Modulation of social memory in male rats by neurohypophyseal peptides

Adult male rats spend a great amount of time investigating novel juveniles. In contrast, rats re-exposed to the same juvenile 30 min after the initial exposure display little investigatory behavior. If the re-exposure occurs 2 h later, the juvenile is thoroughly investigated. These results have been interpreted to mean that rats form a transient memory for a particular juvenile. In the present study, memory was enhanced when the initial exposure to the juvenile was followed by another exposure to the same juvenile (retroactive facilitation) and impaired when exposure to the original juvenile was followed by exposure to another juvenile (retroactive interference). Arginine vasopressin had retroactive facilitating effects on social memory and these effects were blocked by the vasopressor antagonist dPTyr(Me)AVP. Moreover, the antagonist had retroactive interfering effects, since it impaired the recognition of a familiar juvenile. Oxytocin shared the same inhibitory pattern of action. These results suggest that neurohypophyseal peptides may have a prepotent role in modulating the mnemonic processing of chemosensory information associated with social interactions.     

Oxytocin but not vasopressin facilities social recognition following injection into the medial preoptic area of the rat brain

Social recognition of juvenile rats by adult male residents has been shown to be modulated by peripheral administration of neurohypophyseal hormones vasopressin and oxytocin. In the present study, the effects of these peptides on social recognition were investigated after local injection into the medial preoptic area of the hypothalamus. It was found that oxytocin given in a wide range of doses (0.3–1000 pg) facilitated social recognition. This effect was not blocked by pretreatment with oxytocin receptor antagonist desGly(NH₂)⁹-d(CH₂)₅[Tyr(Me)²Thr⁴]OVT. Oxytocin injected into the septum in doses of 0.03–3 pg was not effective. Administration of vasopressin (100 or 1000 pg), [pGlu⁴,Cyt⁶]AVP-(4-8) (200 pg) or [pGlu⁴,Cyt⁶]AVP-(4-9) (200 pg) into the medial preoptic area did not influence social recognition. It is concluded that the medial preoptic area is a sensitive brain site for the oxytocin-induced facilitation of social recognition in rats.     

CCK-A and CCK-B selective receptor agonists and antagonists modulate olfactory recognition in male rats

Modulation of learning and memory is one of the physiological roles that the neuropeptide cholecystokinin (CCK-8) may play. We have used a behavioural model of olfactory recognition among rats to test this hypothesis and to explore the relationship between CCK-A and CCK-B receptors and memory retention. Adult male rats form a transient memory of a juvenile congenere as indicated by a reduction in the duration of investigatory behaviour upon re-exposure 30 min after an initial exposure, but not when re-exposure is delayed until 120 min afterwards. In the present study, rats were treated after the first contact with various compounds; inhibition and facilitation of olfactory recognition were evaluated as the persistence in investigation 30 min and the decrease in investigation 120 min after pharmacological manipulations, respectively. Systemic injection of CCK-8, of a selective CCK-A agonist, or of non-peptide CCK-B antagonists (CI-988 and LY-262691) enhanced olfactory recognition. In contrast, the CCK-B selective agonist BC 264 and the tetrapeptide CCK-4 both disrupted it. Taken together with previous evidence of the detrimental effect of the non-peptide CCK-A antagonist devazepide on olfactory recognition, these results confirm and extend the hypothesis that there is a balance between CCK-A-mediated facilitative effects and CCK-B-mediated inhibitory effects on memory retention.     

Kynurenic acid and 5,7-dichlorokynurenic acids improve social and object recognition in male rats

The present study describes the effect of kynurenic (KYNA) and 5,7-dichlorokynurenic (DCKA) acids, acting as selective antagonists at the glycine site on the NMDA receptor complex, upon short-term memory of male rats. Oxiracetam (OXIR) or pramiracetam (PRAM) were used as reference compounds. In the social recognition test, adult animals were injected SC with a drug or vehicle immediately after the first exposure to a juvenile male, 21–24 days old, and reexposed to the same or a novel juvenile 120 min later. Time spent by adults in social investigation of juveniles was measured. Animals treated with KYNA or DCKA (0.3, 3 and 30 mg/kg in both cases) and OXIR (30 and 60 mg/kg) had significantly reduced investigation time when reexposed to the same juvenile as compared to controls. No reduction of investigation time was found in those drugged animals reexposed to a novel juvenile. The findings suggest that KYNA and DCKA improved retention of memory for olfactory stimuli in adult male rats. In the object recognition test, the duration of exploration of two identical objects during the sample trial and the familiar and a new object during the choice trial, performed 60 min later, was evaluated. Drugs or vehicles were administered SC 30 min prior to the sample trial. On choice one, animals treated with KYNA or DCKA (0.6 and 30 mg/kg in both cases) and PRAM (30 mg/kg) spent more time in exploring a new object than the familiar one as compared to controls. This suggests that the drugged animals were able to remember the familiar object. It may be concluded that KYNA and DCKA participate in mechanisms underlying recognition/memory processes in rats.     

Ethological study of the effects of tetrahydroaminoacridine (THA) on social recognition in rats

Two major difficulties confront ethopharmacological investigations on cognitive abilities such as social recognition in drug-treated animals involved in free social interactions. The first concerns the choice of the most relevant behaviours, those reflecting the cognitive abilities attributed to the animals and assessing the specificity of the drug activity, and those reflecting non-specific drug effects. The second refers to the experimenter's awareness that in contrast to physical objects, social stimuli respond to drug-treated subjects and that their own level of responsiveness may influence the changes of drug-treated subjects' social interest. In addition, their contribution may vary according to the different treatments the drug-treated subjects receive. In examining the effects of tetrahydroaminoacridine (THA) at doses of 0.3, 1 and 3 mg/kg on the ability of adult male rats to recognize previously encountered conspecifics, we attempted to take into consideration such difficulties. A detailed behavioural profile of drug-treated rats was reported to separate specific from non-specific effects of THA. In addition, rats were assigned an index of responsibility for contact which takes into account the interactive dimension of each dyad and allows relevant comparisons between different treatments. The doses of THA which were found to decrease the duration of exploration of a familiar juvenile were also found to decrease the number of contacts initiated by the drug-treated subjects. THA induced a relative increase in body care by comparison to saline treatment. However, it had no effect of locomotor activity and rearing of the subjects. These findings enable dissociation of the effects of THA on cognitive versus non-cognitive processes.     

Low doses of ipsapirone increase growth hormone but not oxytocin secretion in normal male and female subjects

Objective: The present study investigated whether administration of a 5-HT_1A receptor agonist would increase growth hormone (GH) and oxytocin levels in normal human subjects, and whether the responses would be modified according to the age and gender of the subjects. Methods: Ipsapirone (0.3 mg/kg body weight), or placebo was administered to 30 normal subjects (14 males, 19–74 years and 16 females, 22–69 years) using a randomized, double blind design. Results: Stimulation of GH secretion by ipsapirone was significantly greater in male compared to female subjects, with no apparent effect of age. Oxytocin secretion was not stimulated by ipsapirone compared to placebo in any of the groups. Conclusions: The effects of gender and age on the degree of stimulation of GH secretion by 5-HT_1A agonists in human subjects differ from their effects on secretion of the hormones ACTH and cortisol. A higher dose of ipsapirone is required to stimulate oxytocin secretion in normal human subjects. Received: 10 November 1998/Final version: 7 February 1999     

Oxytocin: an extremely potent inducer of penile erection and yawning in male rats

The intracerebroventricular (i.c.v.) injection of oxytocin, in doses ranging from 5 to 90 ng (5–90 pmol) induced penile erection and yawning in male rats. Such response was not induced by doses of the peptide higher than 100 ng, nor by equimolar doses of i.c.v. [Arg⁸]vasopressin, ACTH-(1–24), -MSH, rat corticotropin-releasing factor (rCRF), delta sleep-inducing peptide, neurotensin or substance P. Oxytocin-induced penile erection and yawning were prevented by atropine and morphine, but not by methylatropine or the opiate antagonist naloxone. Haloperidol, a dopamine receptor antagonist, was ineffective at low doses; it partially prevented penile erection but not yawning at high doses. Since oxytocin is present not only in the neurohypophysis but also in other brain areas, our results suggest that oxytocin is implicated in the regulation of penile erection and yawning, and provide further evidence that oxytocin acts as a neuropeptide in the central nervous system.     

Low dose MK-801 reduces social investigation in mice

To characterize MK-801's effect on social behavior in mice, we examined adult male ICR mice for interaction with companion mice (juvenile male). Test mice were injected with either saline or MK-801 (0.1 mg/kg), and were tested 30 min later for their social behavior during a 5-min session. A second encounter took place 30 min later, with either a familiar companion mouse (the same as in the initial encounter) or a novel mouse. In saline controls, second encounter with a familiar companion mouse showed reduced social investigative behaviors (anogenital sniffing and staying together), indicating habituation toward a familiar mouse. Second encounter with a novel companion mouse did not show habituation in social investigative behaviors. Pretreatment with MK-801 reduced anogenital sniffing during the first encounter. At the second encounter, these mice displayed non-discriminative habituation of social investigative behaviors, with reduced anogenital sniffing and staying together, regardless of whether the companion mouse was a familiar or a novel one. These results indicate that MK-801 affected exploratory activities of mice, resulting in both reduced social investigative behaviors during first encounter with a companion mouse, and diminished discriminative capacities for a familiar vs. a novel companion mouse during subsequent encounter.     

A comparison of the effects of vasopressin and oxytocin with amphetamine and chlordiazepoxide on passive avoidance behaviour in rats

On the basis of results obtained from passive avoidance studies, we have argued that the neuropeptide vasopressin could act on arousal, rather than memory processes in rats (Sahgal et al. 1982). In this report, we examine the effects of substances that are known to increase (d-amphetamine) or decrease (chlordiazepoxide) behavioural arousal, and compare the data with those obtained after vasopressin or oxytocin treatment. All four substances yielded broadly similar bimodal results (although the oxytocin data failed to reach significance). We argue for an arousal interpretation which suggests that performance and arousal are related in an inverted-U manner. The data also indicate that care must be taken in selecting appropriate statistical tests.     

缩宫素对大鼠肝脏缺血-再灌注损伤的保护作用及其机制

目的 探讨缩宫素对大鼠肝脏缺血-再灌注(I-R)损伤的保护作用及可能的机制.方法 将48只雌性SD大鼠随机均分为假手术(S)组、I-R组和缩宫素处理(OT)组.建立大鼠70%I-R模型,缺血时间1 h.OT组分别于术前12 h,15 min及再灌注时经腹腔注射缩官索0.5 mg/kg,S组及I-R组在相同时间注射等量生理盐水.各组大鼠分别于肝脏再灌注后2和6 h处死,取肝脏及血液标本,检测血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、肿瘤坏死因子α(TNF-α)以及肝脏组织超氧化物歧化酶(SOD)、髓过氧化物酶(MPO)的活性及丙二醛(MDA)含量,并分别检测肝组织中核因子κB(NF-κB)的表达和肝脏组织的病理改变.结果 与I-R组相比,OT组的ALT、AST、TNF-α水平及MPO、NF-κB阳性表达明显降低(P<0.05),肝脏病理损伤较轻,但是MDA及SOD变化不明显.结论 缩宫素对大鼠肝脏I-R损伤具有保护作用.其机制可能与抑制炎症因子产生及活化有关.     

Sabeluzole improves social recognition and antagonizes chlordiazepoxide's effect on habituation in the rat

The memory enhancing properties of sabeluzole were evaluated in two experimental paradigms in rats. First, we determined the protective action of sabeluzole against a chlordiazepoxide-induced impairment of habituation. Sabeluzole (5 or 25 mg/kg, SC) was administered 1 h before and chlordiazepoxide (20 mg/kg, SC) immediately after the acquisition session. In the retention session 72 h later, chlordiazepoxide-treated animals displayed higher locomotor and rearing activities and this effect was blocked by pretreatment with sabeluzole. The results suggest that sabeluzole prevented the amnesic effect of chlordiazepoxide. The second paradigm was a social recognition test in which the behaviour toward a familiar or a novel conspecific was investigated. Time spent in social investigation and time spent sniffing of scent traces left on the floor was estimated during exposure of an adult to a juvenile male rat. Sabeluzole (25 mg/kg, SC) was injected into the adults immediately after the first exposure. Reexposure to the same or a novel juvenile was performed 120 min later. In contrast to control, sabeluzole-treated animals showed a significant reduction-in social investigation during the second exposure to the same juvenile. Time spent sniffing the floor was significantly decreased in sabeluzole-treated males. Since there was no effect on investigation of a novel juvenile, results suggest that sabeluzole-treated rats are able to remember longer the individual characteristics of juvenile rat obtained through olfactory cues.     

MK-801 can facilitate passive avoidance memory when retention is not present in control animals,and can fail to facilitate when it is present

The results confirm that NMDA receptor blockade can result in improved retention performance of mice in step-down passive avoidance. A series of behavioural variations and analyses revealed that memory in the task depended mainly on the appearance of the grid that had been associated with shock, rather than on the execution of an instrumental response or on the spatial locus of the punishment. When the grid was made invisible during retest, retention was never found. However, MK-801 didnot facilitate retention based on the appearance of the grid. In contrast, conditions were found in which, even though control animals showed no learning, MK 801 given after the learning trial facilitated retention. Thus, the dominant mode of learning and memory in the step-down task is insensitive to the drug, whereas the drug raises a weaker or alternative mode to above threshold levels.     

Neonatal dexamethasone treatment affects social behaviour of rats in later life

Synthetic glucocorticoids, like dexamethasone (DEX), have been frequently administered to premature infants to prevent chronic lung disease. Major concern has arisen about the long-term neurodevelopmental sequelae of this DEX treatment. In the present study, we found that neonatal DEX treatment in rats, using a treatment protocol resembling the one used in the clinical situation, increased social play behaviour in juvenile life. Furthermore, neonatal DEX treatment increased sexual motivation and intromission behaviour in the bi-level chamber, decreased submissive behaviour during an aggressive encounter, and impaired social memory in adulthood. These changes in social behaviour are not due to a general behavioural impairment since anxiety behaviour in the elevated plus maze and exploratory activity in the open-field were not affected in DEX rats. In addition, DEX rats showed no alteration in the total duration of social interest or social activity during a social interaction test. These effects of neonatal DEX treatment on behaviour later in life likely result from neurodevelopmental actions of the hormone since we found no differences in received maternal care between DEX and SAL treated pups. Together these results indicate that neonatal treatment with DEX selectively alters aspects of the behavioural response to social challenges. Thus, neonatal DEX treatment may lead to inappropriate interactions with conspecifics later in life. These data therefore warrant investigation of lasting and potentially adverse effects of treatment of human neonates with DEX on social functioning.     

Cholinergic modulation of a decrement in social investigation following repeated contacts between mice

Social recognition has been inferred from a decline in olfactory investigation of conspecific intruders during repeated or protracted confrontation with a resident rat. A stimulus-response relationship defined by lack of response remains somewhat ambiguous. Since it is likely that behavior continues to be emitted by the resident animal, how behavior reorganizes as the resident becomes familiar with an intruder represents an important issue in the characterization of recognition. We examined the decline in olfactory investigation of ovariectomized females by adult male mice. The duration and frequency of olfactory investigation was measured during four 1 minute confrontations with 10-min intertrial intervals (Training trials). If the same female was presented in each trial, investigation declined to less than 50% of initial levels. Aggressive behavior gradually increased with repeated trials. No decline in investigation or increased aggression was measured when females were changed in each trial. Administration of doses of scopolamine (0.16–1.0 mg/kg, IP) blocked decrements in olfactory investigation in repeated confrontations and significantly reduced aggression. Co-administration of heptylphysostigmine (0.32–5.0 mg/kg, IP) reversed scopolamine's effects on olfactory investigation but not aggression. Acetylcholinesterase inhibitors heptylphysostigmine, galanthamine (0.63–2.5 mg/kg, IP) and tacrine (0.63–10.0 mg/kg, IP) all enhanced the rate of decrement of olfactory investigation when administered alone, but had differential effects on aggression. The decline in investigation corresponds to criteria for habituation. Increased responsivity expressed as aggression indicates recognition may also be characterized as a change in behavioral strategy dependent on the sexual and social status of the stimulus animal. Pharmacological data support a role for acetylcholine release in the development of social recognition as an olfactory memory, or through modulation of olfactory perception.     

Retrograde enhancement of human memory with alcohol

In two experiments with normal male subjects, the ingestion of alcohol (1 ml/kg) immediately after learning significantly improved subsequent remembering. By comparison, marijuana (15 mg) had no significant post-acquisition effect. Facilitation of visual and verbal memory with alcohol under these conditions has implications for the interference and consolidation views of memory.     

Luteinizing-hormone-releasing hormone modifies retention of passive and active avoidance responses in rats

The influence of posttraining subcutaneous administration of luteinizing-hormone-releasing hormone (LHRH) was tested on the retention of either active or passive avoidance conditioning in male rats. Injection of LHRH (200/kg) immediately after the acquisition of an active avoidance response (two-way shuttle behavior) enhanced retention of the response, assessed 7 days later. When the neuropeptide was injected immediately after a passive avoidance conditioning training, the effects varied with the intensity of the footshock applied. LHRH enhanced retention of avoidance training with weak footshock (0.20 and 0.35 mA) but impaired retention of training with strong footshock (0.70 and 1.0 mA). The effects of LHRH seem to be unspecific since they are similar to those observed after treatment with several hormones. The results are discussed based on the interactions between peripherally injected hormones and endogenous substances released following footshock. A modulatory effect on the monoaminergic pathway involved in memory storage processes is postulated.     

Facilitation and disruption of the long-term store of memory with neural excitants

Male hybrid mice (C57BL/6J × DBA/2J) were trained for 2 days in a 6-unit brightness discrimination maze. Beginning 24 hr after training, mice were administered daily injections of strychnine sulphate, Metrazol, d-amphetamine sulphate, caffeine citrate, nicotine alkaloid, or saline for 5 days. Forty-eight hr after the injection series was completed, mice were trained to criterion in the maze. Mice administered strychnine sulphate or Metrazol showed significantly better retention than those administered saline while mice administered d-amphetamine sulphate were significantly poorer. Nicotine alkaloid produced a trend toward facilitation, while caffeine citrate had no effect. The observed facilitation and disruption were not due to enhancement or impairment of learning ability and could not be attributed to effects upon the consolidation process.     

AM251, cannabinoids receptors ligand, improves recognition memory in rats

High density of cannabinoid receptors type 1 (CB1) in the brain suggests that endocannabinoid system plays an important role in the functioning of the central nervous system. Natural and synthetic cannabinoids are known to attenuate learning and memory processes. The adverse effects of cannabinoids are reversed by SR141716A, at first reported to be a selective CB1 receptor antagonist, later shown to possess also inverse agonist properties. The present study was performed in an attempt to determine the influence of different doses of AM251, a member of the same cannabinoid group as SR141716A, on recognition memory evaluated in an object recognition test. Because cannabinoids may alter motor function and affect anxiety, the influence of AM251 on psychomotor activity and anxiety was assessed in an "open-field" test and elevated plus maze, respectively. While the lowest dose of AM251 (1.0 mg/kg) significantly improved recognition memory, higher doses (2.5 mg/kg and 5.0 mg/kg) did not have an influence on it. Moreover, AM251 did not affect anxiety but in the highest dose significantly attenuated psychomotor activity in rats. The main finding of the present study indicates that AM251, at the dose of 1.0 mg/kg, improves recognition memory in rats without alteration of their psychomotor activity and anxiety. The pro-cognitive effect exerted by compounds belonging like AM251 to diarylpyrazole group may be beneficial in therapeutic use of these compounds, especially in patients with cognitive dysfunctions.     

Delayed effect of the vasopressin metabolite VP4-8 on the social memory of sexually naive male rats

RATIONALE: Endogenous vasopressin is involved in the social memory of the male rat and administration of exogenous vasopressin improves social memory. These findings are mainly based on studies using sexually experienced males that were tested in the social recognition test. OBJECTIVE: The present study was aimed to establish whether the modulation of social memory by vasopressin fragments depends on the sexual experience of the male rat. For this purpose, the social discrimination test was used, since this test is more suitable than the social recognition test for measuring social memory in sexually naive males. METHODS: Male rats were tested in the social discrimination test and treated subcutaneously with the vasopressin metabolite [pGlu4,Cyt6]vasopressin-(4-8) (VP4-8). VP4-8 shares with vasopressin the effects on memory processes but lacks the peripheral effects of vasopressin. RESULTS: VP4-8 (1 microgram/kg) acutely improved the social memory of sexually experienced male rats, confirming previous reports. However, in sexually naive males VP4-8 failed to improve social memory in doses ranging from 0.1 microgram/kg to 1 microgram/kg. Instead, 1 microgram/kg VP4-8 or 6 micrograms/kg desglycinamide-vasopressin were found to exert a delayed effect in sexually naive rats. This delayed effect resulted in an improved social memory 2 days after administration. CONCLUSIONS: Vasopressin sensitisation is discussed as a possible underlying mechanism of the observed delayed effect of vasopressin fragments. It is concluded that in male rats sexual experience can influence the modulation of social memory by vasopressin.     

Haloperidol increases false recognition memory of thematically related pictures in healthy volunteers

Dopamine can modulate long‐term episodic memory. Its potential role on the generation of false memories, however, is less well known. In a randomized, double‐blind, placebo‐controlled experiment, 24 young healthy volunteers ingested a 4‐mg oral dose of haloperidol, a dopamine D₂‐receptor antagonist, or placebo, before taking part in a recognition memory task. Haloperidol was active during both study and test phases of the experiment. Participants in the haloperidol group produced more false recognition responses than those in the placebo group, despite similar levels of correct recognition. These findings show that dopamine blockade in healthy volunteers can specifically increase false recognition memory.