Corticotropin releasing factor receptor 1 antagonist differentially inhibits freezing behavior and changes gamma-aminobutyric acidergic activity in the amygdala in low- and high-anxiety rats.

The aim of this study was to examine the effects of non-peptide corticotropin-releasing factor receptor 1 (CRF1) antagonist (antalarmin) administration on rat conditioned fear responses and gamma-aminobutyric acid (GABA)-ergic brain activity (GAD67 expression and GABA concentration) in low-anxiety (LR) and high-anxiety (HR) rats. The animals were divided into the LR and HR groups based on the duration of their conditioned freezing response in the first contextual fear test. After 28 days, the animals were re-subjected to the contextual fear training and test. The rats received an antalarmin injection (10 mg/kg or 20 mg/kg) 80 min before the second exposure to the aversive context. Antalarmin significantly attenuated the conditioned fear response only in the HR rats. The behavioral effect of a lower dose (10 mg/kg) of antalarmin was accompanied by increased GAD67 expression in the prelimbic cortex (PL) and central nucleus of the amygdala (CeA) and an increased GABA concentration in the amygdala. These studies showed that HR rats were more susceptible to the anxiolytic effects of CRF1 antagonist administration, which were associated with increased GABAergic activity in the medial prefrontal cortex and amygdala. The current data may provide insights into the neurobiological mechanism operating within the mesolimbic CRF-GABA neurotransmitter systems, which may be responsible for individual differences in stress-related diseases. This knowledge can be applied to further elucidate the pathophysiology of anxiety and trauma/stress-related disorders.

Is the interaction between fatty acids and tryptophan responsible for the efficacy of a ketogenic diet in epilepsy? The new hypothesis of action.

The effects of a ketogenic diet in controlling seizure activity have been proven in many studies, although its mechanism of action remains elusive in many regards. We hypothesize that the ketogenic diet may exert its antiepileptic effects by influencing tryptophan (TRP) metabolism. The aim of this study was to investigate the influence of octanoic and decanoic fatty acids (FAs), the main components in the MCT diet (medium-chain triglyceride diet, a subtype of the ketogenic diet), on the metabolism of TRP, the activity of the kynurenic pathway and the concentrations of monoamines and amino acids, including branched-chain amino acids (BCAA) and aromatic amino acids (AAA) in rats. The acute effects of FA on the sedation index and hippocampal electrical after-discharge threshold were also assessed. We observed that intragastric administration of FA increased the brain levels of TRP and the central and peripheral concentrations of kynurenic acid (KYNA), as well as caused significant changes in the brain and plasma concentrations of BCAA and AAA. We found that the administration of FA clearly increased the seizure threshold and induced sedation. Furthermore, we have demonstrated that blocking TRP passage into the brain abolished these effects of FA but had no similar effect on the formation of ketone bodies. Given that FAs are major components of a ketogenic diet, it is suggested that the anticonvulsant effects of a ketogenic diet may be at least partly dependent on changes in TRP metabolism. We also propose a more general hypothesis concerning the intracellular mechanism of the ketogenic diet.

Expression of N-methyl-D-aspartate (R)(GluN2B) - subunits in the brain structures of rats selected for low and high anxiety.

In this paper, we studied differences in the density of N-methyl-D-aspartate (NMDA) receptor GluN2B subunits in the brains of low (LR) and high (HR) anxiety rats subjected to extinction trials and re-learning of a conditioned fear response, modeling a natural course of anxiety disorders. Classifications of animals as LR or HR was determined by fear-induced freezing responses in the contextual fear test. Increased basal concentrations of GluN2B subunits were observed in the amygdala of HR rats as compared to the unconditioned control group by Western blot analysis. Re-exposure of HR animals to the fear-conditioned context resulted in elevated concentrations of GluN2B subunits in the amygdala, hippocampus and the prefrontal cortex compared to LR rats as well as in the hippocampus and prefrontal cortex vs. the control group. In addition, it was shown that re-test of a conditioned fear increased the number of cells expressing GluN2B subunits in the basolateral amygdala, dentate gyrus of the hippocampus and secondary motor cortex (M2) in the HR group relative to the LR group. Together, these data suggest that animals that are more anxious have altered patterns of GluN2B subunit expression in the frontal cortex and limbic structures, which control emotional behaviour.

Pregnenolone sulfate potentiates the effects of NMDA on hippocampal alanine and dopamine.

The aim of the present study was to analyze biochemical effects of a neurosteroid, pregnenolone sulfate (PS), which accompany changes in the threshold of seizures, and to establish the contribution of local, hippocampal monoaminergic and amino acid systems, to the control of convulsive activity. Pretreatment of mice with PS (intracerebroventricularly) selectively enhanced the potency of peripherally (intraperitoneally) administered NMDA at the LD16 (88.0 mg/kg) to induce clonic-tonic convulsions (PS, LD84 = 184.7 nM; 95% CL = 181.4-188.1). The proconvulsive actions of picrotoxin and bicuculline, the GABA-A receptor antagonists, were not modified by pretreatment of mice with PS. Administration of PS alone (up to 240 nM icv) did not show any seizure-like activity. PS given at LD84, together with NMDA (at the LD16), increased the hippocampal concentration of alanine, and enhanced local metabolism of dopamine in a period immediately preceding the onset of seizures significantly stronger than did NMDA alone. These and other data indicate that the enhancement by PS of hippocampal levels of alanine may contribute to the seizures development as this amino acid is a precursor of glutamate, and a co-agonist of the NMDA receptors. On the other hand, simultaneously occurring stimulation of hippocampal dopaminergic system may be considered a compensatory phenomenon, limiting seizures propagation through the limbic forebrain. Summarizing, our results show that PS-induced potentiation of NMDA seizures is accompanied by selective changes in hippocampal dopamine turnover and alanine concentration.

Tolerance to the anticonvulsant activity of midazolam and allopregnanolone in a model of picrotoxin seizures.

The effects of an intracerebroventricular (i.c.v.) administration of a non-selective full benzodiazepine receptor agonist, midazolam, and a neuroactive steroid, allopregnanolone, on picrotoxin-induced seizures and striatal dopamine metabolism, were studied in mice. It was found that acute i.c.v. injections of midazolam (ED50=38.25 nmol) and allopregnanolone (ED50=26.34 nmol) blocked picrotoxin-induced seizures to a similar extent. After repeated administration at the ED(85) doses (midazolam-56.6 nmol, allopregnanolone-94.2 nmol; once or twice daily for 5 days) tolerance developed to the anticonvulsant activity of midazolam (ED50=94.14 nmol) and allopregnanolone (ED50=186.70 nmol). Acute i.c.v. injections of midazolam and allopregnanolone (at the ED50 doses established in the model of picrotoxin seizures: 38.25 and 26.34 nmol, respectively), significantly decreased the concentration of dopamine metabolites: 3-methoxytyramine and 3,4-dihydroxyphenylacetic acid, as well as the dopamine turnover rate (homovanilic acid/dopamine ratio; by about 20%), in the mouse striatum. These findings together with the recently published data on the potentiation by midazolam and allopregnanolone of ethanol-induced sleep [Pharmacol. Biochem. Behav. 67 (2000) 345] indicate a very similar central effect profile of benzodiazepines and neurosteroids. Moreover, similar efficacy of allopregnanolone and midazolam at the GABA(A) receptors has been found. Overall, the results of the present study, along with the possibility of neurosteroid conversion in the brain into other steroid hormones (testosterone, estradiol, aldosterone), add to the accumulating evidence suggesting a less favorable pharmacological profile for this class of drugs than was previously thought.

Changes in ethanol preference by rats treated with gamma1 and gamma2 GABA(A) receptor subunit antisense oligodeoxynucleotides.

Micro-injections (10 nmol/day over 5 days) of antisense oligodeoxynucleotides (aODNs) to gamma-aminobutyric acid A (GABA(A)) receptor alpha1 and gamma2 subunits reduce the mRNA for these subunits in rat brain. In this study, the effects of alpha1 and gamma2 subunit aODNs on rat alcohol preference were investigated. Reduction of the alpha1 subunit mRNA decreased, whereas reduction of the gamma2 subunit mRNA increased, ethanol intake in rats.

Effects of a novel uncompetitive NMDA receptor antagonist, MRZ 2/579 on ethanol self-administration and ethanol withdrawal seizures in the rat.

It has been repeatedly reported that NMDA receptors may contribute to ethanol-induced discriminative stimulus effects and withdrawal syndrome. However, the role of NMDA receptors in the reinforcing properties of ethanol remains unclear. The aim of the present study was to evaluate effects of the novel low-affinity, uncompetitive NMDA receptor antagonist, 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride (MRZ 2/579), on ethanol self-administration and ethanol withdrawal-associated seizures in rats. Both an operant (lever pressing for ethanol) and non-operant two-bottle choice setups were employed to initiate ethanol self-administration. In another procedure, forced treatment with high doses (9--15 g/kg/day) was used to induce physical dependence on ethanol. MRZ 2/579 delivered chronically by osmotic minipumps (9.6 mg/day, s.c.) did not alter either operant or non-operant ethanol drinking behaviour in a maintenance phase of ethanol self-administration. In contrast, repeated daily injections of the drug (5 mg/kg, i.p.) led to a progressive decrease in operant responding for ethanol. MRZ 2/579 (0.5--7.5 mg/kg, i.p.) and another low-affinity NMDA receptor antagonist, memantine (1--10 mg/kg, i.p.) dose-dependently suppressed ethanol withdrawal seizures with efficacies comparable with that of a standard benzodiazepine derivative, diazepam. The results of the present study indicate that: (i) intermittent administration of MRZ 2/579 may lead to a gradual decrease of operant responding for ethanol; and (ii) the group of low-affinity uncompetitive NMDA receptor antagonists may be an interesting alternative to benzodiazepines in the treatment of alcohol withdrawal.

Neonatal treatment with 5,7-dihydroxytryptamine induces decrease in alcohol drinking in adult animals.

It has long been suggested that serotonin (5-HT) neurotransmitter system activity is associated with ethanol (ETOH) intake and dependence. The authors studied the effects of neonatal 5,7-dihydroxytryptamine (5,7-DHT) lesions on voluntary alcohol drinking in adult Wistar rats. At 3 days after birth animals were pretreated with desipramine (DMI) and then given a bilateral injection of 5,7-DHT into lateral ventricles. Afterwards, the rats were kept under standard laboratory conditions until at least 2 months of age following which they were tested. 5,7-DHT induced a marked and permanent decrease in brain 5-HT content, measured in the prefrontal cortex, hippocampus and striatum, but did not modify noradrenaline content in these structures. Lesioned animals, both males and females displayed lower preference for ETOH than sham-lesioned animals. Total fluid intake was significantly higher in 5,7-DHT-lesioned than sham-lesioned rats. A significant decrease in body weight was observed in 5,7-DHT-treated rats. This effect was not caused by a significant change in food intake. Both groups showed high preference for a 0.1% saccharin. In conclusion, the present results demonstrated that neonatal treatment with 5,7-DHT evoked long-lasting neurochemical changes and reduction of ETOH intake in adult rats. Neonatally 5,7-DHT-treated rats may be considered as a suitable model in further research on the relationship between the function of central 5-HT system and alcohol intake and dependence.

Rapid down-regulation of GABA-A receptors after pretreatment of mice with progesterone.

The effect of a single administration of a high dose of progesterone on brain [3H]muscimol binding, was examined in mice using quantitative autoradiography. It was found that progesterone given at the dose of 150 mg/kg ip (the ED85 dose established previously in the model of picrotoxin seizures, Czlonkowska et al., Pharmacol. Biochem. Behav., 2000, 67, 345-353), significantly decreased the specific binding of [3H]muscimol to the nucleus caudatus and nucleus accumbens, as early as 1 h after injection. A similar tendency, close to the statistically significant level, was also present in the dentate gyrus of the hippocampus (p = 0.07). It is suggested that a high dose of progesterone and ensuing excessive stimulation of GABAA receptors by its metabolites, neurosteroids, could bring about rapid changes in the GABAA receptor number and/or affinity.

The effects of neurosteroids on picrotoxin-, bicuculline- and NMDA-induced seizures, and a hypnotic effect of ethanol.

The effects of intraperitoneally (IP) or intracerebroventricularly (ICV) administered neurosteroids [allopregnanolone (AP); 5beta-tetrahydrodeoxycorticosterone (5beta-THDOC); dehydroepiandrosterone sulfate (DHEAS); pregnenolone sulfate (PS)] and their precursors [progesterone (PROG), pregnanedione (PREG)] on N-methyl-D-aspartic acid (NMDA)-, picrotoxin (PTX)- and bicuculline (BIC)-induced seizures and ethanol-induced sleep were studied in mice. It was found that IP injections of (+)MK-801 most potently antagonized NMDA-, PTX- and BIC-induced seizures, as compared to diazepam (DZP), PROG and PREG. Both precursors of neurosteroids appeared only marginally active in the applied models of convulsions. ICV injections of AP selectively blocked PTX- and BIC-induced seizures, whereas 5beta-THDOC and (+)MK-801 also antagonized NMDA-induced convulsions. ICV administered DHEAS induced seizures in a dose-dependent way. ICV injections of AP and midazolam shortened the latency and prolonged the duration of sleep induced by IP injections of ethanol (5.0 g/kg). On the contrary, DHEAS and PS significantly reduced the hypnotic-like effect of ethanol. The obtained results suggest that neurosteroids may modulate in an agonistic (AP, 5beta-THDOC), or antagonistic way (PS, DHEAS), the GABA(A) receptor complex functions. Some of them (5beta-THDOC) also interact with NMDA receptors. AP appeared to be the most selectively acting compound, with its profile of action fully comparable to that of midazolam. AP also enhanced the hypnotic effect of ethanol, pointing out to the propensity to interact with centrally depressant agents. These findings, together with the possibility of conversion of some neurosteroids in the brain to other steroid hormones (testosterone, estradiol and aldosterone), indicate the limitations of their use for the treatment of neurological and psychiatric disorders.

Nitric oxide donors antagonize N-nitro-L-arginine and haloperidol catalepsy: potential implication for the treatment of Parkinsonism?

Nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine (NNLA) produced dose-dependent, long-lasting catalepsy in rats, the effect being attenuated by NO donors L-arginine and molsidomine. Catalepsy induced by haloperidol (0.4 mg/kg i.p.), D2 receptor antagonist, was reduced dose-dependently by molsidomine (10.0-100.0 mg/kg) and by L-arginine at a dose of 100.0 mg/kg. Low, non-cataleptic doses of NNLA (0.1 mg/kg) and haloperidol (0.1 mg/kg) given in combination produced a marked and long-lasting catalepsy. The results suggest that NO plays a role in NNLA-induced catalepsy as well as in catalepsy elicited by haloperidol.

Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization.

A series of novel tricyclic pyrido-phthalazine-dione derivatives was tested for antagonistic effects at the strychnine-insensitive modulatory site of the N-methyl-D-aspartate (NMDA) receptor (glycineB). All compounds displaced [3H]MDL-105,519 binding to rat cortical membranes with IC50 values of between 90 nM and 3.6 microM. In patch-clamp experiments, steady-state inward current responses of cultured hippocampal neurons to NMDA (200 microM, glycine 1 microM) were antagonized by these same compounds with IC50 values of 0.14 to 13.8 microM. The antagonism observed was typical for glycineB antagonists, i.e., they induced desensitization and their effects were not use or voltage dependent. Moreover, increasing concentrations of glycine were able to decrease their apparent potency. Much higher concentrations (>100 microM) were required to antagonize alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced currents. They were potent, systemically active NMDA receptor antagonists in vivo against responses of single neurons in the rat spinal cord to microelectrophoretic application of NMDA with ID50 values in the low milligram per kilogram i.v. range. They also inhibited pentylenetetrazol-, NMDA- and maximal electroshock-induced convulsions in mice with ED50 values ranging from 8 to 100 mg/kg i.p. The duration of anticonvulsive action was rather short but was prolonged by the organic acid transport inhibitor probenecid (200 mg/kg). The agents tested represent a novel class of systemically active glycineB antagonists with greatly improved bioavailability.

Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo.

The amino-adamantane derivatives memantine (1-amino-3,5-dimethyladamantane) and amantadine (1-amino-adamantane) are relatively low affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists which have been used clinically in the treatment of dementia and Parkinson's disease respectively for several years without serious side effects. The aim of this study was to test whether memantine, amantadine and other low affinity uncompetitive NMDA receptor antagonists also have better therapeutic indices than high affinity antagonists in preclinical models of epilepsy by assessing the potency, kinetics and voltage-dependency of open channel blockade for a series antagonists in vitro and comparing these effects to anticonvulsive and motor impairment activity in vivo. The compounds tested were memantine, amantadine, 14 other amino-adamantanes, (+)-MK-801, ketamine, dextrorphan, dextromethorphan and phencyclidine. The offset kinetics of open-channel blockade assessed with whole cell patch clamp recordings from cultured superior colliculus neurones were highly correlated to potency i.e. the less potent antagonists showed faster unblocking kinetics (Koff, r = 0.904). Although, onset kinetics as assessed by Kon were not correlated to potency (r = 0.023), tau on estimated at IC50 is perhaps a more meaningful measure of onset kinetics at equieffective concentrations and was also well correlated to potency (r = -0.863). All amino-adamantanes tested were strongly voltage-dependent. There was also a good correlation between the in vitro potencies of uncompetitive NMDA receptor antagonists assessed with patch clamp recordings and displacement of equilibrium [3H](+)-MK-801 binding and their in vivo activity against maximal electroshock (MES) and pentylenetetrazol (PTZ) induced tonic convulsions and NMDA-induced lethality in mice. Memantine and four other amino-adamantanes with somewhat lower potency and faster blocking kinetics had better therapeutic indices (ED50 rotarod and traction reflex over ED50 in MES-induced convulsions; TI = 2-4) than substances with higher affinity such as ketamine, dextrorphan and (+)-MK-801 (TI < 2). However, amantadine and several other amino-adamantanes with lower potency than memantine actually had poorer therapeutic indices (TI < or = 0.5) which may have been due to additional actions at other ion channels or receptors at the doses necessary to protect against seizures. In fact, ED50 in the MES test was negatively-correlated to therapeutic indices (traction r = -0.790, rotarod r = -0.797) i.e. the less potent uncompetitive antagonists had worse therapeutic indices. The data from the present study do not lend support to the idea that low affinity, open channel NMDA receptor blockers are also effective in models of epilepsy at doses having little effect on physiological processes. It should be stressed that these data do not contradict the known therapeutic safety of memantine and amantadine in dementia and Parkinson's disease respectively. Thus the good clinical profile of memantine in dementia has been attributed not only to its fast blocking/unblocking kinetics but also to its strong voltage-dependency. These biophysical properties may allow therapeutically-relevant concentrations to block chronic, low level pathological activation of NMDA receptors whilst leaving their synaptic activation intact. Precisely these properties may also underlie the poor therapeutic indices seen in the present study on antiepileptic activity due to the synaptic nature of both seizures and normal glutamatergic transmission.

Studies on the effects of certain 5-HT-3 receptor antagonists on ethanol preference and withdrawal seizures in the rat.

We tested how certain antagonists of 5-HT-3 receptors affect ethanol consumption and withdrawal seizures in ethanol-dependent Wistar male rats. Low doses of tropisetron (0.001-0.01 mg/kg ip) and ondansetron (0.00025 mg/kg ip) reduced ethanol consumption and preference. Increased ethanol intake was observed, however, after administration of higher doses of ondansetron (0.125 g/kg ip) and granisetron (0.125-0.25 mg/kg ip). Audiogenic seizures in rats withdrawn from ethanol were attenuated by low doses of tropisetron and ondansetron.

Effect of glutamate receptor antagonists on N-methyl-D-aspartate- and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced convulsant effects in mice and rats.

Selected antagonists of N-methyl-D-aspartate (NMDA) and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, acting through different recognition sites were studied in three in vivo experimental procedures: systemic administration of NMDA or AMPA to mice and 7-day-old rats or i.c.v. injection in adult rats. Antagonists were given i.p. before the agonists. Of the substances tested (+)-5-methyl-10,11- dihydro-5H-dibenzocyclohepten-5,10-imine maleate ((+)-MK-801, an uncompetitive NMDA receptor antagonist) and DL-(E)-2-amino-4-methyl-5- phosphono-3-pentanoic acid (CGP-37849, a competitive NMDA receptor antagonist) were the most potent and selective NMDA receptor antagonists, having ED50s below 1 mg/kg in all three tests. 1-Amino-3,5-dimethyladamantane (memantine, an uncompetitive NMDA receptor antagonist) was less potent and, additionally, inhibited AMPA-induced seizures in adult rats. Aminocyclopropane carboxylic acid--a partial agonist at the glycine site coupled to NMDA receptors (GlyB)--was a weak antagonist (ED50 > 150 mg/kg) in mice. Other partial GlyB receptor agonists, aminocyclobutane carboxylic acid, (+,R)-3-amino-1-hydroxy-2-pyrrolidine ((+,R)-HA-966) and d-cycloserine, and antagonists, 5,7-dinitroquinoxaline-2,3-dione (MNQX) and 5,7-dichlorokynurenic acid, were ineffective in mice after systemic administration. The last two agents however were active in adult rats when given i.c.v. Thus affinity, intrinsic activity (GlyB receptor partial agonists) and/or penetration into the brain (GlyB receptor antagonists) seem to be important factors in determining the effectiveness of these agents.(ABSTRACT TRUNCATED AT 250 WORDS)

The abilities of 5-HT3 receptor antagonist ICS 205-930 to inhibit alcohol preference and withdrawal seizures in rats.

Recent evidence suggests that central 5-HT3 are intimately involved in the ethanol (ETOH) dependence mechanism. In the present study we observed the effects of the 5-HT3 receptor antagonist ICS 205-930 on audiogenic seizure response (ASR) in ETOH-withdrawn rats and on ETOH intake and preference. Low doses of ICS 205-930 (0.001 mg/kg), but not higher doses (0.1 mg/kg), markedly reduced both ASR and ETOH intake in a high preference group of animals. The possible mechanism of different effects of low and high drug doses is discussed.

Comparative study of nifedipine and isradipine in animal models of ethanol dependence.

The effects of calcium channel inhibitors on ethanol intake and dependence in Wistar rats were studied. Nifedipine and isradipine were suspended in 1% Tween 40 saline solution and administered ip 60 min prior to testing. Audiogenic seizure response evaluation was performed after 5 days of ethanol treatment. Both nifedipine and isradipine significantly reduced the intensity score of convulsions and, in doses of 2.5 and 5.0 mg/kg, respectively, abolished them. Both drugs significantly reduced ethanol preference and intake in the high preference group of animals. Our results support the observations that certain dihydropyridine derivatives are capable of attenuating both ethanol preference and physical dependence.

[The effect of naloxone on the activation, inducible by chronic alcoholic intoxication, of the membrane-bound form of enkephalin convertase in the midbrain and hypothalamus of rats]. / Vliianie naloksona na indutsiruemuiu khronicheskoi alkogol'noi intoksikatsiei aktivatsiiu membranno-sviazannoi formy énkefalinkonvertazy v srednem mozge i gipotalamuse krys.

The activity of membrane-bound and soluble enkephalin convertase was determined with dansyl-Phe-Leu-Arg as substrate in midbrain, including hypothalamus, of Wistar rats, who were given ethanol (20% solution i.g., 9-15 g/kg per day during 4 days) or naloxone (2 mg/kg i.p. twice a day during 4 days) or their combination. It was shown that activation of membrane-bound enzyme, observed after alcohol treatment of rats, didn't develop by combined ethanol-naloxone administration. It's supposed that alcohol-stimulating effect on this enzyme realizes throughout the hyperstimulation of opioid receptors by enkephalins and, possible, by other opioid-active compounds.

5-Hydroxytryptamine1A receptor agonists in animal models of depression and anxiety.

The effects of different doses of buspirone, 3-dipropyl-amino-5-hydrochromar (NDO 008) and 8-hydroxydipropyl-aminotetralin (8-OH-DPAT) (administered intraperitoneally) were studied in tests of anxiolytic and antidepressant action in rats. These tests included the elavated plus maze test, the forced swim test, stress-induced suppression of open-field behavior, and the differential-reinforcement-of-low-rates-of-behaviour-72 sec (DRL 72 s) test. Buspirone (0.125 mg/kg) and NDO 008 (1.0 to 2.0 mg/kg) produced anxiolytic activity in the elevated plus maze, whereas 8-OH-DPAT did not in the doses employed. All three compounds increased activity in the forced swim test, although buspirone did so at a lower dose than NDO 008 and 8-OH-DPAT. In the stress-induced suppression test of open field activity all three compounds induced an antidepressant-like effect at different doses dependent on whether footshock (stressor) was presented 24 hr before or just prior to the open-field test. All three compounds even caused some reduction of activity in the non-shocked rats. 8-OH-DPAT (1.0 mg/kg) produced a significant and reliable increase in the Reinforcement/Response rate quotient in the DRL 72s test. These diverse results may provide an indication of potential clinical efficacy of the 5-HT1A agonists in the treatment of anxiety and depression.

MIF-1 potentiates the action of tricyclic antidepressants in an animal model of depression.

In the present paper, the effect of simultaneous treatment of rats with low doses of MIF-1 and tricyclic antidepressants on rat behavior in the forced swim test was studied. It was found that MIF-1 stimulated in a dose-dependent manner "active" behavior of animals in this paradigm. The effect of MIF-1 appeared to be independent of changes in rats' locomotion in the open field test. The combined treatment of rats with MIF-1 (0.01 mg/kg IP) and amitriptyline (5 mg/kg IP) or desipramine (1.25 mg/kg) IP) significantly stimulated active behavior in the forced swim test above the level obtained with each of the drugs given separately. The present data suggest the potential clinical efficacy of a combined therapy of depressive patients with MIF-1 and small doses of tricyclic antidepressants.