Scopolamine given pre-Trial 1 prevents the one-trial tolerance phenomenon in the elevated plus-maze Trial 2

A learned avoidance response has been one of the hypotheses proposed to explain the 'one-trial tolerance' (OTT) phenomenon, which represents a drug's loss of anxiolytic-like effect in the elevated plus-maze (EPM) test in experienced rodents. Based on these facts, if some kind of learning occurs throughout Trial 1, then an impairment of its acquisition would maintain the drug's anxiolytic-like effect on Trial 2. Using male Wistar rats, the present study examined whether scopolamine (SCO; 0.5-1.5 mg/kg), a drug that impairs learning acquisition, given 30 min prior to Trial 1, actually prevents the OTT phenomenon to either the midazolam (MDZ; 0.5 mg/kg) or the memantine (MEM; 8.0 mg/kg) anxiolytic-like effect on the EPM Trial 2 (48 h later). According to the results, both MDZ and MEM increased open-arm exploration (indicating anxiolysis) on Trial 2 only in rats that had been treated previously with 1.5 mg/kg SCO. These results were observed in the absence of change in general exploratory activity. The present findings suggest that SCO impaired the acquisition of the behavioral strategy to cope with the subsequent EPM exposure that supposedly underlies the OTT phenomenon, thereby revealing the anxiolytic-like effects of MDZ and MEM on Trial 2.     

Factors triggering abolishment of benzodiazepines effects in the Four-Plate Test--retest in mice.

Abolishment of anxiolytic-like effects of diazepam occurs during re-exposure to some animal tests of anxiety. We investigated the loss of anxiolytic-like effects of diazepam during Trial 2 on previously undrugged mice, namely one-trial tolerance (OTT). Swiss mice were subjected to 1) Four-Plate Test (FPT) without punishments in Trial 1 or 2) FPT without punishments in both Trials or 3) FPT with spatial modifications in Trial 1 or 4) Elevated Plus Maze (EPM), then 24 h later to FPT, with saline, diazepam (1 mg/kg) or DOI (1 mg/kg). Removing punishments in Trial 1 does not counteract the effect reduction of diazepam in Trial 2, but spatial modifications of the aversive environment. Previous exposure to EPM does not trigger a loss of efficacy of diazepam in FPT. Electric punishments do not trigger OTT to benzodiazepines; whilst knowledge of the environment seems to be responsible for this phenomenon. FPT may be useful to study OTT because punishments potentate OTT in this model of anxiety.     

Absence of repeated-trial tolerance to the anxiolytic-like effects of chlordiazepoxide in the rat triple test

The triple test, recently developed to assess anxiety-related behaviors in rodents, combines three widely used behavioral tests: the open field (OF), elevated plus maze (EPM) and light/dark box (LDB). The EPM and LDB, individually, are normally sensitive to the anxiolytic effects of benzodiazepines only in the first trial, due to the phenomenon of one-trial tolerance, which limits their use in longitudinal studies. The main objective of the present investigation was to verify whether the anxiolytic-like effects of chlordiazepoxide (CDZ), previously observed in naive animals submitted to the triple test, would persist after repeated testing. To this end, three experiments were carried out where male Wistar rats received CDZ (10 mg/kg) 30 min before the triple test for 2, 3 or 20 consecutive days. Except for the first day of drug treatment following a previous test experience in an undrugged state, CDZ had enduring anxiolytic-like effects under all schedules, promoting an increase in the exploration of the EPM open arms (and in some cases of the white compartment of the LDB), without affecting the number of closed-arm entries. The finding that rats did not develop tolerance to CDZ even with chronic treatment and repeated exposures to the triple test suggests that this new device is a promising tool to be used in longitudinal studies involving pharmacological manipulations of anxiety-related behaviors.     

Aversive learning as a mechanism for lack of repeated anxiolytic-like effect in the elevated plus-maze

Rodents re-exposed to the elevated plus-maze no longer respond to anxiolytic-like drugs, such as benzodiazepines. This phenomenon is thought to be due to retrieval of aversive learning associated with the initial exploration of this potentially dangerous environment. Based on this assumption, one might expect the maintenance of the drug's anxiolytic-like effect in rodents already experienced in the elevated plus-maze if the acquisition and/or consolidation of this learning were impaired. Using male Wistar rats, we investigated whether the systemic administration of propranolol, at putative learning-impairing doses, prior to or immediately after the first (Trial 1) elevated plus-maze exposure would retain the midazolam anxiolytic-like effect on the second (Trial 2) exposure to this apparatus. There was an anxiolytic-like effect, characterized by an increase in the open-arms exploration, in response to 0.25 mg/kg of midazolam on Trial 2 only in rats administered with 20 mg/kg of propranolol before Trial 1. Although propranolol had a dose-dependent and behaviorally-selective anti-anxiety effect (significant at 20 mg/kg) on Trial 1, further minute-by-minute analysis confirmed the propranolol-induced learning acquisition deficit in this group on Trial 2. The knowledge of the environment actually contributes to the unresponsiveness to anxiolytic-like drugs observed in rats re-exposed to the elevated plus-maze.     

Aversive learning as a mechanism for lack of repeated anxiolytic-like effect in the elevated plus-maze

Rodents re-exposed to the elevated plus-maze no longer respond to anxiolytic-like drugs, such as benzodiazepines. This phenomenon is thought to be due to retrieval of aversive learning associated with the initial exploration of this potentially dangerous environment. Based on this assumption, one might expect the maintenance of the drug's anxiolytic-like effect in rodents already experienced in the elevated plus-maze if the acquisition and/or consolidation of this learning were impaired. Using male Wistar rats, we investigated whether the systemic administration of propranolol, at putative learning-impairing doses, prior to or immediately after the first (Trial 1) elevated plus-maze exposure would retain the midazolam anxiolytic-like effect on the second (Trial 2) exposure to this apparatus. There was an anxiolytic-like effect, characterized by an increase in the open-arms exploration, in response to 0.25 mg/kg of midazolam on Trial 2 only in rats administered with 20 mg/kg of propranolol before Trial 1. Although propranolol had a dose-dependent and behaviorally-selective anti-anxiety effect (significant at 20 mg/kg) on Trial 1, further minute-by-minute analysis confirmed the propranolol-induced learning acquisition deficit in this group on Trial 2. The knowledge of the environment actually contributes to the unresponsiveness to anxiolytic-like drugs observed in rats re-exposed to the elevated plus-maze.     

Prior maze experience required to alter midazolam effects in rats submitted to the elevated plus-maze

In rodents, prior maze experience increases open arm avoidance (OAA) and compromises the anxiolytic effects of benzodiazepines in a subsequent exposure to the elevated plus-maze (EPM), a phenomenon referred to as "one trial tolerance" (OTT). Nevertheless, a possible correlation between these intriguing events remains unclear. Using maze-naive and maze-experienced (free exploration of the EPM for 5 min) rats, Experiment 1 confirmed the anxiolytic effects of midazolam (MDZ; 0.125-1.0 mg/kg) in maze-naive rats, while both increased OAA and OTT to the MDZ anxiolytic effects were observed in maze-experienced rats. However, our results from Experiment 2, designed to assess whether open, enclosed or both arms experience is involved in increased OAA and OTT, showed that MDZ retained its efficacy in rats confined either to an open or enclosed arm, where no significant changes in open arm exploration were observed when compared to the maze-naive group, therefore suggesting that prior experience in the whole apparatus may be involved in the loss of the anxiolytic MDZ effects. Results are discussed in terms of a possible correlation between increased OAA and the OTT phenomenon elicited in a subsequent exposure to the EPM.     

Anxiolytic-like effects of NMDA/glycine-B receptor ligands are abolished during the elevated plus-maze trial 2 in rats

Rationale Drugs enhancing the GABA_A and/or reducing the NMDA/glycine-B receptor activity produce an anxiolytic effect. Regarding the former drugs (e.g. benzodiazepines), prior elevated plus-maze (EPM) test experience abolishes the trial 2 anxiolytic activity, a phenomenon referred to as "one-trial tolerance" (OTT).Objectives The present study examined whether the OTT phenomenon occurs with drugs that reduce the NMDA/glycine-B receptor activity. Methods. Maze-naive and maze-experienced (prior EPM exposure) rats were treated with (±)-HA-966 (2.0 or 4.0 mg/kg), (+)-MK-801 (0.03 or 0.06 mg/kg) or memantine (4.0 or 8.0 mg/kg) and submitted to the EPM. To investigate whether the loss of drug responsiveness was due to pharmacological tolerance, rats received memantine (8.0 mg/kg) both 48 h and 30 min before the first EPM exposure.Results All drugs increased open arms exploration, indicating an anxiolytic effect, in maze-naive but not in maze-experienced rats, in which increased open arms avoidance was observed. An anxiolytic effect was also observed after repeated memantine administration in maze-naive/drug-experienced rats. These effects were observed in the absence of changes in enclosed arms entries, an EPM general exploratory activity index.Conclusions The present findings extend the OTT phenomenon to drugs that reduce the NMDA/glycine-B-receptor activity, and emphasize the repeated test exposure rather than repeated drug administration as a critical determinant for the drug anxiolytic activity. Considering the mechanisms by which the EPM experience alters the drug effects, the present findings favor the hypothesis in which the OTT phenomenon emerge as a consequence of the development and adoption of an anxiolytic-insensitive behavioral strategy.     

Lack of midazolam-induced anxiolysis in the plus-maze Trial 2 is dependent on the length of Trial 1

The influence of the first exposure length upon the effect of midazolam (MDZ) administration prior to the second exposure in the elevated plus-maze (EPM) was investigated. Drug-free rats were assigned to freely explore the EPM for 1, 2 or 5 min (Trial 1). Twenty-four hours later, each group was subdivided in two further groups, which were retested in the EPM for 5 min, 30 min after either saline or MDZ (1.5 mg kg(-1)) administration (Trial 2). The data showed that during Trial 2, the percentage of entries (%Open arm entries) and time spent in the open arms (%Open arm time) were decreased if rats were pre-exposed to the EPM for 2- or 5-min Trial 1, while the group submitted to 1-min Trial 1 length displayed decreased %Open arm time only. The anxiolytic effect of MDZ prior to Trial 2 was present in the group submitted to 1-min, impaired in the group submitted to 2-min and absent in the group submitted to 5-min Trial 1 length. Data are analyzed taking into account the emotional learning which underlies the exploratory behavior during the EPM Trial 2.     

Central, but not basolateral, amygdala involvement in the anxiolytic-like effects of midazolam in rats in the elevated plus maze

The role of the amygdala in the mediation of fear and anxiety has been extensively investigated. However, how the amygdala functions during the organization of the anxiety-like behaviors generated in the elevated plus maze (EPM) is still under investigation. The basolateral (BLA) and the central (CeA) nuclei are the main input and output stations of the amygdala. In the present study, we ethopharmacologically analyzed the behavior of rats subjected to the EPM and the tissue content of the monoamines dopamine (DA) and serotonin (5-HT) and their metabolites in the nucleus accumbens (NAc), dorsal hippocampus (DH), and dorsal striatum (DS) of animals injected with saline or midazolam (20 and 30 nmol/0.2 μL) into the BLA or CeA. Injections of midazolam into the CeA, but not BLA, caused clear anxiolytic-like effects in the EPM. These treatments did not cause significant changes in 5-HT or DA contents in the NAc, DH, or DS of animals tested in the EPM. The data suggest that the anxiolytic-like effects of midazolam in the EPM also appear to rely on GABA-benzodiazepine mechanisms in the CeA, but not BLA, and do not appear to depend on 5-HT and DA mechanisms prevalent in limbic structures.     

Anxiolytic effects of ethanol and phenobarbital are abolished in test-experienced rats submitted to the elevated plus maze

Prior test experience compromises the anxiolytic efficacy of benzodiazepines (BZs) either in rats or mice, a phenomenon not exclusive to the elevated plus-maze (EPM) animal model of anxiety, which is referred to as "one-trial tolerance." However, it remains to be determined whether a similar event occurs when testing other drugs that also possess binding-sites on the GABA(A) receptor, such as ethanol and barbiturates. In the present study, we have addressed this issue using maze-naive and maze-experienced (free exploration of the EPM 48 h earlier for 5 min) rats pretreated with ethanol (1.0-1.4 g/kg) or phenobarbital (20-60 mg/kg) and submitted to the EPM. The results confirmed the anxiolytic profile of both drugs, represented by increased open arm exploration and decreased risk assessment behavior, in maze-naive rats. However, in maze-experienced rats, neither ethanol nor phenobarbital anxiolytic effects were observed, suggesting that prior maze experience compromised the drugs' anxiolytic activity. Thus, the "one-trial tolerance" phenomenon might also be extended to other drugs that bind to the GABA(A) receptor complex.     

Pirenperone does not attenuate morphine analgesia in spinal rats

In the elevated plus-maze test of anxiety the scores of control animals remain stable over repeated tests. However, a single prior exposure to the plus-maze renders an animal insensitive to the anxiolytic effects of chlordiazepoxide. This phenomenon of one-trial tolerance persisted even when the two trials were separated by as much as 2 weeks. It has previously been shown that the drug state of the animal on trial 1 is not important to the development of the phenomenon, but one-trial tolerance did not develop if a very high dose (75 mg/kg) of chlordiazepoxide was given on trial 1; it is suggested that this is due to the amnesic effects of the drug. The learning on trial 1 was not specific to a particular plus-maze and tolerance could be observed even when the maze on trial 1 was made from different material. The crucial experience on trial 1 was experience of an open arm of the maze. Whereas tolerance could be obtained as a result of a previous plus-maze experience, there was no evidence of an anxiogenic withdrawal response when rats were tested the following day undrugged. The phenomenon of one-trial tolerance is explained within our recently proposed two-factor theory of benzodiazepine dependence; it is suggested that one-trial tolerance provides a method for studying the mechanism underlying the development of tolerance to anxiolytic effects, independently from the mechanism underlying the development of withdrawal responses.     

One-trial tolerance to the anxiolytic effects of chlordiazepoxide in the plus-maze

Chlordiazepoxide (CDP 7.5 mg/kg) had a significant anxiolytic effect in rats tested on the plus-maze for the first time. On a second trial the control scores did not change, but those of the CDP group did and they no longer differed from controls. Rats previously tested undrugged or after flumazenil (4 mg/kg) also failed to show an anxiolytic response to CDP. Thus this phenomenon of one-trial tolerance depended on prior experience with the plus-maze. It also depended on CDP acting at the benzodiazepine receptors on trial 2, since the joint administration of CDP and flumazenil on trial 2 reversed the phenomenon.     

The endocannabinoid and endovanilloid systems interact in the rat prelimbic medial prefrontal cortex to control anxiety-like behavior

Cannabinoid receptor 1 (CB(1)) agonists usually induce dose-dependent biphasic effects on anxiety-related responses. Low doses induce anxiolytic-like effects, whereas high doses are ineffective or anxiogenic, probably due to activation of Transient Receptor Potential Vanilloid Type 1 (TRPV(1)) channels. In this study we have investigated this hypothesis by verifying the effects of the CB(1)/TRPV(1) agonist ACEA injected into the prelimbic medial prefrontal cortex (PL) and the participation of endocannabinoids in the anxiolytic-like responses induced by TRPV(1) antagonism, using the elevated plus-maze (EPM) and the Vogel conflict test (VCT). Moreover, we verified the expression of these receptors in the PL by double labeling immunofluorescence. ACEA induced anxiolytic-like effect in the intermediate dose, which was attenuated by previous injection of AM251, a CB(1) receptor antagonist. The higher and ineffective ACEA dose caused anxiogenic- and anxiolytic-like effects, when injected after AM251 or the TRPV(1) antagonist 6-iodonordihydrocapsaicin (6-I-CPS), respectively. Higher dose of 6-I-CPS induced anxiolytic-like effects both in the EPM and the VCT, which were prevented by previous administration of AM251. In addition, immunofluorescence showed that CB(1) and TRPV(1) receptors are closely located in the PL. These results indicate that the endocannabinoid and endovanilloid systems interact in the PL to control anxiety-like behavior.     

Vasopressin analogs: sedative properties and passive avoidance behavior in rats.

The effects of several types of vasopressin analogs that are considered to be resistant to some of the physiologically significant enzymatic systems were investigated utilizing rats trained in a passive avoidance task. Enhancement of avoidance latencies was observed 2, 7 and 13 days after the single learning trial when deamino-carbavasopressins, triglycyl-8-lysine-vasopressin or its des-glycinamide derivative, and deamino-D-arginine-vasopressin were given shortly after the learning trial in the dose of 1 microgram s.c. (8-L-Arginine)deamino-6-carba-vasopressin and (8-L-ornithine)deamino-6-carba-vasopressin were also active in the dose of 0.1 microgram. Lysine vasopressin and its des-glycinamide derivative failed to enhance avoidance latencies in part of the experiments if doses of 0.3--3 micrograms were administered and 7 or 13 day intervals were used between the learning and the test trials. Enhancement of avoidance latencies was also observed, if some of the peptides were injected 20 min but not 120 or 180 min before the test trial. Marked depression of exploratory behavior of rats in an open field was found after s.c. injections of low doses (1--3 micrograms kg-1) of deamino-carba-vasopressins. Higher doses (10--30 micrograms kg-1) induced sleep-like immobility not accompanied by ataxia or catalepsy.     

Anxiolytic-like activity of the mGLU2/3 receptor agonist LY354740 in the elevated plus maze test is disrupted in metabotropic glutamate receptor 2 and 3 knock-out mice

Rationale (1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) is a potent and selective agonist for group II metabotropic glutamate (mGlu2 and mGlu3) receptors, with anxiolytic-like activity in animal and human models, and efficacy in anxiety patients. However, the lack of mGlu2 or mGlu3 receptor specific agonists has prevented in vivo characterization of individual functions of these two receptors in mediating the anxiolytic-like effects of LY354740.Objective To utilize mGlu2 receptor and mGlu3 receptor knockout animals and the mGlu2/3 selective antagonist (2S,1S,2S)-2-(9-xanthylmethyl)-2-(2-carboxycyclopropyl)glycine (LY341495) to further investigate the roles of mGlu2 and mGlu3 receptors in mediating the anxiolytic-like actions of LY354740 in a mouse model of anxiety [elevated plus maze (EPM) test].Methods To confirm that mGlu2/3 receptors are responsible for anxiolytic-like activity in the EPM under these test conditions, mice were pretreated with LY341495 at 30 min prior to s.c. administered LY354740. Subsequently, saline vehicle or LY354740 was administered (s.c.) 30 min before the EPM testing in wild-type, mGlu2 receptor knockout, and mGlu3 receptor knockout mice.Results LY354740 reduced in a dose-dependent manner anxiety-related behavior on the EPM in wild-type mice with a maximally effective dose of 10–20 mg/kg s.c. Pretreatment with LY341495 potently prevented the anxiolytic-like effects of LY354740 (20 mg/kg, s.c.) in mice. Although the mGlu2 receptor knockout and mGlu3 receptor knockout mice were grossly normal, the anxiolytic-like activity of LY354740 (20 mg/kg, s.c.) was not evident in either mGlu2 or mGlu3 receptor knockout mice, when compared to their wild-type controls.Conclusions The activation of both mGlu2 and mGlu3 receptors by LY354740 appears to be required for anxiolytic-like activity in the EPM test in mice. These studies serve as a foundation for additional studies on underlying circuits, brain structures, and receptor subtypes involved in the anxiolytic-like actions of mGlu receptor active agents, and the design of future drugs for anxiety disorders in humans.     

The effect of chlordiazepoxide on measures of activity and anxiety in Swiss-Webster mice in the triple test

The effects of the anxiolytic drug chlordiazepoxide (CDZ) on general activity and anxiety-related behaviour of male and female Swiss-Webster mice were investigated in the triple test, which combines the open field (OF), elevated-plus maze (EPM) and the light-dark box (LDB). Mice were injected with saline or CDZ (1.0, 7.5 or 15.0 mg/kg) and their behaviour was observed for 15 min in the triple test on each of two days. On day 1, increasing doses of CDZ increased open arm exploration and total distance travelled, and decreased risk assessments in the EPM. In the LDB, CDZ increased time in the light compartment and number of transitions between compartments. In spite of habituation to the apparatus, CDZ increased the number of transitions in the LDB, increased percent time in the open arms and total distance travelled in the EPM on day 2. Thus, there was a significant effect of CDZ in the triple test on both days, even though there was habituation to the apparatus after day 1. These results show that the drug effect was independent of the day effect and that there was no one-trial tolerance effect in the triple test of anxiety.     

A comparison of the effects of scopolamine and diazepam on acquisition and retention of inhibitory avoidance in mice

Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function.     

Evaluation of the anxiolytic-like effect of NKP608, a NK1-receptor antagonist,in two rat strains that differ in anxiety-related behaviors

Rationale NKP608, a selective NK1 receptor antagonist, has been shown to produce anxiolytic-like effects in rodents tested in different anxiety models. However, most of these findings are based on social behaviors and, to our knowledge, there is no report concerning the effects of NKP608 in the elevated plus-maze (EPM) and the open field (OF), two classical models of anxiety/emotionality. Moreover, this compound has never been tested in rodent strains that display contrasting levels of anxiety-related behaviors.Objectives To investigate the anxiolytic-like effects of NKP608 in Lewis and SHR inbred rats, proposed as a genetic model of anxiety for showing high and low indices of anxiety, respectively.Methods Lewis and SHR rats of both sexes were tested in the EPM and OF tests following acute administration of NKP608 (0.003, 0.03 or 0.3 mg/kg) or chlordiazepoxide (CDZ, 5 mg/kg). Measures of approach/avoidance towards the open arms of the EPM and the central area of the OF were used as indices of anxiety.Results All doses of NKP608 produced anxiolytic-like effects, similar to those of CDZ, in SHR males tested in the OF but not in the EPM. Conversely, this compound had a partial anxiolytic effect in LEW males (and, to a lower degree, in SHR females) in the EPM, but not in the OF. LEW females were unaffected following all pharmacological treatments.Conclusions These findings indicate that the anxiety-related effects of NKP608 are strain-, sex- and test-dependent. Moreover, the present data confirm and extend the therapeutic potential of NK1 receptor antagonists for the treatment of anxiety.     

Behavioral effects of saredutant, a tachykinin NK2 receptor antagonist, in experimental models of mood disorders under basal and stress-related conditions

The present study was made to investigate the role of tachykinin NK2 receptors in the expression of stress-related behaviors in animals. Under basal conditions, intraperitoneal (i.p.) administration of the selective tachykinin NK2 receptor antagonist, saredutant (1 and 3 mg/kg) or diazepam (1 mg/kg) exerted anxiolytic-like effects in rodents, as they reduced grooming score of Wistar male rats tested in the novelty-induced grooming sampling test (NGT) and increased percentage of time and entries in open arms of Swiss male mice tested in the elevated plus maze (EPM) test. After previous exposure to stress-related conditions, as induced by a 2-min forced swim made 5 min prior to the EPM test, saredutant but not diazepam, exhibited anxiolytic-like effects in mice. To study the antidepressant-like activity of tachykinin NK2 receptor antagonist under basal conditions, different groups of rats were injected i.p. with saredutant (2.5, 5 and 10 mg/kg) or the tricyclic antidepressant, clomipramine (50 mg/kg) and tested in the forced swim test (FST), a widely used antidepressant-responsive test. The influence of stress-related conditions was studied in rats subjected to electric foot-shocks (1 mA, 1 s) 24, 5 and 1 h prior to FST, after drugs injection. In the FST, clomipramine decreased the immobility time only under basal conditions, but not after application of acute foot-shocks. To the contrary, saredutant-treated rats also exhibited more active behavior in FST after previous exposure to stressors. These results give further support to the hypothesis that tachykinin NK2 receptors may be a therapeutic target for pharmacological treatment of stress-related diseases, such as anxiety and depression.     

MIF-1 facilitates passive avoidance retention

MIF-1 (Pro-Leu-Gly-NH2) is an endogenous substance which seems to be involved in the regulation of some central nervous system functions. It was recently shown to affect learning and memory processes. In order to further clarify the role of MIF in these processes we used two different passive avoidance tests: one-trial step down (SD) and shock suppressed drinking (SSD). Z-Pro-Leu-Gly-NH2 was administered on the training day ip either 15 minutes before trial or immediately after. The doses used were as follows: SD--1.0 mg/kg, SSD--0.05 mg/kg (in the group injected before trial) and 1.0 mg/kg--SD and SSD, in the groups injected post-trial. Only the immediate post-training injection of peptide resulted in significant prolongation of the step-down latencies on the retention-day. Similarly, in the SSD procedure only post-training MIF markedly attenuated water intake on the day after training. In a separate experiment we have found that in the dose of 1.0 mg/kg, but not 0.1 mg/kg, MIF significantly inhibited water intake. These results suggest that this naturally occurring peptide can contribute to the processes of memory consolidation and water intake.