Strain-dependent effects of anandamide on memory consolidation in mice are antagonized by naltrexone

Post-training administration of anandamide (1.5, 3, 6 mg/kg) dose-dependently impaired retention of an inhibitory avoidance response in DBA/2 mice, while improving it in C57BL/6 mice. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation. They were observed when drug was given at short, but not long, periods of time after training, i.e. when the memory trace was susceptible to modulation. These effects of anandamide parallel those of opioid agonists, as previously reported. Moreover, the opioid antagonist naltrexone improved retention in DBA/2 mice, while impairing it in C57BL/6 mice. Pre-treatment with the opioid antagonist at a non-effective dose (0.1 mg/kg) antagonized the effects of anandamide on memory consolidation in both strains. These results strongly suggest that endogenous cannabinoids affect memory processes through opioid systems. The possible involvement of other neurotransmitter systems, such as dopamine, in strain-dependent effects of anandamide in memory consolidation is discussed.     

Strain-dependent effects of cocaine on memory storage improvement induced by post-training physostigmine

Post-training administration of the inhibitor of cholinesterase enzymes, physostigmine, dose-dependently (0.025–0.4 mg/kg) improved retention of an inhibitory avoidance response in C57BL/6 (C57) as well as in DBA/2 (DBA) mice, the latter being more responsive than C57 mice. The effects on retention performance induced by physostigmine in C57 and DBA mice appeared to be due to an effect on memory consolidation. In fact, they were observed when drugs were given at short, but not long, periods of time after training, which is when the memory trace is susceptible to modulation. Moreover, these effects are not to be ascribed to a rewarding or non-specific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training were not affected by the post-training drug administration. Post-training administration of cocaine (1–5 mg/kg) dose-dependently improved retention of an inhibitory avoidance response in C57 mice, while impairing it in the DBA strain, thus confirming previous results (Puglisi-Allegra et al. 1994b). Pretreatment with cocaine at ineffective doses as well as at an effective one potentiated the effects of an ineffective as well as of an effective dose of physostigmine in C57 mice, while it antagonized the effects of the inhibitor of cholinesterase enzymes on memory consolidation in DBA mice. The present results indicate that the indirect DA receptor agonist cocaine affects physostigmine action on memory consolidation in an opposite manner in the two inbred strains, pointing to genotype-dependent interaction between cholinergic and dopaminergic activity in memory consolidation.     

Strain-dependent effects of post-training cocaine or nomifensine on memory storage involve both D1 and D2 dopamine receptors

Post-training administration of cocaine (1–10 mg/kg) or nomifensine (1–10 mg/kg) dose-dependently improves retention of an inhibitory avoidance response in C57BL16 mice, while impairing it in the DBA/2 strain. The effects on retention performance induced by the psychostimulant and the dopamine (DA) reuptake blocker in C57BL/6 and DBA/2 mice appear to be due to an effect on memory consolidation. In fact, they were observed when drugs were given at short, but not long, periods of time after training, i.e. when the memory trace is susceptible to modulation. Moreover, these effects are not to be ascribed to an aversive or a rewarding or non-specific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during the training were not affected by the post-training drug administration. The strain-dependent effects of an intermediate dose (5 mg/kg) of both cocaine and nomifensine were reversed by pretreatment with either selective D₁ or D₂ DA receptor antagonists SCH 23390 and (-)-sulpiride administered at per se non-effective doses (0.025 and 6 mg/kg, respectively), thus suggesting that D₁ and D₂ receptor types are similarly involved in modulating memory processes. These results show that the effects of cocaine on memory consolidation are related to its dopaminergic action, since they are similar to those produced by nomifensine and, what is more important, are antagonized by pretreatment with DA receptor antagonists. Moreover, they point to possible genotype-dependent factors in DA mediated effects of cocaine on memory consolidation, indicating inbred mice as an experimental tool to investigate neural mechanisms underlying interindividual susceptibility to drug addiction.     

Modulation of memory processing in the cingulate cortex of mice

To evaluate the possible role of the cingulate cortex in memory processing for training using a noxious stimulus, we trained mice on foot shock avoidance in a T-maze. Cholinergic, GABAergic, serotonergic, and glutamatergic agonists and antagonists were administered into the cingulate cortex immediately after training. Retention for the foot shock avoidance training was tested 1 week later. The results indicate that muscarinic and nicotinic agonists improved retention, while antagonists impaired it. GABA and serotonin agonists impaired retention, while antagonists improved it. Drugs acting on GABA(A) and GABA(B) receptors had similar effects on retention, as did drugs acting on serotonin 1 and 2 receptor subtypes. Glutamate improved retention, and AP5, an antagonist of the excitatory amino acid site of the NMDA receptor, impaired retention. The cingulate cortex, like other parts of the limbic system, is involved in memory processing that occurs shortly after training.     

Effects of GABAergic drugs on physostigmine-induced yawning in rats

In the present work the effects of GABA agonists and antagonists on yawning induced by physostigmine have been studied. Intraperitoneally (IP) injection of physostigmine (0.05–0.3 mg/kg) induced dose-related yawning in rats. The maximum yawning response was observed with 0.2 mg/kg of the drug. The GABA agonists muscimol (1–4 mg/kg) and baclofen (0.125–1 mg/kg) decreased yawning induced by physostigmine (0.2 mg/kg) dose dependently. Combination of both GABA agonists elicited greater inhibition of yawning. The GABA-A antagonists bicuculline or picrotoxin but not the GABA-B antagonist phaclofen reduced the inhibitory response induced by muscimol, whereas phaclofen but not bicuculline or picrotoxin reduced baclofen's inhibitory effect. Administration of bicuculline, picrotoxin or phaclofen also decreased the yawning induced by physostigmine. However, when the GABA-A and GABA-B antagonists were employed in combination, the inhibitory responses of both drugs were lost. It is concluded that GABA-A and/or GABA-B receptor stimulation may inhibit physostigmine-induced yawning.     

Effects of GABA-ergic drugs on penile erection induced by apomorphine in rats

The effects of GABA agonists and antagonists on penile erection (PE) induced by apomorphine were investigated in rats. Subcutaneous (SC) administration of apomorphine (0.01–0.1 mg/kg) induces a dose-dependent PE in rats. The maximum effect was obtained with 0.1 mg/kg of the drug. The response was decreased with increasing doses of apomorphine from 0.1 to 0.5 mg/kg. The response induced by apomorphine (0.1–0.5 mg/kg) was decreased in animals pretreated with either the GABA-A agonist muscimol or the GABA-B agonist baclofen. Combination of muscimol with baclofen caused a stronger inhibitory effect on apomorphine-induced PE. Bicuculline or picrotoxin but not phaclofen reduced the inhibitory effect of muscimol on PE induced by apomorphine, whereas phaclofen but not GABA-A antagonists decreased the inhibitory action of baclofen on apomorphine-induced PE. Pretreatment of animals with higher doses of the GABA-A antagonists bicuculline and picrotoxin or the GABA-B antagonist phaclofen elicited inhibition of apomorphine-induced PE. However, the inhibitory effects of GABA-A and GABA-B antagonists are lost on combination. Administration of GABA-A and GABA-B receptor stimulation inhibit PE induced by dopaminergic mechanism(s).     

Effects of kappa-opioid receptor agonists on locomotor activity and memory processes in mice

The effects of the kappa-opioid receptor agonists tifluadom, bremazocine and U-50,488 on locomotor activity (test: toggle-floor box) and memory (test: passive avoidance) were assessed in C57BL/6 (C57) and DB/2 (DBA) mice. The drugs administration resulted in activity depression in both strains, the effect was higher in DBA mice and was enhanced by pretreatment with haloperidol and with muscimol. Memory impairment was observed in DBA mice following posttraining administration of all drugs. This effect was enhanced by immobilization stress and decreased by familiarization with the apparatus. Memory improvement was evident in C57 mice (U-50,488 experiments). In a research carried out with CD1 mice, amygdaloid lesions decreased the memory impairing effect of U-50,488. The results are compared with those previously obtained with mu agonists and, as concerns memory, are discussed in terms of the involvement of emotional factors in mice responses to kappa agonists administration.     

Effect of various GABA-receptor agonists and antagonists on anaphylactic histamine release in the guinea-pig ileum

In this paper we confirm the previously reported inhibition by GABA of anaphylactic histamine release from isolated guinea-pig ileum longitudinal muscle. Moreover we report that: GABA-inhibition of anaphylactic histamine release is mimicked both by GABA-A and GABA-B agonists; both GABA-A and GABA-B antagonists are effective in reversing GABA's inhibitory effect; the effect is exerted specifically by GABA-ergic drugs: taurine and beta-alanine are ineffective; the GABA-ergic effect seems not to involve cholinergic and adrenergic transmission. It is concluded that it might be interesting to assess the clinical value of GABA-ergic drugs in allergic gut disorders.     

Post-training minaprine enhances memory storage in mice: involvement of D1 and D2 dopamine receptors

Post-training administration of minaprine (2.5, 5 and 10 mg/kg) dose-dependently improved retention of an inhibitory avoidance response in mice. Animals receiving nine daily injections of 5 mg/kg and administered a challenge dose post-training showed an improvement in memory consolidation similar to that produced by acute injection of 10 mg/kg. The effects on retention performance induced by the drug appear to be due to an effect on memory consolidation. They were observed when drugs were given at short, but not long, periods of time after training, i.e. when the memory trace was susceptible to modulation. Moreover, these effects are not to be ascribed to an aversive or a rewarding or non-specific action of the drugs on retention performance, as the latencies during the retention test of those mice that had not received a footshock during training were not affected by post-training drug administration. The effects of an acutely injected dose (10 mg/kg) of minaprine as well as those of a challenge dose (5 mg/kg) of the drug administered to repeatedly treated animals were reversed by pretreatment with either selective D₁ or D₂ dopamine receptor antagonists SCH 23390 and (-)-sulpiride administered at per se non-effective doses (0.025 and 6 mg/kg, respectively), thus suggesting that D₁ and D₂ receptor types are similarly involved in the effects of minaprine on memory consolidation. These results show that minaprine improves memory consolidation and that repeated drug administration leads to potentiation of this effect. Moreover, the effects of minaprine on memory consolidation are related to its dopaminergic action.     

Gamma-aminobutyric acid (GABA)-C receptor stimulation increases prolactin (PRL) secretion in cultured rat anterior pituitary cells

Gamma-aminobutyric acid (GABA) reportedly inhibits secretion of anterior pituitary hormones by directly acting on GABA-A and GABA-B receptors on anterior pituitary cells, but the roles of GABA-C receptors are little known. In this study, involvement of GABA-C receptors in the secretion of prolactin (PRL) was examined using cultured rat anterior pituitary cells. GABA-C receptor agonist, cis-4-aminocrotonic acid (CACA, 0.1-1 mM) increased PRL secretion dose-dependently, while GABA-A receptor agonist, 100 microM muscimol, but not GABA-B receptor agonist, 100 microM baclofen, decreased the secretion. GABA-C receptor antagonist, 15 microM (1,2,5,6-tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA), and GABA-A receptor antagonist, 100 microM bicuculline, not only reversed such an agonist-induced increase or decrease in PRL secretion, but also suppressed or enhanced spontaneous PRL secretion, raising a possibility of GABA-C or GABA-A receptor stimulation by intrinsic pituitary-derived GABA. GABA-C receptor subunits (rho1, rho2, rho3) and GABA synthesizing enzymes (GAD 65 and GAD 67) were shown to be expressed as assayed by RT-PCR, and GABA-C receptor stimulation by CACA obviously increased intracellular Ca2+ concentration in the anterior pituitary cells. Thus, PRL secretion from anterior pituitary cells appears to be enhanced via direct GABA-C receptor stimulation by GABA originating from the anterior pituitary cells besides well-known hypothalamic GABA.     

The role of GABA-ergic signal in the regulation of melatonin biosynthesis in vertebrate retina.

The in vivo effects of GABA-ergic drugs on the activity of serotonin N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), two enzymes involved in melatonin biosynthesis, were investigated in light-exposed chicken retina. The ip administration of muscimol and baclofen (direct agonists of GABA-A and GABA-B receptors, respectively), aminooxyacetic acid (an inhibitor of GABA transaminase), and nipecotic acid (an inhibitor of GABA reuptake), significantly increased the retinal NAT activity by 50-100%. Similar rises in NAT activity were observed following intraocular treatment of ether-anesthetized chickens with muscimol, baclofen and GABA. In contrast to NAT, there was no effect of the tested drugs on the retinal HIOMT activity. Aminophylline (a phosphodiesterase inhibitor) markedly elevated the retinal NAT activity, and a combined treatment with the GABA-ergic drugs and aminophylline resulted in additive effects. The actions of both muscimol and baclofen were antagonized by picrotoxin and bicuculline (two GABA-A receptor blockers), whereas the effect of baclofen was not changed by a selective GABA-B receptor blocker, CGP 35,348. Melatonin given ip significantly raised NAT activity, and its combination with muscimol further stimulated the enzyme. Picrotoxin and bicuculline given to chickens during the dark phase of 12 h light--12 h dark illumination cycle significantly suppressed the nocturnal NAT activity in retina. Neither GABA nor muscimol and baclofen significantly affected basal and forskolin (1 microM)-stimulated adenylate cyclase activity in vitro in light-exposed chicken retina. It is concluded that a GABA signal (acting through type A of GABA receptors) plays an important role in a complex mechanism regulating the rhythmic melatonin biosynthesis in vertebrate retina.     

Role of GABA during the multiple consolidation of memory

Alzheimer's disease (AD) is the most common form of senile dementia and it is a neurodegenerative disorder associated with a progressive deterioration of memory and cognitive capacity. Although one of the most characteristic abnormalities in AD patients is the reduced cholinergic input to the cortex, AD is a disorder that affects different neuronal populations in the brain, including the GABAergic neurons. The data regarding the participation of the central GABAergic system on memory indicate that: (1) drugs that facilitate GABA-A and GABA-B neurotransmission impair memory in experimental animals and in humans; (2) drugs that reduce GABA-A neurotransmission facilitate memory in rodents; (3) the facilitatory effect of thee drugs has not been corroborated at the clinical level, as they show a small therapeutic window, but new drugs are presently being evaluated in clinical studies; (4) the cognitive effects of the GABAergic agents are dose- and time-related, and cannot be explained by state-dependency; (5) the effects of the GABAergic antagonists are centrally mediated, as peripherally acting drugs are ineffective in memory tests; (6) GABA and endogenous benzodiazepines are released in different brain areas during learning of different tasks and after the induction of long-term potentiation (LTP); (7) GABA-A antagonists facilitate LTP while diazepam blocks LTP in hippocampal slices; and (8) the amygdala, the basal forebrain, the septo-hippocampal pathway, the trisynaptic circuit and the entorhinal cortex are likely candidate regions for the central actions of GABAergic drugs. The consolidation process of memory storage can be presently envisioned as multiple consolidation process that takes place in different brain circuits and at different times after the learning experience. The anatomical evidence on the presence of GABAergic neurons in brain areas relevant to memory (and affected in Alzheimer's patients) like the cortex, amygdala, septum, hippocampus and NBM, together with the electrophysiological and biochemical changes induced by the learning experience, suggest that the GABAergic neurons can critically modulate the electrical activity of these brain areas during the “multiple consolidation” process of memory storage. © 1993 Wiley-Liss, Inc. © 1993 Wiley-Liss, Inc.     

Effects of oxotremorine on inhibitory avoidance behaviour in two inbred strains of mice: interaction with 5-methoxy-NN-dimethyltriptamine

The effects of the cholinergic muscarinic agonist, oxotremorine (0.005, 0.01, 0.02 and 0.04 mg/kg), the serotonergic agonist, 5-methoxy-NN-dimethyltriptamine (5-MeODMT) (0.5, 1 and 2 mg/kg), and their combination, were investigated in C57BL/6 and DBA/2 mice using a one-trial inhibitory avoidance task, drug treatment being given immediately after the acquisition trial. Post-trial administration of oxotremorine facilitated, while post-trial administration of 5-MeODMT inhibited memory retention of both strains in a dose-dependent fashion. The DBA/2 strain was more affected by oxotremorine than the C57BL/6 mice; no strain-dependent sensitivity to serotonergic agonist administration was observed. In both strains, the combination of oxotremorine plus 5-MeODMT inhibited the performance improvement shown by the administration of the cholinergic agonist alone. The facilitatory role of cholinergic stimulation on retention performance was confirmed and an inhibitory action of the serotonergic system on memory processes was suggested. Moreover, the present results support a functional interaction between cholinergic and serotonergic systems on memory consolidation.     

Prejunctional GABA-B inhibition of cholinergic,neurally-mediated airway contractions in guinea-pigs

GABA is a known inhibitory neurotransmitter in the CNS. Recent studies have also demonstrated the presence of GABA in peripheral tissue, including lung. To delineate a role for GABA in lung, the effect of GABA and selective GABA agonists and antagonists on neuronally-induced airway contractions in guinea pigs were studied. In vitro, tracheal contractions induced by electrical field stimulation (EFS) were inhibited by tetrodotoxin and atropine indicating that the contractions were mediated by neuronal release of acetylcholine. The contractions caused by EFS, but not those by exogenous acetylcholine, were inhibited by GABA (EC₅₀ = 4.5 μM) and the selective GABA-B agonist baclofen (EC₅₀ = 9 μM), but not by the GABA-A agonist, muscimol. The inhibitory effect of baclofen was not affected by the GABA-A antagonist, bicuculline, but was significantly reversed with the GABA-B antagonists, 3-aminopropylphosphonic acid (3-APPA) (pA₂ = 4.5) and 2-hydroxysaclofen (pA₂ = 4.1).In vivo, vagal nerve stimulation (5 V, 20 Hz, 0.5 ms, 5 s) in anesthetized, mechanically ventilated guinea-pigs caused cholinergic-dependent bronchospasms that were inhibited by intravenous GABA (3 and 10 mg/kg) and baclofen (1–10 mg/kg), but not by muscimol. The inhibitory effects of GABA and baclofen against vagal bronchospasm were blocked by 3-APPA (5 mg/kg, iv), but not by bicuculline. Responses to the GABA-B agonists were unaltered after the treatment of animals with phentolamine or propranolol to block α-adrenergic and β-adrenergic receptors, respectively. Bronchospasm due to intravenous methacholine was also unchanged by GABA and baclofen. These results demonstrate that GABA inhibits cholinergic bronchoconstriction in guinea-pigs and does so by a mechanism involving inhibitory prejunctional GABA-B receptors.     

Effects of GABA agonists and GABA-A receptor modulators on cocaine discrimination in rhesus monkeys

RATIONALE: Dopaminergic systems thought to mediate the abuse-related effects of cocaine are under inhibitory control by GABAergic systems. These findings suggest that GABA agonists may attenuate some abuse-related effects of cocaine. OBJECTIVE: To assess the effects of GABA receptor agonists and GABA-A receptor modulators on cocaine discrimination in rhesus monkeys. METHODS: Rhesus monkeys were trained to discriminate 0.4 mg/kg cocaine from saline in a two-key, food-reinforced drug discrimination task. The effects of the GABA-A agonist muscimol, the GABA-B agonist baclofen, the barbiturate GABA-A receptor modulator pentobarbital, and the benzodiazepine GABA-A modulators triazolam and imidazenil were examined alone and as pretreatments to cocaine. For comparison, the effects of pentobarbital pretreatment on the cocaine-like discriminative stimulus effects of amphetamine were also examined. RESULTS: When administered alone, the GABA agonists and GABA-A receptor modulators produced primarily saline-appropriate responding. When administered as pretreatments to cocaine, pentobarbital attenuated the discriminative stimulus effects of cocaine in all monkeys tested, and the high efficacy benzodiazepine agonist triazolam attenuated cocaine's effects in three of five monkeys. Muscimol, baclofen and the low efficacy benzodiazepine agonist imidazenil did not alter cocaine's discriminative stimulus effects. Although pentobarbital blocked the effects of the monoamine reuptake blocker cocaine, it did not alter the cocaine-like effects of the monoamine releaser amphetamine. CONCLUSIONS: These results are consistent with the hypothesis that GABA-A receptor modulators attenuate the discriminative stimulus effects of cocaine in rhesus monkeys by decreasing the activity of dopaminergic systems. Direct GABA receptor agonists may be less effective in blocking the abuse-related effects of cocaine in rhesus monkeys.     

Further evidence for the GABAergic influence on memory. Interaction of GABAergic transmission with angiotensin II on memory processes

In experiments on male Wistar rats trained on active avoidance (shuttle-box) and passive avoidance (step-through) tasks, we found that (-) nipecotic acid, the inhibitor of GABA reuptake, and muscimol, a GABAA-receptor agonist, applied after training either improved or had no effect on retention, depending on the dose used. Angiotensin II (ATII) at a dose of 0.1 microgram/kg injected intracerebroventricularly (i.c.v.) after training facilitated retention. Combinations of ATII and (-) nipecotic acid or muscimol potentiated the memory effects of ATII and GABAergic drugs, respectively. Blockade of GABA receptors (GABAA) by bicuculline or picrotoxin abolished the effects of GABAergic agonists on ATII. It is suggested that GABAergic transmission participates in the consolidation and formation of memory traces and in the retention-facilitating mechanism of action of ATII.     

Effects of chlorpromazine and imipramine on discrimination learning,consolidation, and learned behavior in two inbred strains of mice

Chlorpromazine and imipramine were administered to DBA/2J and C57BL/6J mice swimming in a Y water maze toward a light source (L Procedure, corresponding to innate tendency) or towards the dark (D Procedure, sorresponding to the acquisition of a new pattern of behavior). In two sets of experiments the drugs were administered to naive mice before and after each training session, respectively.In both strains, in the pretrial experiments, the innate tendencies were improved by both drugs; the acquisition of a new pattern of behavior was improved following imipramine but impaired following chlorpromazine. In the posttrial experiments (D procedure) the consolidation processes of both strains were improved following imipramine and impaired following chlorpromazine.In a third set of experiments imipramine was administered to previously trained mice of both strains and chlorpromazine to previously trained C57 mice. In both procedures the administration of increasing doses of both drugs was followed by a progressive lengthtening of the swimming times in the previously trained C57 mice; performance disruptions were evident in both procedures in trained DBA mice following imipramine.     

Effects of intrahippocampal injection of GABAergic drugs on memory retention of passive avoidance learning in rats

The effect of post-training intrahippocampal injection of gamma-aminobutyric acid (GABA) receptor agonists and antagonists, immediately after a training session on memory retention of passive avoidance learning in rats, was measured in the presence and absence of physostigmine. Post-training treatments were carried out in all the experiments. The different doses of the GABAA receptor agonist muscimol (2, 4 and 6 microg/rat) decreased memory retention in rats dose-dependently. The higher response was obtained with 6 microg/rat of the drug. When the GABAA receptor antagonist bicuculline (0.5, 1, 2 and 4 microg/rat) was administered, only one dose of the drug (1 microg/rat) increased memory retention; however, the antagonist reduced the effect of muscimol. The GABAB receptor agonist, baclofen (0.25, 0.5, 1 and 2 microg/rat) also reduced memory retention in the animals. Intrahippocampal injection of lower doses of the GABAB receptor antagonist CGP35348 (P-[3-aminopropyl]-p-diethoxymethyl-phosphinic acid) (2.5, 5, 10 microg/rat) did not effect memory retention, although the higher doses of the drug (25 and 50 microg/rat) decreased memory retention. The doses of antagonist (2.5, 5 and 10 microg/rat), which did not elicit any response alone, reduced the effect of baclofen. The inhibitory response of CGP35348 was also decreased by bicuculline. In another series of experiments, physostigmine improved memory retention. The GABA receptor agonists, muscimol and baclofen, as well as the GABA receptor antagonists bicuculline and CGP35348, decreased the effect of physostigmine. Atropine decreased memory retention by itself and potentiated the response of muscimol and baclofen. It is concluded that GABAA and GABAB receptor activation may be involved in the impairment of memory retention.     

Strain-dependent effects of MK-801 on passive avoidance behaviour in mice: interactions with morphine and immobilization stress

Rationale: Post-training treatments (drugs, stress, ECS) influence retention performance of laboratory animals, sometimes in a strain-dependent way. In a previous study, an interaction between the effects of morphine and of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 on retention performance was observed, in random bred mice. Objective: In the present research, we have investigated the effects on retention of C57BL/6 (C57) and DBA/2 (DBA) mice exerted by a) morphine, b) MK-801 and c) naltrexone. Further, we have studied in both strains the effects exerted on retention by combinations of morphine and MK-801, and of MK-801 and immobilization stress. Finally, the naltrexone-reversibility of the interaction between immobilization stress and MK-801 was also assessed. Methods: All treatments were administered immediately after training in mice tested in a passive avoidance task. Drugs were injected IP. Results: The results of our experiments showed that morphine and the non-competitive NMDA receptor antagonist MK-801 exerted dose- and time-dependent facilitatory effects on retention performance in C57 mice, and dose- and time-dependent impairments in DBA mice. Further, dose- and time-dependent deleterious effects on retention performance, in the C57 strain, and dose- and time-dependent enhancing effects, in the DBA strain, were observed following post-training IP naltrexone administration. MK-801 enhanced, in both strains, the effects of morphine. Finally, immobilization stress enhanced in both strains the effects of MK-801 and these effects were naltrexone-reversible. Conclusions: In conclusion, the results of this study show that the genetic make-up of the mice played an important role in all the effects observed, and, in particular, in the interaction between the opioid and the glutamatergic systems. Further, the naltrexone reversibility of the interaction between MK-801 and immobilization stress suggests that opioid mechanisms were involved. Received: 1 November 1998 / Final version: 20 April 1999     

Inhibitory effect of GABAergic drugs in cocaine-induced genital reflexes in paradoxical sleep-deprived male rats

The aim of this study was to seek whether GABAergic drugs were involved in the action of cocaine on spontaneous genital reflexes (penile erection-PE, and ejaculation-EJ) of paradoxical sleep-deprived (PSD) male rats. After a 4-day period of PSD, each group was administered with GABAergic drugs 1 h prior to cocaine and placed in observation cages. The administration of gamma-aminobutyric acid (GABA)-A agonist (muscimol, 2 and 3 mg/kg sc) reduced the number of animals displaying PE, whereas all doses tested of muscimol and bicuculline significantly reduced the frequency of PE. Pretreatment with the lower doses of GABA-B antagonist, phaclofen (1 and 2 mg/kg sc), also significantly reduced the percentage of rats showing PE; however, after the higher dose injection, the proportion of animals with PE was similar to those seen after vehicle pretreatment. Both GABA-B agonist and antagonist significantly reduced the PE frequency for all doses used compared with the vehicle group. There were no significant differences between control and GABA-A drugs in EJ behavior, whereas phaclofen 2 mg/kg pretreatment increased the ejaculatory latency. These data show that GABAergic compounds inhibited PE in male PSD rats suggesting that this inhibition points to a differential role of GABA receptor subtypes.