Residual effects of prolonged cannabis treatment on shuttle-box avoidance in the rat

Chronic oral administration of cannabis extract to rats was examined for its residual effects on shuttle-box avoidance learning. In experiment 1 avoidance learning was assessed in rats that had been tested previosly on other behavioral tests. Chronic treatment (3 months) facilitated the learning of shuttle-box avoidance in cannabis-treated animals relative to vehicle controls. In experiment 2 very similar results were obtained in naive rats. These and other residual effects of chronic cannabis treatment are similar to the effects of hippocampal lesions.     

Time-dependent changes in the effects of cholinesterase inhibitors on shuttle-box avoidance

Physostigmine and neostigmine were compared for their effects on shuttle-box avoidance acquisition and retention. Physostigmine impaired acquisition at doses lower than neostigmine. Avoidance performance 1, 7, or 14 days after acquisition was impaired by the administration of 0.4 mg/kg physostigmine or an equimolar dose of neostigmine. The effects of lower doses of physostigmine, but not of neostigmine, were dependent upon the time of original training relative to drug administration and retesting. The results suggest that the peripheral effects of higher doses of cholinesterase inhibitors impair avoidance performance. The effects of lower doses of physostigmine on acquisition and the time-dependent effects on subsequent performance are probably due to the central actions of this drug.     

Postnatal orotate treatment: Effects on learning and memory in adult rats

During the postnatal period, male Wistar rats were treated with orotate, either from the 6th to 15th, 16th to 25th, or 26th to 35th day of life. Learning and memory were tested in adulthood. Rats that received orotate from the 6th to 15th day showed a better retention of a learned brightness discrimination (Y-maze) than controls. An active avoidance (pole jumping) was learned more quickly by the rats orotatetreated from the 6th to 15th day than by controls. The spontaneous locomotor activity of previously orotatetreated rats was the same as in controls. Body weight measurements revealed no differences between orotate rats and control rats. The results suggest that memory retention in adulthood can be improved by postnatal orotate treatment.     

Effects of orotic acid and pirazetam on cortical bioelectrical activity in rabbits

In order to obtain further evidence of the pharmacological effects of retention-facilitating substances, the influence of sodium-orotate, methylglucamine orotate, and pirazetam on the bioelectrical activity of central nervous system structures were studied. Sodium orotate showed no influence on the cortical and hippocampal spontaneous EEGs of conscious nonimmobilized rabbits. The amplitude of the first surface-positive wave of the cortical evoked potential that was elicited by stimulation of tooth pulp was, however, significantly increased in long-lasting terms by both pirazetam and the two salts of orotic acid. Similarly, the three substances also influenced the changes in excitability induced by PTP of tooth pulp. The findings suggest that these chemicals facilitate in nonspecific manner responses to externally applied stimuli through central structures. The relationships between the altered stimulus response and the retention-facilitating action of these substances are discussed.     

Facilitation of avoidance acquisition in rats produced by P-chlorophenylalanine or P-chloroamphetamine.

The effects of reducing brain serotonin using p-chlorophenylalanine (PCPA) were examined as a follow up to our previous report that reducing serotonin with p-chloroamphetamine (PCA) facilitated Y-maze avoidance acquisition and reduced open field activity. In the current work, PCPA was also found to facilitate Y-maze avoidance acquisition, while open field activity, although reduced, was not reduced significantly. In a second experiment, we re-examined PCA, except that the apparatus was changed in order to test the generality of the effect of PCA on avoidance performance in a task other than the Y-maze. Testing was also run at varying shock intensities to determine if this was a significant determinant of the effect. PCA reliably facilitated shuttle-box avoidance acquisition and did so at all shock intensities tested. Finally, in a third experiment, the time course of the onset of the PCA-induced avoidance facilitation was examined and found to develop 8--10 hours following drug treatment and not at a shorter drug to test interval of 4 hours. The present data, in conjunction with our previous data support the concept that lowered brain serotonin content facilitates avoidance acquisition regardless of the specific method used to reduce serotonin or to assess avoidance acquisition.     

Self-administration of central stimulants by rats: A comparison of the effects of d-amphetamine,methylphenidate and McNeil 4612

Rats were trained to press a lever for the intravenous administration of d-amphetamine. The rate of responding was decreased in a dose-dependent and time-related manner by non-contingent injections of d-amphetamine, methylphenidate or McNeil 4612. Methylphenidate and McNeil 4612 also maintained self-administration behavior when they were substituted for d-amphetamine, whereas substitution of saline for d-amphetamine resulted in extinction of the self-administration behavior. These data suggest that methylphenidate and McNeil 4612, like d-amphetamine, can act as reinforcers in rats.     

Effect of L-fucose on brain protein metabolism and retention of a learned behavior in rats

The intraperitoneal or intraventricular application of L-fucose (100 mg/kg or 75 μg, respectively) prior to training in shuttle box avoidance as well as in shock-motivated brightness discrimination in rats significantly improved the retention of learned behavior 24 hr later. The application of D-fucose was without influence on retention. In naive animals, intraventricularly applied L-fucose (75–200 μg) caused an increase in the rate of protein synthesis in the hippocampus, resulting in a significant increase in total proteins of this brain structure, mainly attributed to the Tris-insoluble protein fractions. The r results are discussed in terms of an activation of glycoprotein formation by increasing supply with L-fucose.     

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.     

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.     

The effects of age and illumination on the dose-response curves for three stimulants

The dose-response relationships for three stimulants have been explored. These drugs have been shown to differ in potency and, with successive doubling of doses, have been found to have dose-response curves of differing slopes. In addition, the relationship between dose and activity level was not the same for younger and older rats. The relationship between dosage of both d-amphetamine and methylphenidate and locomotor activity was not the same in the light and the dark. The latter finding suggests a difference between these two stimulants and the third stimulant studied, caffeine, whose effects where unaltered by ambient illumination level.This work was supported by research grant (MH 22140) from the National Institute of Mental Health.     

A comparison of methylphenidate induced active avoidance and water maze performance facilitation.

Methylphenidate was shown to facilitate both active avoidance and water performance compared to controls. Repetitive errors on both tasks were greater in the drug than the nondrug group and were positively correlated to water maze performance. These results fail to support the view that water maze acquisition is less influenced by performance variables than active avoidance. An unanticipated enhancement of water maze performance was also noted in the control group which had been previously tested on active avoidance compared with naive controls. Moreover, this group made fewer repetitive errors than naive controls, suggesting that previous shock exposure reduced inappropriate responses.     

Hyperalgesia, low-anxiety, and impairment of avoidance learning in neonatal caffeine-treated rats

Rationale The nonselective adenosine receptor antagonist caffeine is used clinically to treat apnea in preterm infants. The brain developmental stage of preterm infants is usually at a period of rapid brain growth, referred as brain growth spurt, which occurs during early postnatal life in rats and is highly sensitive to central nervous system (CNS) acting drugs. Objectives The aim of this work was to study whether caffeine treatment during brain growth spurt produces long-term effects on the adenosine receptor-regulated behaviors including nociception, anxiety, learning, and memory. Methods Neonatal male and female Sprague–Dawley rats were administered either deionized water or caffeine (15–20 mg kg⁻¹ day⁻¹) through gavage (0.05 ml/10 g) over postnatal days (PN) 2–6. The hot-plate test, elevated plus-maze, dark-light transition test, and step-through inhibitory avoidance learning task were examined in juvenile rats. Furthermore, the responses to adenosine A₁ receptor agonist N(6)-cyclopentyladenosine (CPA)-induced hypothermia and A_2A receptor agonist CGS21680-induced locomotor depression were also compared. Results Caffeine-treated rats showed hyperalgesia in hot-plate test, less anxiety than controls in the elevated plus-maze and dark–light transition, and impairment in step-through avoidance learning test. Moreover, the responses to CPA-induced hypothermia and CGS21680-induced locomotor depression were enhanced in caffeine-treated rats. Conclusion These results indicate that caffeine exposure during brain growth spurt alters the adenosine receptor-regulated behaviors and the responsiveness to adenosine agonists, suggesting the risk of adenosine receptor-related behavioral dysfunction may exist in preterm newborns treated for apnea with caffeine.     

Effect of NC-1900, an active fragment analog of arginine vasopressin, and inhibitors of arachidonic acid metabolism on performance of a passive avoidance task in mice

In this study, we investigated the effect of administration of inhibitors of each of the arachidonic acid metabolism pathways and the effect of co-administration of these inhibitors with NC-1900, a fragment analog of arginine vasopressin, on step-through passive avoidance task performance. All drugs were administered just after the acquisition trial in the passive avoidance task. Intracerebroventricular (i.c.v.) administration of nordihydroguaiaretic acid (NDGA, 1 and 10 microg), a phospholipase A2 (PLA2) and lipoxygenase (LOX) inhibitor, and of arachidonyl trifluoromethyl ketone (ATK, 1 and 10 microg), a specific PLA2 inhibitor caused reductions in latency on the retention trial. The i.c.v. administration of either of baicalein (0.1-10 microg), a 12-LOX inhibitor, or AA-861 (0.1-10 microg), a 5-LOX inhibitor, did not influence the latency. Intraperitoneal administration of indomethacin (20 mg/kg), a non-specific COX inhibitor, or NS-398 (10 mg/kg), a specific COX-2 inhibitor, impaired performance on the retention trial in the task, while piroxicam (20 mg/kg), a specific COX-1 inhibitor, did not. Subcutaneous administration of NC-1900 (0.1 ng/kg) ameliorated the reduction of latency caused by NDGA, ATK, indomethacin, or NS-398. These results suggested that the COX-2 pathway of arachidonic acid metabolism may be important for learning and/or memory in the passive avoidance task in mice, and that the ameliorating effect of NC-1900, in part, is due to mimicking of the effects of metabolites of the COX-2 pathway.     

Enhancement by secoverine and physostigmine of retention of passive avoidance response in mice

A one-trial passive avoidance test in the mouse, in which drugs were injected intraperitoneally immediately after the shocked acquisition trial, was used. The effects of enhancing central cholinergic transmission on retention of passive avoidance was investigated using secoverine, which blocks muscarinic autoreceptor-mediated inhibition of acetylcholine release, and using physostigmine, an acetylcholinesterase inhibitor. Secoverine (1.0–5.0 mg/kg) and physostigmine (0.1–0.4 mg/kg) were found to improve retention of the avoidance response measured 24 h after acquisition. These effects were augmented when the two drugs were given in combination. In contrast, atropine (5.0 mg/kg) tended to impair retention of passive avoidance and blocked the facilitatory effects of physostigmine. The results support the hypothesis of a novel approach to treatment of memory disorders based on blockade of muscarinic autoreceptors, to augment central cholinergic activity.     

Cholinergic drugs reverse AF64A-induced impairment of passive avoidance learning in rats

The cholinergic neurotoxin AF64A was administered to rats in order to produce learning impairment to test the effect of cholinergic drugs. Seven days after receiving an intracerebroventricular injection of AF64A (2.5–7.5 nmol), rats were subjected to one-trial passive avoidance acquisition and tested 24 h later. Learning was significantly impaired at 3.75 nmol AF64A, a dose at which significant reduction in acetylcholine level and choline acetyltransferase and acetylcholinesterase activity in the hippocampus was observed but changes in monoamine levels in the hippocampus, general behavior, or sensory sensitivity were not observed. Arecoline (4 mg/kg, IP) and physostigmine (0.1 mg/kg, IP) significantly decreased the learning impairment produced by AF64A (3.75 nmol) when given before the acquisition of passive avoidance learning but not when given after the acquisition or before the 24 h retention test. These drugs and oxotremorine (0.1 mg/kg, IP) given immediately after the acquisition, however, improved passive avoidance retention when the interval between the acquisition and the test was shortened to 1 h. These results indicate that the impairment of learning in AF64A-treated rats is caused by a memory retention deficit and suggest that such impairment can be effectively ameliorated by cholinergic drugs.     

Reversal of propoxur-induced impairment of step-down passive avoidance, transfer latency and oxidative stress by piracetam and ascorbic acid in rats

Propoxur, a carbamate pesticide has been shown to adversely affect memory and induce oxidative stress. The present study was designed to correlate the effect of propoxur, piracetam (a nootropic drug) and ascorbic acid (an antioxidant) on oxidative stress and cognitive function. Cognitive function was assessed using step-down latency (SDL) on a passive avoidance apparatus and transfer latency (TL) on elevated plus maze. Oxidative stress was assessed by examining brain malondialdehyde (MDA) and non-protein thiol (NP-SH) levels. A significant reduction in SDL and prolongation of TL was found for the propoxur-treated group at weeks 6 and 7 as compared with control (p < 0.001). One week treatment by piracetam (400 mg/kg/d, i.p.) or ascorbic acid (120 mg/kg/d, i.p.) antagonized the effect of propoxur on SDL as well as TL. Both piracetam and ascorbic acid attenuated the propoxur-induced increase in brain MDA levels and decrease in brain NP-SH levels. Results of the present study show that ascorbic acid and piracetam have the potential to reverse cognitive dysfunction and oxidative stress induced by propoxur in the brain.     

Effect of naloxone and amphetamine on acquisition and memory consolidation of active avoidance responses in rats

Pretraining IP injection of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) enhanced performance during acquisition, but did not improve retention of active avoidance responses in rats. Naloxone (0.1 or 3 mg/kg) had no effect on acquisition or on retention. The combination of naloxone (0.3 mg/kg) plus amphetamine (2 mg/kg) did not produce the facilitation observed when each of the two drugs was administered alone. Pretreatment with the higher dose of naloxone (3 mg/kg) blocked the facilitative effect of amphetamine on acquisition. Post-training administration of naloxone (0.3 mg/kg) or amphetamine (2 mg/kg) improved retention. Naloxone (0.1 or 3 mg/kg) had no effect. When naloxone and amphetamine were combined, at respective doses of 0.3 mg/kg and 2 mg/kg, the improvement did not occur, i.e., the higher dose of naloxone prevented the facilitative effect of amphetamine. In addition, an ineffective dose of amphetamine (0.5 mg/kg), given either pre-or post-training together with the lower dose of naloxone (0.1 mg/kg), produced a significant enhancement of acquisition or consolidation, respectively. The results are consistent with the possibility that naloxone might exert its facilitative action on acquisition and memory consolidation through the release of catecholaminergic systems from inhibitory influences of opioids.     

Model insomnia by methylphenidate and caffeine and use in the evaluation of temazepam

Experimental sleep disturbances (model insomnia) were produced by the administration of methylphenidate (MPD) 10 mg and caffeine (CAF) 150 mg. The effect of temazepam (TEM), 15 mg or 30 mg, on the model was investigated. All-night polysomnography was performed on 8 normal young male subjects under each of the following 9 conditions: baseline, MPD 10 mg, CAF 150 mg, TEM 15 mg, TEM 30 mg, MPD + TEM 15 mg, MPD + TEM 30 mg, CAF + TEM 15 mg, CAF + TEM 30 mg. A reduction in total sleep time and total amount of stage REM (S-REM) sleep and an increase in the sleep latency and wake time (S-W) were observed in both the MPD and CAF nights. The sleep latency was significantly longer in the CAF night than in the MPD night. Administration of TEM 15 mg or TEM 30 mg alone caused very few modifications in the sleep parameters. These drugs in combination with MPD or CAF resulted in almost complete recovery of the sleep disturbance induced by MPD or CAF. The results indicate that CAF and MPD produced similar models of insomnia except for a greater sleep latency for CAF than for MPD. Both models were useful in the evaluation of hypnotic drugs such as temazepam.     

The mechanism of action of α2 adrenoceptor blockers as revealed by effects on open field locomotion and escape reactions in the shuttle-box

The precise mechanism of action of α₂ adrenoceptor blockers is not known, although in principle they have two main effects: (i) they stimulate the norepinephrinergic system by inhibiting the negative feed back of norepinephrine release (presynaptic effect) and (ii) they inhibit the effects of norepinephrine on postsynaptic α₂ adrenoceptors. We postulate that if the presynaptic actions of the antagonists prevail, the enhanced norepinephrine release leads to an activation of postsynaptic α₁ or β adrenoceptors. In this case the effects of α₂ adrenoceptor blockers can be reversed by antagonists acting on the latter two adrenoceptors, since postsynaptic α₂ adrenoceptors are also blocked. If the postsynaptic blockade of α₂ adrenoceptors is the main cause of effects, than the blockade of α₁ or β adrenoceptors should not reverse the action of α₂ blockers. The α₂ blocker idazoxan (dose 0.5–5 mg/kg) increased locomotor activity in an open field, an effect that was abolished by both α₁ and β receptor blockers (prazosin and propranolol, respectively). Escape responses in a shuttle box were strongly suppressed by idazoxan (0.5–2 mg/kg). However, this effect was not changed by concomitant α₁ or β receptor blockade. These results suggest that the mechanism of action of α₂ adrenoceptor blockers depends on which effects are studied. Exploration seems to be affected by a presynaptic mechanism as neurons bearing postsynaptic α₁ or β adrenoceptors are involved in the control of this behavior, while escape reactions appear to be affected by the postsynaptic blockade of α₂ adrenoceptors (i.e. neurons bearing postsynaptic α₂ adrenoceptors are involved in its control). Thus, there is no generalized mechanism of action for α₂ adrenoceptor blockers; their precise mode of action should be investigated in each particular case. Received: 15 November 1996 /Final version: 5 June 1997     

Antagonism of L-glycine to seizures induced by L-kynurenine,quinolinic acid and strychnine in mice

L-glycine (1–12.5 μg, intracerebroventricularly, i.c.v.) completely prevented seizures induced by i.c.v. administration of L-kynurenine, and practically did not modify those induced by another convulsant quinolinic acid, a metabolite of tryptophan, and by strychnine. L-Glycine administered intraperitoneally (i.p.) (1000 mg/kg) decreased lethality after K-kynurenine and quinolinic acid; at doses of 3000 and 4000 mg/kg which are sedative and hypothermic it prolonged the latency of strychnine and L-kynurenine seizures. The convulsant action of pentylenetetrazol was not modified. Kynurenine seizures are suggested to be related to the action of kynurenine on glycine receptors in the central nervous system.