Evidence that Release of Dopamine in the Brain is Involved in the Inhibitory Effect of Cholecystokinin Octapeptide on Ingestion of Intraorally Administered Sucrose in Male Rats

To study the possibility that release of dopamine in the brain mediates the inhibitory effect of Cholecystokinin octapeptide on ingestive behaviour, the effect of amphetamine on intake of pellets or an intraorally administered sucrose solution was compared with that of Cholecystokinin octapeptide. Additionally, comparisons were made between the effect of Cholecystokinin octapeptide and pargyline, a monoamine oxidase inhibitor, and α-methyl-ρ-tyrosine, a tyrosine hydroxylase inhibitor. While amphetamine dose-dependently inhibited pellet intake it failed to inhibit sucrose intake in doses which caused behavioural stereotypies (<800 μg). Cholecystokinin octapeptide (5 μg) inhibited ingestive behaviour in both tests. A very high dose of amphetamine (2 mg) was required to inhibit sucrose intake to a level comparable to that of Cholecystokinin octapeptide. Pargyline (5 to 25 mg) or α-methyl-p-tyrosine (25 to 100 mg) dose-dependently inhibited pellet intake but had only weak effects on the intake of sucrose. Pargyline increased the concentration of dopamine and 3-methoxytyramine in the dorsal striatum and decreased the concentration of 3,4-dihydroxyphenylacetic acid. α-Methyl-ρ-tyrosine decreased the concentration of dopamine and 3,4-dihydroxyphenylacetic acid, but not that of 3-methoxytyramine. Injection of amphetamine (2 mg), but not Cholecystokinin octapeptide, in rats pretreated with pargyline increased the concentration of 3-methoxytyramine in the dorsal striatum and this effect was blocked by pretreatment with α-methyl-ρ-tyrosine. Pretreatment with α-methyl-ρ-tyrosine partially reversed the inhibitory effect of Cholecystokinin octapeptide on sucrose ingestion, enhanced the effect of amphetamine but did not affect that of apomorphine, a dopamine agonist. The results support the possibility that the inhibitory effect of Cholecystokinin octapeptide on consummatory ingestive behaviour, in part, is mediated via release of dopamine in the brain.     

八肽胆囊收缩素对正常及脑缺血大鼠大脑皮层NO水平的调节作用

目的 探讨中枢八肽胆囊收缩素(CCK—8)对正常及脑缺血大鼠脑组织一氧化氮(NO)水平的影响及其可能的机制。方法 给正常或局部脑缺血1h再灌注24h大鼠脑室内(icv)分别注射体积均为5μl的溶剂(人工脑脊液)、CCK—8、丙谷胺或丙谷胺十CCK—8。给药后25h分别取正常大鼠的大脑皮层及脑缺血大鼠缺血中心区、半暗区、非缺血半球皮层，检测脑组织NO水平及一氧化氮合酶(NOS)活性。结果 (1)与假手术组相比，缺血溶剂组大鼠脑缺血中心区及半暗区NO水平显著增加(P＜0．05)，缺血CCK—8组NO水平无明显变化；与缺血溶剂组相比，缺血CCK—8组脑缺血中心区及半暗区NO水平显著降低(P＜0．05或0．01)；缺血CCK—8组非缺血半球皮层NO水平显著高于假手术组(P＜0．05)，而缺血溶剂组非缺血半球NO水平的升高不明显。(2)正常大鼠给CCK—8后，脑皮层NO水平、NOS活性明显升高(P＜0．05或0．005)，丙谷胺可部分拮抗这一作用；单独给丙谷胺对NO水平、NOS活性无影响。结论 中枢给予CCK—8对局部脑缺血再灌注引起的脑皮层缺血中心区及半暗区NO水平的升高具有抑制作用；对正常脑皮层组织NO水平、NOS活性有上调作用，丙谷胺可部分拮抗这一作用。     

Behavioural changes following lesions of the orbital prefrontal cortex in male rats

Bilateral lesions were made, confined to the orbitofrontal part of the prefrontal cortex (OF) of male WEZOB rats at 3 different ages (30, 45 and 60 days) and behavioural changes were studied in adulthood. In a test situation for intermale aggression OF-lesioned animals showed a higher level of aggression than their control-operated opponents. Such changes were not witnessed in encounters with male rats of the less aggressive Wistar strain which emphasizes the importance of the choice of the opponents in tests for agonistic behaviour. OF lesioning did not interfere with male sexual behaviour. When tested in an open field, activity scores of OF-lesioned animals exceeded those of the control group. OF lesioning resulted in a slight but significant long-term weight reduction, 2–3 months following surgery, in comparison with the control group. However, a severe reduction in food intake (aphagia), immediately after the operation, was not observed.

Increase in both aggression and locomotor activity was seen in all 3 age groups, and data do not support the hypothesis that sparing of function had occurred in the 30-day operates, as compared with the 60-day operates. However, the duration of allogrooming bouts per approach in the social agonistic situation did show a pattern depending on the lesion momentum: prepubertal OF lesions resulting in less frequent approaches and grooming bouts of longer duration. These findings are explained in terms of perseverative tendencies following OF lesions.     

Effects of repeated administration of low doses of apomorphine in three behavioural models in the rat

Summary A low dose of the dopamine (DA) receptor agonist apomorphine (APO 0.05 mg/kg) was given repetitively and the effects were tested in three different behavioural models: reduction of spontaneous locomotion, induction of yawning and decrease in water intake in water-deprived animals. The APO-induced suppression of exploration and decrease in water intake were not affected by a previous injection of APO given 1 or 3 hours before the test dose of APO. There was a small, but significant, decrease in the induction of yawning by a previous dose of APO given 1 hour or 30 min before the test dose. However, pretreatment with APO 3 hours before the test dose did not diminish the yawning response. It is suggested that the dopaminergic mechanisms mediating APO induced yawning are different from those mediating decrease in water intake and suppression of exploration. The results are also discussed in relation to the proposed efficiency of low doses of DA agonists in the treatment of various neurological and psychiatric disorders.     

Differential effects of estrogen and androgen on locomotor activity induced in castrated male rats by amphetamine, a novel environment, or apomorphine

Four experiments were conducted using male rats to determine whether testosterone (T), or its neural metabolites estradiol (E₂) and 5α-dihydrotestosterone (DHT), influence the expression of locomotor activity, which is thought to depend in part on the activation of mesolimbic dopaminergic neurons. Subcutaneous implantation of silastic capsules containing E₂, but not T or DHT, caused a significant increase in the amount of activity displayed by castrated rats which had been habituated to infrared photobeam activity cages prior to receiving an i.p. injection ofd-amphetamine sulfate (1.5 mg/kg). Administration of E₂, but not T or DHT, also significantly increased the amount of activity which other groups of castrated rats displayed when they were first placed in the photobeam cages. Likewise, administration of E₂, but not T or DHT, to castrated rats which had previously received bilateral injections of 6-hydroxydopamine into the nucleus accumbens septi, caused a significant increase in the activity displayed in response to an i.p. injection of apomorphine HC1 (1.0 mg/kg). However, administration of estrogen or androgen to castrated rats which were neurologically intact had no effect on the amount of stereotyped behavior displayed in response to increasing doses (1.0, 2.0 and 4.0 mg/kg) of apomorphine. It is suggested that the selective, facilitatory effect of E₂ on drug- and novelty-induced locomotor activity resulted from increased postsynaptic receptor activation at dopaminergic synapses in the nucleus accumbens septi.     

CCK—8及损毁MFB对腹侧被盖区和伏核多巴胺,CCK—8含量的影响

应用荧光分光光度法和放射免疫法,在以６－羟基多巴胺（６－ＯＨＤＡ）单侧损毁内侧前脑束（ＭＦＢ）制备的偏侧帕金森病（ＰＤ）大鼠模型身上,测定了腹侧被盖区（ＶＴＡ）和伏核（Ａｃｂ）中多巴胺（ＤＡ）和八胺胆囊收缩素（ＣＣＫ－８）的含量,并测定了ＴＶＡ和Ａｃｂ区微量注射ＣＣＫ－８对正常大鼠ＤＡ含量的影响。结果如下：ＰＤ大鼠模型损毁侧ＶＴＡ和Ａｃｂ的ＤＡ和ＣＣＫ－８的含量与健康及对照组相比均减少（Ｐ〈０．０     

Comparative analysis of immunoreactive cells for androgen receptors and oestrogen receptor alpha in copulating and non-copulating male rats

In some species, including gerbils, guinea pigs, mice, rams and rats, some apparently normal males fail to mate. These kinds of animals have been named 'noncopulating (NC)'. The cause of this behavioural deficit is unknown. The present study aimed to determine whether NC male rats have alterations in the amount of androgen (AR) and oestrogen receptor alpha (ERalpha) in a neuronal circuit important for the control of male sexual behaviour; the vomeronasal projection pathway. We evaluated the number of AR and ERalpha immunoreactive (AR-IR and ERalpha-IR) cells in the accessory olfactory bulb (AOB), the bed nucleus of the stria terminalis (BNST), the anterior-dorsal medial amygdala (MeAD), the posterior dorsal amygdala (MePD) and the medial preoptic area (MPOA). The results demonstrate that the number of AR-IR cells in NC males was significantly higher compared to copulating (C) males in the MePD, but no significant differences were found in any of the other structures analysed. ERalpha-IR cells were more abundant in NC than in C males in the MeAD and the MePD. However, in the MPOA the number of ERalpha-IR cells was significantly reduced in NC males. No significant differences were found in the AOB or in the BNST. A similar pattern of results was observed when regions within these structures that are activated by Fos expression, on mating or exposure to sexually relevant cues were analysed. The differences in the number of AR and ER in particular brain areas could be associated with alterations in sexual behaviour as well as partner and olfactory preference for receptive females seen in NC male rats.     

Inhibitory effect of cholecystokinin octapeptide on neurons in the nucleus tractus solitarius

We investigated the effect of the cholecystokinin octapeptide (CCK8) applied locally to neurons of the nucleus tractus solitarius (NTS). Results demonstrate an inhibitory effect of CCK8 on spike discharges including those related to respiration. It is suggested that CCK8 acts at this level through specific receptor mechanisms since CCK8-induced inhibitions were not reproduced by application of related peptides and were resistant to antagonists of different inhibitory transmitters.     

Changes in dopamine and DOPAC following systemic administration of apomorphine and 3,4-dihydroxyphenylamino-2-imidazoline (DPI) in rats

Rats were injected systemically with either saline, apomorphine, or one of four doses of DPI (3,4-dihydroxyphenylamino-2-imidazoline) and the levels of dopamine and DOPAC determined in the nucleus accumbens and the caudate regions. DPI reduced dopamine and DOPAC levels in the nucleus accumbens, while apomorphine did not. On the other hand, apomorphine reduced the levels of dopamine and DOPAC in the caudate but not the nucleus accumbens. DPI largely was without effect in the caudate. The results are discussed in terms of possible specificity of the two dopamine agonists in the two forebrain regions.     

Strain differences in the behavioral responses of male rats to chronically administered methylphenidate

Genetic variability in the behavioral responses of experimental subjects to psychostimulants such as amphetamine and cocaine have been reported. However, genetic differences in the locomotor responses of rat strains to methylphenidate (MPD), a commonly used psychostimulant in the treatment of attention deficit/hyperactivity disorder, have not been extensively investigated. Research using genetically defined rodent strains can enhance our understanding of the role genetic factors play in drug-related behaviors and the development of animal models for drug-sensitive diseases or behaviors. The objective of the present study was to investigate strain differences in the locomotor responses to MPD among three rat strains: Sprague-Dawley (SD), Wistar-Kyoto (WKY), and spontaneously hypertensive rats (SHR). Eight-week-old adult, male SD, WKY, and SHR were given a regimen of daily MPD administration (0.6, 2.5, or 10 mg/kg, i.p.) for 6 consecutive days followed by 3 days of washout and a day of MPD re-challenge with similar dosages as previously used. An automated activity monitoring system recorded their horizontal activity, total distance traveled, rearing, stereotypic movements, and number of discrete movements. Repeated administration of 0.6 mg/kg MPD produced no significant effect on locomotor activity compared with saline in all three strains. However, there were strain differences in the locomotor activity of SD, SHR, and WKY rats to repeated 2.5- and 10-mg/kg MPD treatment. Repeated administration of 2.5 mg/kg MPD elicited locomotor sensitization in SD and WKY rats but not in SHR. Repeated administration of 10 mg/kg MPD induced locomotor tolerance in SD and WKY rats, while SHR had variable locomotor responses to this MPD dose. In conclusion, rat strains play a significant role in the response to acute and chronic administration of MPD.     

Effects of mild stress on adrenal and heart catecholamines in male and female rats

Summary The present study was undertaken with the aim of evaluating the sensitivity and convenience of a stress model reflecting sympatho-adrenal activation. Rats of both sexes were subjected to mild stress, consisting of four body temperature recordings, and investigated with regard to adrenal and heart catecholamine levels. Adrenal dopamine (DA) levels were considered to reflect medullary synthesis activity and heart adrenaline (A) concentrations were presumed to reflect A released from the adrenals. Expressed in relation to heart weight, adrenal catecholamine levels were about 50% higher in female rats. Following stress, adrenal DA levels were enhanced in both male and female rats; the magnitude of the stress response appeared similar in the two sexes. Concentrations of A in the hearts of unstressed animals were about 85% higher in females than in males but rose to a similar extent in male and female rats following stress. On the other hand, the stress-induced alterations in heart DA and NA concentrations, reflecting sympathetic activity, were gender-dependent.The advantages of the present model in relation to other techniques for measuring sympatho-adrenal activation in response to mild stress are discussed.     

Enhanced apomorphine sensitivity and increased binding of dopamine D2 receptors in nucleus accumbens in prepubertal rats after neonatal blockade of the dopamine D3 receptors by (+)-S14297

The role of dopamine (DA) D3 receptors is controversial in early developmental stages of specially locomotor activity. Past studies have only tested behavioral changes induced by neonatal administration of nonselective dopamine antagonist such as haloperidol or sulpiride in adult rats. We investigated the role of neonatal blockade of DA D3 receptors at (postnatal day, P1 to P12) using the DA D3 receptor antagonist (+)-S14297 on paradigms related to DA behaviors including locomotor activity in novel environment and after administration of the DA nonspecific agonists d-amphetamine, and apomorphine. Additionally, autoradiographic studies were performed to correlate behavioral alterations with DA D1-like, D2-like, and D3 receptors. All studies were performed at two critical ages, prepubertal (P35) and postpubertal (P60). The quantitative autoradiogaphic study revealed increases in the expression of DA D2-like receptor expression in the nucleus accumbens (NAcc) in prepubertal animals that received the DA D3 antagonist (+)-S14297 at neonatal age. In addition, novel environment and apomorphine administration (0.5 mg/kg, s.c.), induced increases of locomotor activity in prepubertal animals that received the DA D3 antagonist (+)-S14297. Autoradiographic and behavioral results suggest that blockade of DA D3 receptors after birth may mediate different neurodevelopmental aspects of the dopaminergic pathway before and after puberty.     

The mating movements of male decorticate rats: evidence for subcortically generated movements by the male but regulation of approaches by the female

The study shows that although many features of copulation in decorticate male rats are normal, copulatory success is importantly dependent upon the control of approaches exerted by the normal female rat. Copulation by neonatally decorticated adult rats and normal adult rats was studied in cohabitation and videotaped tests. Seven of 10 decorticate rats and 6 of 6 normal rats sired pups in the cohabitation test. When initially paired with ovariectomized and primed female rats, in the videotaped tests, all normal rats, but only one decorticated rat, copulated. All decorticate rats made movements indicative of sexual interest including: treading on the female's back, passing over the female, and sniffing the female's genitals. After activating stimulation, 5 of 6 remaining decorticated males copulated. After one successful mount the remaining copulatory patterns proceeded relatively normally. Numbers of mounts, intromissions, ejaculations, postejaculatory songs, and the intromission and ejaculatory patterns were like those of control rats, although the decorticate rats had fewer mount bouts and showed abnormalities in the execution of movements. Precopulatory movements were notated, using the Eshkol-Wachmann system, and compared with copulatory movements. Non-copulatory and copulatory approaches were similar, except that clasping appeared to be the key movement involved in the transition of an approach movement into a copulatory movement. The analysis also showed that the females' movements of hopping, turning, and kicking were important for regulating the males' approaches, and were instrumental in the success achieved by the decorticated males. The study shows that although the cortex, insofar as it facilitates the appearance of certain movements and contributes to their efficiency, is involved in male sexual activity, in its absence well organized sexual activity is possible, although this is dependent, in part, upon the behaviour of the female.     

Electrophysiological evidence of modulatory interaction between dopamine and cholecystokinin in the nucleus accumbens

Dopamine has been shown to modulate responses of accumbens neurones to excitatory inputs from the amygdala. The demonstration that cholecystokinin (CCK) co-exists and appears to be co-released with dopamine in the accumbens suggests that the modulatory action of dopamine in the accumbens may in turn be modified by CCK. This possibility was investigated in the present study. Single unit recordings were obtained in the medial and caudal accumbens of urethane-anaesthetized rats. These neurones were strongly excited by amygdala stimulation, and concurrent stimulation of the ventral tegmental area (VTA) at 10 Hz attenuated the responses, presumably due to dopamine release. Iontophoretic application of proglumide (PRG) at 30 nA enhanced the attenuating effect of VTA stimulation on the excitatory response to amygdala stimulation. Exogenous dopamine produced a similar attenuation in response and the attenuation was in turn suppressed by concurrent iontophoresis of sulphated CCK fragments applied at a current titrated not to produce significant effect on the spontaneous activity of the neurone nor its response to amygdala stimulation. These results demonstrate that exogenous and endogenous CCK can modify the postsynaptic action of dopamine in the nucleus accumbens in addition to modulating its release shown in other studies, and further suggests that CCK is likely an endogenous functional antagonist of dopamine, serving a comodulatory role in regulating synaptic transmission in the ventral striatum.     

Differential effects of gonadal steroids on dopamine metabolism in mesolimbic and nigro-striatal pathways of male rat brain

Thirty days after castration the concentration of dopamine (DA) was significantly reduced in the septum and n. accumbens septi, but not in the caudate-putamen, of male rat brain. The concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the principle metabolites of DA, also tended to be lower in septum and n. accumbens septi after castration. Chronic s.c. administration of testosterone (T), estradiol (E₂), 5α-dihydrotestosterone (DHT), or E₂ plus DHT in silastic capsules effectively reversed these effects of castration in septum and n. accumbens septi without affecting concentrations of DA, DOPAC, or HVA in caudate-putamen. The accumulation of DOPA after inhibition of aromatic amino acid decarboxylase activity, which was taken as an in vivo index of tyrosine hydroxylase activity, was not affected in these brain regions by long-term castration or by chronic administration of DHT to castrated males. Acute administration of haloperidol caused equivalent, significant increments in concentrations of DOPAC and HVA in all brain regions studied, regardless of whether castrated rats had been implanted with DHT capsules or no hormone. However, in the absence of haloperidol treatment the concentration of DOPAC in septum and n. accumbens septi, but not in caudate-putamen, was significantly higher in castrated rats implanted with DHT as opposed to no hormone. These results suggest that chronic exposure to T, or to its neural metabolites, E₂ and DHT, selectively enhances metabolic activity in mesolimbic DA neurons.     

羟基喜树碱抑制大鼠角膜移植免疫排斥反应：与环孢素A的比较

背景：近期研究表明羟基喜树碱在一些器官移植过程中具有免疫抑制作用,但在角膜移植中的免疫抑制作用却未见报道。 目的：观察羟基喜树碱对大鼠穿透性角膜移植术后免疫排斥反应的影响,并与经典抗排斥药环孢素A进行比较。 方法：18只成年雌性Wistar大鼠为供体,36只成年雄性SD大鼠为受体,建立大鼠穿透性角膜移植动物模型。受体大鼠随机分为3组,羟基喜树碱组、环孢素A组和对照组,每组12只。羟基喜树碱组和环孢素A组分别在术后腹腔注射羟基喜树碱2.0 mg/(kg•d)和环孢素A 10 mg/(kg•d),连续用药12 d。对角膜植片进行临床观察,以混浊、水肿和新生血管3 项指标作为临床评估标准,记录角膜植片存活时间。 结果与结论：羟基喜树碱组、环孢素A组和对照组角膜植片的存活时间分别为(21±2),(19±2)和(11±2) d,各用药组与对照组比较角膜植片存活时间显著延长(P < 0.01),羟基喜树碱组比环孢素A组植片存活时间明显延长(P < 0.05)。实验结果提示羟基喜树碱能对大鼠穿透性角膜移植术后免疫排斥反应具有明显的抑制作用,可延长植片存活时间,抑制新生血管,其作用优于环孢素A。 关键词：角膜移植;大鼠;免疫排斥;羟基喜树碱;免疫抑制剂     

Enhanced intestinal motor response to cholecystokinin in post-Nippostrongylus brasiliensis-infected rats: modulation by CCK receptors and the vagus nerve

The jejunal inflammation induced in rats by the nematode Nippostrongylus brasiliensis is followed by intestinal neuroimmune alterations including mast cell hyperplasia and nerve remodelling. On the other hand, cholecystokinin (CCK) plays a pivotal role in the regulation of intestinal motility. The aim of this study was to determine whether the intestinal motor response to CCK is altered 30 days after infection by N. brasiliensis. Thus, CCK-8 (50 microg kg(-1) intraperitoneally) disrupted the pattern of jejunal migrating myoelectric complexes for a longer time in postinfected rats (95.5 +/- 3.5 min) than in controls (48.1 +/- 5.1 min). This enhanced jejunal response was also found after oral administration of the potent releaser of endogenous CCK, soybean trypsin inhibitor. In contrast, no alteration of the inhibition of colonic motility by CCK administration was observed. The increased responsiveness of jejunal motility to CCK persisted after mast cell stabilisation or depletion but was prevented by atropine, devazepide and L-365260 (CCK-A and CCK-B receptor antagonists, respectively) and vagotomy. These results indicate that neuroimmune alterations after N. brasiliensis infection lead to an increased intestinal motility response to CCK that involves a cholinergic mediation, a vagal pathway and alterations in intestinal CCK-A and CCK-B receptors.     

Lateralizing effects of apomorphine on taxis, postural support and rotation in rats

1. Subcutaneous injections of apomorphine, a dopamine receptor agonist, induced a lateralization of taxis for edges in 16% of rats and a reliable lateralization of postural support in 82% of rats.

2. The relation among these effects and the lateralizing effects of apomorphine on rotational behavior were examined. Lateralized rotation did not reliably correlate with lateralized taxis. However, it correlated with a relatively large asymmetry of postural support.

3. The lateralizing effects of apomorphine on taxis and rotation may reflect attentional and directional asymmetries, respectively. It is proposed that apomorphine can induce different types of lateralizations, including attentional, postural and directional, and that the lateralizing effects of apomorphine on posture and locomotor direction are interrelated. Regional brain interhemispheric asymmetries in the responsiviness of dopamine receptors may underlie different types of apomorphine-induced lateralizations.     

伏隔核毁损对MAP模型大鼠行为及脑内DA受体的影响

目的 探讨立体定向伏隔核毁损对甲基苯丙胺（MAP）模型大鼠行为学及不同脑区多巴胺D2受体表达的影响。方法 将80只SD大鼠随机分为对照组、模型组、假手术组和手术组，每组各20只。经腹腔注射MAP制备精神分裂症模型，采用立体定向一直流电毁损伏隔核，观察大鼠刻板行为变化；并采用原位杂交法观察额叶、颞叶、边缘区及脑干部位的D2受体表达。结果 与对照组比较，模型组及假手术组大鼠刻板行为评分及各个脑区D2受体表达均显著性增加；与模型组及假手术组比较，手术组大鼠刻板行为评分及各脑区DA受体阳性细胞数目均显著性减少。结论 伏隔核毁损可能通过抑制MAP诱发的脑内D2表达亢进而改变其行为学异常。     

Effects of precocious pinealectomy and hemicastration on pituitary and plasma LH levels in immature male rats

Summary In the immature male rat (7 to 28 days of age) precocious hemicastration provokes a marked compensatory testicular hypertrophy accompanied by a significant increase in pituitary LH content, and a non-significant increase in plasma LH level.In pinealectomized and sham-pinealectomized animals, hemicastration had the same effect with some exceptions at certain ages.Pinealectomy alone causes less evident changes in pituitary LH content than hemicastration. Only a transient effect was found, which was more evident in the hemicastrated rats. Plasma LH was only increased in the pinealectomized hemicastrated rats at days 16 and 18.It is concluded that pinealectomy in immature male rats seems to have only a transient stimulatory effect on pituitary and plasma LH levels, which is more striking in hemicastrated rats. So, hemicastration seems to sensitize the animals to the effect of pinealectomy.