Opioid peptidergic systems modulate the activity of beta-adrenergic mechanisms during memory consolidation processes

Post-training administration of the opioid receptor antagonist naloxone (0.1 mg/kg) facilitated 48-hr retention, in mice, of a one-trial step-through inhibitory avoidance response. The naloxone-induced memory facilitation was blocked in animals given the selective brain-noradrenergic neurotoxin DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) (50.0 mg/kg, ip) 7 days before training. Pretreatment with the norepinephrine-uptake inhibitor desmethylimipramine (10.0 mg/kg, ip, 30 min), but not with the serotonin-uptake inhibitor fluoxetine (5.0 mg/kg, ip, 30 min), prevented this antagonism. The simultaneous administration of the central beta-adrenoceptor blocker l-propranolol (2.0 mg/kg, ip), also blocked the effects of naloxone on memory. The effects of naloxone were not blocked by d-propranolol (2.0 mg/kg, ip), the peripheral beta-adrenoceptor blocker sotalol (2.0 mg/kg, ip), the alpha-adrenoceptor blocker phenoxybenzamine (10.0 mg/kg, ip), or the predominantly peripheral alpha-adrenoceptor blocker phentolamine (10.0 mg/kg, ip). These findings suggest that central beta-adrenergic mechanisms are involved in the effects of naloxone on memory. Naloxone (0.1 mg/kg, ip) potentiated the effects of the central beta-adrenoceptor agonist clenbuterol (0.001-1.00 mg/kg, ip), which, when administered alone, facilitates or impairs retention as a function of the dose injected. The simultaneous administration of beta-endorphin (0.1 micrograms/kg, ip) exerted effects opposite to those elicited by naloxone, that is, shifted the dose-response curve of clenbuterol to the right. Considered together, these findings are consistent with the view that the facilitatory action of naloxone on memory results from the release of central beta-adrenergic mechanisms from an inhibition induced by opioid peptides released during or immediately after training.     

Diazepam prevents post-training drug effects related to state dependency, but not post-training memory facilitation by epinephrine

Rats were trained and tested in a step-down inhibitory avoidance task (0.3-mA footshock). Training-test interval was 6 h. In Experiment 1, animals received, 1 h before training, an ip injection of vehicle or diazepam (2.0 mg/kg) and, 30 s after training and/or 30 min prior to testing, ip saline, epinephrine (6.25 micrograms/kg or 125.0 micrograms/kg), naloxone (0.5 mg/kg), or beta-endorphin (1 micrograms/kg). In the vehicle-pretreated animals, post-training epinephrine (6.25 micrograms/kg) and naloxone enhanced, and post-training beta-endorphin and epinephrine (125.0 micrograms/kg) reduced, retention test performance; and pretest beta-endorphin and epinephrine (125.0 micrograms/kg) reversed the latter effect and enhanced retention on their own. Diazepam lowered memory scores on its own and prevented all other drug effects with the exception of post-training facilitation by epinephrine (6.25 micrograms/kg). In previous papers it was shown that post-training facilitation by epinephrine is due to an influence on storage processes, whereas all the other drug effects described above result from the post-training establishment of state dependency to either beta-endorphin or epinephrine, and therefore to a process involving further acquisition and storage. The present findings suggest that diazepam selectively hindered the acquisition and/or storage processes involved in state dependency. This conclusion is strengthened by the findings from Experiment 2, which showed, using a classic 2 x 2 design, that diazepam itself did not induce state dependency but, rather, depressed acquisition and/or storage of the avoidance task.     

Effects of reserpine on retention of escape reversal in mice: absence of state-dependent learning.

A discriminated escape training paradigm was used to study the effects of reserpine on learning and memory in mice. Intraperitoneal injection of reserpine before reversal training had no effect on acquisition but did produced a time-and dose-dependent impairment of retention test performance 10 days later. These results suggested that reserpine may have interfered with some aspect of memory storage. Retention impairments observed when a 2.0 mg/kg reserpine injection was given 2 hr before reversal training were not attenuated by readministering the drug before testing, a finding that provides no support for a state-dependency interpretation. Furthermore, animals treated with reserpine exhibited inferior retention of previous training, regardless of the pharmacological state present during that learning. This was interpreted as a drug-induced impairment of memory retrieval. In addition, performance during the initial discriminated escape training session suggested that reserpine may also impair acquisition under some conditions. In the last experiment, it was found that when the catecholamine precursor L-dihydroxyphenylalamine (100 mg/kg) and the indole amine precursor D,L-5-hydroxytryptophan (125 mg/kg) were both given after reserpine treatment, subsequent retention performance was not significantly impaired. The results are discussed in terms of the possible roles of biogenic amines in arousal, learning, and memory.     

Involvement of central cholinergic mechanisms in the effects of oxytocin and an oxytocin receptor antagonist on retention performance in mice

Oxytocin (OT, 0.10 microg/kg, sc) impaired retention of a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. In contrast, the immediate post-training administration of the putative oxytocin receptor antagonist d(CH(2))(5)[Tyr(Me)(2), Thr(4), Thy-NH(9)(2)] OVT (AOT, 0.30 microg/kg, sc) significantly enhanced retention performance. Neither OT nor AOT affected response latencies in mice not given footshock on the training trial, and neither the impairing effects of OT nor the enhancing effects of AOT were seen when the training-treatment interval was 180 min, suggesting that both treatments influenced memory storage. The effects of OT (0.10 microg/kg, sc) on retention were prevented by AOT (0.03 microg/kg, sc) given immediately after training, but 10 min prior to OT treatment. The central acting anticholinesterase physostigmine (35, 70, or 150 microg/kg, i.p.), but not its quaternary analogue neostigmine (150 microg/kg, i.p.), reversed the impairment of retention performance induced by OT, whereas low subeffective doses of the centrally active muscarinic cholinergic antagonist atropine (0.5 mg/kg, i.p.) or the central acting nicotinic cholinergic antagonist mecamylamine (5 mg/kg, i.p.), but not methylatropine (0.5 mg/kg, i.p.) or hexamethonium (5 mg/kg, i.p.) prevented the enhancement of retention performance caused by AOT. We suggest that oxytocin negatively modulates the activity of central cholinergic mechanisms during the posttraining period that follows an aversively motivated learning experience, leading to an impairment of retention performance of the inhibitory avoidance response.     

Scopolamine effects on memory retention in mice: a model of dementia?

Scopolamine-treated normal young human subjects exhibit memory dysfunctions analogous to those observed in demented patients. The dysfunctions are reversible by physostigmine but not by d-amphetamine which suggests that the memory impairment is specifically related to reduced cholinergic transmission caused by scopolamine. Scopolamine-induced amnesia has been proposed as a model for dementia where reduced cholinergic function is the suspected cause. We report seven experiments in young adult mice which examine scopolamine's effects on memory retention and whether its amnestic effects are specifically blocked by cholinergic agonists or cholinomimetics. Young adult mice were trained to avoid footshock in a T maze and their retention tested 1 week after training. Pretraining subcutaneous injection of scopolamine improved retention scores of "undertrained" mice at a dose of 0.01 mg/kg but impaired at a dose of 0.1 mg/kg. Post-training injection showed no effect at 0.01 mg/kg, enhanced retention scores at 0.1 mg/kg, and impaired at 1.0 mg/kg. The impairment by 1.0 mg/kg was blocked by injection 45 min post-training of each of two cholinergic drugs but was also counteracted by six drugs which act upon five other neural systems (catecholamine, serotonin, glycine, GABA, and hormonal). When scopolamine was injected 40 min pretraining, and each of eight drugs was injected immediately after training, the amnestic effect of scopolamine was only partially counteracted. This suggests that scopolamine impaired acquisition, in addition to some impairment of memory processing. This was confirmed by a direct study of acquisition rates of the avoidance response; 0.1 mg/kg of scopolamine impaired acquisition. The overall results indicate that pretraining administration of scopolamine impairs learning and to some degree memory processing. Counteracting scopolamine-induced amnesia, by either pretraining or post-training drug administration, is not specific to the cholinergic system.     

Memory-modulatory effects of centrally acting noradrenergic drugs: possible involvement of brain cholinergic mechanisms.

Post-training administration of the centrally acting muscarinic agonist oxotremorine (50.0 microgram/kg, ip) facilitated 48-hr retention, in mice, of a one-trial step-through inhibitory avoidance response. Oxotremorine-induced memory facilitation was not prevented by the simultaneous post-training administration of the central beta-adrenoceptor antagonist propranolol (2.0 mg/kg, ip). In contrast, post-training administration of atropine (0.5 mg/kg, ip), but not methylatropine (0.5 mg/kg, ip), completely prevented the facilitatory effects of the central beta-adrenoceptor agonist clenbuterol (30.0 micrograms/kg, ip) on retention. Low subeffective doses of clenbuterol (3.0 micrograms/kg, ip) and oxotremorine (6.25 or 12.5 micrograms/kg, ip) potentiated their effects and facilitated retention when given simultaneously immediately post-training. These results suggest that clenbuterol may induce memory facilitation through an increase of the release of acetylcholine in the brain. Post-training administration of a high dose of clenbuterol (1.0 mg/kg, ip) significantly impaired retention. Clenbuterol (1.0 mg/kg, ip)-induced impairment of retention was completely prevented by simultaneous post-training administration of oxotremorine (6.25, 12.5, or 50.0 micrograms/kg, ip). The centrally acting anticholinesterase physostigmine (21.5 or 68.0 micrograms/kg, ip) partially prevented clenbuterol-induced impairment of memory. The peripherally acting anticholinesterase neostigmine (68.0 micrograms/kg, ip) modified neither retention nor the amnestic effects of clenbuterol. Considered together, these findings are consistent with the view that brain muscarinic cholinergic mechanisms are involved in both the facilitatory and impairing effect of post-training clenbuterol on the modulation of memory storage.     

The Impairment of Retention Induced by Insulin in Mice May Be Mediated by a Reduction in Central Cholinergic Activity

Immediate posttraining intraperitoneal injection of nonconvulsive doses of insulin (2-20 IU/kg) significantly impaired retention of male Swiss mice tested 24 h after training in a one-trial step-through inhibitory avoidance task. The dose-response curve showed a U-shaped form. However, of the doses tested, only 8 IU/kg was effective. Insulin did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of insulin on retention performance were not due to nonspecific proactive effects on response latencies. The impairing effects of insulin (8 IU/kg) on retention were time-dependent, which suggests that insulin impaired memory storage. The simultaneous administration of glucose (10-1000 mg/kg) antagonized, in a dose-related manner, the actions of insulin (8 IU/kg) on retention, suggesting that the hormone may have produced a hypoglycemic response leading to a decrease in CNS glucose availability with a subsequent memory impairment. Low subeffective doses of atropine (0.5 mg/kg) or mecamylamine (5 mg/kg), but not methylatropine (0.5 mg/kg) or hexamethonium (5 mg/kg), given immediately after training but 10 min before an ineffective dose of insulin (4 IU/kg), interacted with and impaired retention. The central anticholinesterase physostigmine (35 or 70 μg/kg), but not its quaternary analog neostigmine (35 or 70 μg/kg), prevented the memory impairment induced by insulin (8 IU/kg). Considered together, these findings are consistent with the view that a decrease in the CNS glucose availability impairs the synthesis and/or release of acetylcholine in brain regions critically involved in memory storage.     

Factors that influence test session performance measured 0, 3, or 6 h after inhibitory avoidance training

Rats were trained in a step-down inhibitory avoidance task using a 0.3-mA, 60-Hz footshock, and were tested at 0, 3, and 6 h from training. Retrieval scores (test session minus training session step-down latencies) were higher in control groups at 0 than at 3 or 6 h. Test session performance at 0 h was unaffected by the pretraining ip injection of ACTH1-24 (0.2 microgram/kg), epinephrine-HCl (5.0 micrograms/kg), human beta-endorphin (1.0 microgram/kg), or naloxone-HCl (0.4 mg/kg); or by a pretreatment with dexamethasone phosphate (2.0 mg/kg in divided doses 24 and 12 h before training); or by anterior or posterior hypothalamic deafferentation. Test session performance at 0 h was depressed by prior bilateral transection of the fornix, which suggests it depends on hippocampal function. The effect of the fornix lesion on test session performance at 0 h was not counteracted by ACTH, epinephrine, or beta-endorphin administration. When animals were tested 3 h after training, the post-training administration of ACTH and epinephrine caused an enhancement of test session performance; neither post-training beta-endorphin or naloxone, nor pretest ACTH, epinephrine, or beta-endorphin administration, had any effect in these animals. At 6 h from training, the post-training facilitatory action of ACTH and epinephrine was still present and the post-training depressant effect of beta-endorphin and the post-training facilitatory effect of naloxone became manifest, and so did the naloxone-reversible pretest facilitation induced by ACTH, epinephrine, or beta-endorphin. The influence of post-training naloxone or pretest beta-endorphin on retrieval scores at 6 h was not observed in the fornix-lesioned animals. In conclusion: Test session performance of this task at 0 h from training is regulated by different mechanisms than those which regulate test session performance at 3 or 6 h; in particular, it is less susceptible to modulation by the drugs used in the present study and it depends on the fornix; At least two major classes of modulatory factors influence retrieval scores at later times: consolidation-enhancing effects of ACTH and epinephrine, which become manifest at 3 h, and mechanisms related to beta-endorphin, which involve a form of state dependency and only become manifest at 6 h from training.     

Active and passive avoidance following the administration of systemic DSP4, xylamine, or p-chloroamphetamine

Groups of rats were administered either DSP4 (50 mg/kg, ip), xylamine (50 mg/kg, ip), or p-chloroamphetamine (2 X 10 mg/kg, ip), either 2 weeks or 1 week before the testing of two-way active avoidance. DSP4 and xylamine, the selective noradrenaline (NA) neurotoxins, caused a two-way avoidance impairment but p-chloroamphetamine, the selective 5-hydroxytryptamine (5-HT) neurotoxin, did not do so. Pretreatment with desipramine (20 mg/kg, ip) blocked the avoidance impairment caused by DSP4 and xylamine treatment. Neither DSP4 nor xylamine caused any alteration of passive avoidance retention. The biochemical analyses indicated severe NA, but not 5-HT, depletions in the DSP4 and xylamine conditions and drastic 5-HT, but not NA, depletions in the p-chloroamphetamine conditions. These results confirm and extend earlier findings concerning the role of NA in avoidance behavior.     

Effect of a novel experience prior to training or testing on retention of an inhibitory avoidance response in mice: involvement of an opioid system

These experiments examined the effects of a novel experience prior to training or retention testing on 24-h retention of an inhibitory avoidance response in mice. The experiments were based on previous evidence that novel training experiences release hypothalamic beta-endorphin. When given 1 h prior to training, the novel experience (clinging to the wire-mesh ceiling and exploring a small box) attenuated the memory-enhancing effects of post-training administration of naloxone as well as the enhancing effects of beta-endorphin administered prior to the retention test. The novel experience given prior to training did not block the enhancing effects of post-training administration of epinephrine. beta-Endorphin and the novel experience both enhanced retention performance when administered 1 h (as well as 3 but not 6 h) prior to the retention test. The enhancement found with both treatments was blocked by simultaneous administration of naloxone or by administration of propranolol a few minutes prior to the retention test. The findings of these experiments are consistent with the view that the effects of the novel experience are due to a release of endogenous beta-endorphin and provide additional evidence that the effects, on retention, of naloxone given post-training and beta-endorphin given prior to a retention test, are based on training-induced release of beta-endorphin.     

Retention and extinction of delay eyeblink conditioning are modulated by central cannabinoids

Rats administered the cannabinoid agonist WIN55,212-2 or the antagonist SR141716A exhibit marked deficits during acquisition of delay eyeblink conditioning, as noted by Steinmetz and Freeman in an earlier study. However, the effects of these drugs on retention and extinction of eyeblink conditioning have not been assessed. The present study examined the effects of WIN55,212-2 and SR141716A on retention and extinction of delay eyeblink conditioning in rats. Rats were given acquisition training for five daily sessions followed by one session of retention training with subcutaneous administration of 3 mg/kg of WIN55,212-2 or 5 mg/kg of SR141716A and an additional session with the vehicle. Two sessions of extinction training were then given with WIN55,212-2, SR141716A, or vehicle. Retention and extinction were impaired by WIN55,212-2, whereas SR141716A produced no deficits. The extinction deficit in rats given WIN55,212-2 was observed only during the first session, suggesting a specific impairment in short-term plasticity mechanisms. The current results and previous findings indicate that the cannabinoid system modulates cerebellar contributions to acquisition, retention, and extinction of eyeblink conditioning.     

Opposite effects of a single versus repeated doses of gabapentin on retention performance of an inhibitory avoidance response in mice

CF-1 male mice were trained in an inhibitory avoidance (IA) task. A single gabapentin (GBP) administration (50mg/kg, ip) immediately after training enhanced retention performance when mice were tested 8 days after training. On the contrary, when the same dose of the anticonvulsant drug was given twice a day for 7 days (repeated treatment), a significant impairment on retention performance 12h after the last injection of GBP was observed. When the retention test was delayed 7 days after the end of the repeated treatment, the retention performance was not significant different from the control group, whereas if the retention test was delayed 14 days, retention performance was higher than control group but similar to that observed when GBP was administered once immediately after training. The impairment on retention performance was correlated with a significant decrease in the high affinity choline uptake in the hippocampus at the end of the retention test. The pretest administration of the direct muscarinic cholinergic agonist oxotremorine (50 microg/kg, ip) reversed the impairment on retention performance. This reversion was prevented by the muscarinic cholinergic antagonist scopolamine (0.5 mg/kg, ip). Taken together, these results suggest that the impairment on retention performance of an IA task in mice induced by repeated administration of GBP affected memory retrieval but not memory consolidation and that this impairment may be attributable to a reduction on central cholinergic activity.     

Naloxone administration impairs autoshaped learning

Effects of naloxone on acquisition of autoshaped behavior were investigated. Rats deprived to 85% of free-feeding weights were trained to touch a retractable lever; delivery of a food pellet occurred on every trial following lever retraction. The lever was retracted immediately if a touch occurred within 15 s, or automatically after 15 s. Analyses were conducted on number and latencies of touches of the extended lever, nose-pokes (touches) directed at the retracted lever during intertrial intervals (a measure less constrained by ceiling effects than extended lever touches), and unconditioned exploratory rearing activity, measured as touches of a metal strip mounted above the grid floor of the apparatus. In an initial experiment, male Sprague-Dawley rats were given saline or naloxone (2.0 mg/kg, ip) 5 min before a training session of 12 trials. Two days later they were tested, in the absence of drug, in a session of 36 (three blocks of 12) trials. Naloxone depressed training levels of lever responding, in addition to slowing acquisition rate. No effect of naloxone was observed on rearing activity. Previous work showed that injection of saline 5 min before behavioral testing increases the rate of autoshaping compared to injections 30 min before (Messing & Sparber, 1984). Thus, effects of naloxone on acquisition of lever-directed behaviors may have been confounded by behavioral depressant effects and/or by an injection effect such a short time before testing. In a second experiment naloxone (0.5 or 2.0 mg/kg) was injected after five of seven training sessions (12 trials each) to male and female rats. A 6-s delay of reinforcement was inserted between lever retraction and food delivery, slowing acquisition rates and providing the opportunity to test the effects of naloxone throughout a multiple-session task. The low dose retarded acquisition of extended lever touching in both sexes; both doses retarded acquisition of interim lever touching in males. Thus, in some circumstances, post-training naloxone administration may impair learning. The results support the notion that low doses of naloxone may have agonist activity.     

Effect of beta-funaltrexamine on retention of passive-avoidance conditioning

Rats received administration of an opiate antagonist immediately following single-trial passive-avoidance training. Retention of passive-avoidance conditioning was assessed 1 week after training. Compared to noninjected and vehicle-injected control groups, post-training naloxone (2.0 mg/kg) administration significantly increased retention. A comparable facilitation of retention was also observed when animals received post-training administration of beta-funaltrexamine (40 mg/kg). These data provide additional support for mu opiate receptor activity in the regulation of memory processes.     

The impairment of retention induced by pentylenetetrazol in mice may be mediated by a release of opioid peptides in the brain

Pentylenetetrazol (PTZ, 45 mg/kg, ip) impaired retention of a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. The amnestic effect of PTZ was prevented by naltrexone (0.01 or 0.10 mg/kg, ip) administered after training, but prior to PTZ-treatment. On the contrary, neither naltrexone methyl bromide (0.01, 0.10, or 10.0 mg/kg, ip), a quaternarium analog of naltrexone, nor MR2266 (0.01 or 0.10 mg/kg, ip), a putative kappa opiate receptor antagonist, modified the behavioral effects of PTZ. On the other hand, the body seizures produced by PTZ were unaffected by any of the three opiate receptor antagonists that were given before the convulsant. Taken together, these results suggest that the effects of PTZ on retention are mediated, at least in part, by opioid peptides of central origin, and rules out a possible participation of opioid peptides derived from prodynorphin-precursor molecule. Administration of beta-endorphin (0.01 or 0.10 microgram/kg, ip) 10 min prior to testing attenuate the retrograde amnesia caused by PTZ. The effect of beta-endorphin was prevented by the simultaneous administration of naltrexone (0.10 mg/kg, ip) prior to testing. Naltrexone has no effect of its own upon retrieval. These results suggest that the impairment of retention induced by PTZ is probably due, at least in part, to a release of opioid peptides in the brain during the post-training period. PTZ given after training do not affect consolidation or memory storage, as mice thus treated may retrieve the learned information when they are submitted to an appropriate neurohumoral and/or hormonal state in the test session, that is, beta-endorphin injection. Therefore, the action of PTZ would be primarily at the level of the mechanism that make stored information available for late retrieval.     

Vasopressin modulates the activity of nicotinic cholinergic mechanisms during memory retrieval in mice

Lysine vasopressin (0.03 micrograms/kg, sc) enhanced retention test performance on a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 20 min before the retention test. Tests were done 48 h following training. A low dose of the vasopressin antagonist AAVP (0.01 microgram/kg, sc, 20 min prior to testing) did not significantly affect retention test performance, whereas a higher dose (0.03 microgram/kg, sc) impaired it. Neither lysine vasopressin nor AAVP when given prior to testing modified latencies to step-through of mice that had not received a footshock during training. The simultaneous administration of AAVP (0.01 microgram/kg, sc) prevented the enhancement of retention test performance induced by lysine vasopressin. The influence of lysine vasopressin on retention test performance was antagonized by the simultaneous administration of mecamylamine (5 mg/kg, sc) but not by hexamethonium (5 mg/kg, sc), atropine (0.5 mg/kg, sc), or methylatropine (0.5 mg/kg, sc). A modulatory role of vasopressin on the activity of central cholinergic nicotinic mechanisms which probably operate at the time of testing is suggested.     

Methylphenidate, amygdalectomy, and active avoidance performance in the rat

Amygdalectomized and control rats were given 400 active avoidance training trials in a shuttle box. Control animals received 0, 4, 8, or 16 mg/kg of methylphenidate throughout acquisition. Amygdalectomized animals were given the first 200 trials without drug, followed by 200 trials with drug. The administration of methylphenidate produced an abrupt and large improvement in performance in the amygdalectomized animals. One month after acquisition under the drug, retraining without drug revealed a significant retention effect for the three amygdaloid-drug groups relative to the nondrug-amygdaloid group. These results indicate that although amygdalectomy impairs the performance of avoidance responses, it does not prevent the learning or retention of such responses. Since methylphenidate appears to act primarily on dopaminergic mechanisms, the possible influence of amygdalectomy on such mechanisms is discussed.     

Retention enhancement with post-training picrotoxin: lack of state dependency

Immediate post-training intraperitoneal administration of the GABA-antagonist picrotoxin (0.5 or 1.0 mg/kg) significantly enhanced retention of CD1 mice tested 24 h after training in an inhibitory avoidance task. Administration of picrotoxin prior to the retention test did not affect the retention performance of mice given post-training injections of either saline or picrotoxin. These findings indicate that the memory-enhancing effects of post-training administration of picrotoxin are not state-dependent.     

Memory-Enhancing Treatments Do Not Reverse the Impairment of Inhibitory Avoidance Retention Induced by NMDA Receptor Blockade

The aim of the present research was to verify whether the impairment of retention induced by the N-methyl-d-aspartate (NMDA) receptor blocker (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cycloheptene-5,10 imine (MK-801) can be reversed by memory-enhancing treatments. Adult female Wistar rats were trained and tested in a step-down inhibitory avoidance task (0.3-mA foot shock, 24-h training-test interval). Animals were given an ip injection of saline (SAL) or MK-801 (0.0625 mg/kg) 30 minutes before training, and an ip injection of SAL, epinephrine (EPI) (25 microg/kg), the opioid receptor antagonist naloxone (NAL) (0.4 mg/kg), the glucocorticoid receptor agonist dexamethasone (DEX) (0.3 mg/kg), or glucose (GLU) (320 mg/kg) immediately after training. There was an impairment of inhibitory avoidance retention in the MK-801-SAL, MK-801-EPI, MK-801-NAL, MK-801-DEX, and MK-801-GLU groups. There was an enhancement of retention in the SAL-EPI, SAL-NAL, SAL-DEX, and SAL-GLU groups. A control experiment showed that the amnestic effects of MK-801 could not be attributed to decreased reactivity to the foot shock. The results suggest that memory-enhancing treatments directed at modulatory mechanisms do not reverse the memory impairment induced by NMDA receptor blockade.     

Serotonin neurons and aversive conditioning in the rat

The acute and long-term effects of p -chloroamphetamine (PCA) on one-way and two-way active avoidance (AA), passive avoidance (PA) learning, fear retention (FR) and on central monoamine concentrations were examined in the male rat. Acute PCA administration (0.63–5 mg/kg i.p.), which releases presynaptic 5-HT, produced a dose-related impairment of both one-and two-way AA acquisition, AA retention, PA and fear retention. The selective serotonin (5-HT) uptake inhibitor zimelidine, but not the noradrenaline (NA) uptake inhibitor desipramine, blocked the avoidance deficit induced by acute PCA. Degeneration of brain 5-HT neurons by a high neurotoxic dose of PCA (2 × 10 mg/kg i.p.) failed to change AA and PA learning but blocked the avoidance deficit induced by acute PCA. Degeneration of locus coeruleus NA neurones with DSP4 (1 × 50 mg/kg), a selective NA neurotoxin, failed to block the acute PCA action. Thus, the acute avoidance learning impairment appears to be specifically related to the acute release of endogenous 5-HT. Both acute and long-term PCA treatment affected 5-HT neurones preferentially in the forebrain while marginal effects were observed in the midbrain and spinal cord. A marked impairment in the retention and retrieval of fear conditioning in the rat was also observed following acute PCA administration. The serotoninergic mechanisms underlying the retrieval deficit were found to be similar but not identical to those involved in AA acquisition. These results suggest an important role for central 5-HT neurones in aversive learning processes. The possible involvement of 5-HT neurones in learning, memorial and/or retrieval processes is discussed.