxiety, depression) was assessed pre- and 5 hr post-ingestion using the Multiple Affect Adjective Checklist. Overall, the tryptophan manipulation resulted in significant changes in hostile mood. Analyses also revealed a stronger association between changes in plasma tryptophan and changes in hostility in subjects with high levels of pre-existing hostile traits compared with low levels of hostile traits, and in subjects with high vs. Low antisocial traits. There was no significant association between changes in plasma tryptophan and changes in depression. The results suggest that persons with high levels of trait hostility may be more susceptible to the effects of acute manipulation of plasma tryptophan on hostile mood. Aggr. Behav. 24:173–185, 1998. © 1998 Wiley-Liss, Inc.     

Regional studies of brain biogenic amines in castrated muricidal and non-muricidal wistar rats

Castrated Wistar rats were isolated for 8 months and their muricidal behavior was investigated. Significantly fewer (35%) of such rats became muricidal (CM) compared to controls. The steady-state levels of 5-HT, 5-HIAA, DA, DOPAC, and NE, as well as the changes in synthesis or utilization rats of 5-HT and DA, were analyzed in 15 brain areas derived from CM rats and non-muricidal (CNM) control subjects. In CM rats, higher 5-HT levels were recorded in 5 areas considered to be involved in muricidal behavior: raphe, amygdala, olfactory tubercles, olfactory bulbs, and striatum. The alterations of serotonergic neurotransmission in castrated muricidal rats differ strikingly from those observed in non-castrated muricidal rats. An increase of 5-HT level and in the 5-HT synthesis index as well as a lower 5-HT utilization index were recorded in the raphe of CM rats. Our data suggest that the decrease of 5-HT levels generally said to be the main alteration in the muricidal rat's brain has to be reconsidered. Increased DA levels were observed in CM rats: raphe (50%), amygdala, olfactory tubercles, striatum, and septum (40%), while DA was decreased in cortical areas. There were slight increases of DA synthesis indices in the septum, olfactory tubercles and striatum with a decreased utilization index in the olfactory tubercles. Few alterations in NE levels were observed in CM rats: a decrease in the olfactory tubercles, superior colliculus, and striatum and an increase in temporal cortex. The monoaminergic alterations correlate with the modulation of muricidal behavior. Some areas (the olfactory tubercles, raphe, striatum, and temporal cortex) seem to be particularly involved. © 1992 Wiley-Liss, Inc.     

Role of 5HT1A receptors in a variety of kinds of aggressive behavior in wild rats and counterparts selected for low defensiveness towards man

The 5HT_1A receptor agonist ipsapirone (10 mg/kg) suppressed shock-induced aggression in wild and domesticated rats but did not affect predatory aggression in either group of animals. Ipsapirone decreased neophobia and inhibited defensive reactions by wild rats towards man in the glove test. [³H]8-OH-DPAT binding, which labels 5HT_1A receptors, was significantly increased in the hypothalamus of domesticated rats in comparison with wild counterparts, while 5HT_1A density was unchanged in the frontal cortex in domesticated animals. In essence, the aggressive reactions contributing to the defensive behavior complex in wild rats appear to be regulated through 5HT_1A receptors. © 1992 Wiley-Liss, Inc.     

Shock-induced fighting (SIF): Psychopharmacological studies

Shock-induced fighting in rats is briefly reviewed and the role of catecholamine serotonin and cholinergic neuromodulation is discussed in terms of specific agonists or antagonists to each system. The balance of action on presynaptic and postsynaptic receptors as well as the interconnections among the various neuromodulating systems help to determine the ultimate behavioral outcome as a response to drugs.