Cocaine enhances memory storage in mice

Mice were trained on a one-trial inhibitory avoidance task and given immediate post-training intraperitoneal injections of cocaine (0.03–1.00 mg/kg). On a retention test 24 h later, the retention latencies of mice given the 0.10 mg/kg dose were significantly higher than those of the controls. The effect of cocaine on retention was time-dependent: retention latencies were not altered in animals given cocaine 60 min after training. Administration of cocaine (0.1 mg/kg) prior to the retention test did not modify the retention performance of mice that received either saline or cocaine (0.1 mg/kg) immediately post-training. The findings suggest that cocaine affects retention by influencing post-training processes involved in memory storage.     

The effect of the CS-UCS interval and extinction on place conditioning and analgesic tolerance with morphine

In experiment 1, a CS-UCS interval study of place conditioning and analgesic tolerance with morphine was conducted. Morphine (10 mg/kg i.p.) was administered to separate groups of rats either 2 h prior to, 1 h prior to, immediately prior to, immediately after or 2 h after 30-min confinement in one end compartment of a place conditioning apparatus. A total of three choice tests was given, one after every six morphine injections. A preference for the end compartment contingent upon morphine injection was shown in groups that received morphine prior to end compartment placement. Groups that received morphine after end compartment placement were not different in their preference behavior from groups that received only saline during place conditioning training. A hot-plate test for tolerance to the analgesic effect of morphine was given at the end of all choice testing. All groups that had received morphine during place conditioning training were equally tolerant. These results indicate a dissociation between the analgesic effect of morphine and the effect that produces place preference, since the former was not affected by temporal parameters that did affect the latter. In the second experiment, the effect of extinction on a morphine-induced place preference was studied using extinction procedures that, in contrast to previous studies, equated exposure to both end compartments. Whereas the morphine-induced place preference was undiminished by a 10-day retention period in which animals received saline injections in the home cage, extinction trials during the same period eliminated the place preference. These results provide evidence that morphine-induced place preferences involve associative processes.     

Effects of chlorpromazine on acquisition and extinction of a conditioned response in mice

Summary Mice acquired a tone-shock association under conditions of saline injections, or an injection of 1.5 mgm./kgm. or 4.5 mgm./kgm. of chlorpromazine. Five days later the Ss were tested for retention of the response by being given extinction trials. Each of the three groups were divided and received either a saline injection or an injection of 1.5 mgm./ kgm. chlorpromazine just prior to extinction testing.A significant linear dose response function was obtained between amount of chlorpromazine injected during acquisition and performance under extinction, with the saline group requiring the greatest number of trials to extinguish. The presence or absence of chlorpromazine during extinction did not affect performance, nor was there any interaction between drug levels during acquisition and drug levels during extinction.This study was supported in part by a research grant, M-1604, from the National Institute of Mental Health to the University of Maryland.Summer College student     

Amnesia induced by short-term treatment with ethanol: attenuation by pretest oxotremorine

CD-1 mice were administered a series of tones paired with footshock in the closed arm of a Y maze. On a test session 8 days later the animals were tested for retention of the conditioned emotional response (CER). On the 2-min test session, the three arms of the maze were open and the number of entries into the arms was counted. Retention of the CER was measured by the decrease in the number of entries in comparison with animals trained with no footshock. Starting 24 hr after training, and continuing for the 7 days between training and testing, the animals in different groups received a daily IP injection of saline, 3.6 g/kg of ethanol, 150 micrograms/kg of the cholinergic muscarinic agonist oxotremorine, or ethanol plus oxotremorine. Retention was evaluated 24 hr after the last injection. Ethanol reduced retention of the conditioned emotional response. This effect was attenuated by oxotremorine (150 micrograms/kg) given IP 6 min prior to testing, but not by the same dose of oxotremorine given daily together with the ethanol treatment. Oxotremorine injections administered prior to the retention test also enhanced the retention performance of the control group. Daily oxotremorine administration had no effect. These findings suggest that ethanol weakened retention of the conditioned emotional response, that this effect was unrelated to acquisition or consolidation, and that the deleterious effect of the ethanol treatment can be attenuated by oxotremorine administered prior to the retention test.     

Persistence of retrieval enhancement by amphetamine following scopolamine-induced amnesia

Little information is available on the permanence of pharmacologically-induced retrieval enhancement following amnesia. This was studied by comparing the rate of forgetting of a memory reactivated by d-amphetamine after amnesia with spontaneous forgetting of undisturbed fear conditioning. Mice were treated with either saline or scopolamine before conditioning and retention was tested three days later. Scopolamine-treated mice received either saline or amphetamine before testing while the saline controls received a second saline injection. The scopolamine-saline group exhibited robust amnesia, whereas both saline-saline and scopolamine-amphetamine groups showed good retention. To test the persistence of these effects mice in the three groups were subdivided and given a second retention test either 1 day, 1 week or 1 month after the first test. Amphetamine was not administered before the second test. The scopolamine-saline mice continued to exhibit amnesia for up to 1 month while the scopolamine-amphetamine and saline-saline groups continued to show strong memory with only a modest decrement in performance by 1 month after the first test. These results show that amphetamine results in a permanent recovery from scopolamine amnesia.     

Effects of sildenafil on long-term retention of an inhibitory avoidance response in mice

Sildenafil (1, 3, 10, and 30mg/kg, intraperitoneally (i.p.)), a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitor, facilitated retention performance of a one-trial step-through inhibitor avoidance task, when administered to male Swiss mice immediately after training, as indicated by performance on a retention test 48 h later. The dose-response curve was an inverted U in this dose range, although only the dose of 3 mg/kg of sildenafil produced significant effects. Sildenafil did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of sildenafil on retention were not due to non-specific proactive effects on retention performance. The effects of sildenafil (3 mg/kg, i.p.) were time-dependent, and the administration of sildenafil (3 mg/kg, i.p.) 30 min prior to the retention test did not affect retention in mice given post-training injections of vehicle or sildenafil (3 mg/kg, i.p.). However, the administration of sildenafil (3mg/kg, i.p.) 30 min before training also enhanced retention performace. Further, when mice were trained and received immediate post-training sildenafil (3 mg/kg) and were tested for retention either 1 week or 1 month later, at each retention interval the performance was comparable to that found with a 48-h retention interval. Finally, an enhancement of retention was also observed in female Swiss mice that received sildenafil (3 mg/kg, i.p.) immediately, but not 180min, after training. These findings could indicate that the actions of sildenafil on retention are not sex-dependent. The results suggest that sildenafil influences retention by modulating time-dependent mechanisms involved in memory storage and that the effects are long lasting. A possible participation of the nitric oxide (NO)-guanylyl cyclase-cGMP system also is suggested.     

Time-related memory effects of vasopressin analogues in rats

The present study was designed to investigate critical time periods for the memory modulating effect of vasopressin and several analogues in rats using a passive avoidance test as the behavioral paradigm. AVP, AVP-(4-8) and AVP-(5-8) were more effective when given immediately after the learning trial (consolidation), while AVP-(1-8) (DGAVP) and AVP-(5-9) were more active when administered one hour prior to the retention test (retrieval). DDAVP and AVP-(4-9) were highly active both when given immediately after the learning trial or 1 hour before the retention test. The period between 12 and 18 hr after the learning trial appeared to be another sensitive period. Administration, in particular of DGAVP, and AVP-(5-9) at 12, 15, and 18 hr after the learning trial induced marked retention of the avoidance response at the 24 hr retention test. Injection at 6 and 21 hr after the learning trial was the least effective in facilitating passive avoidance latencies. The more stable analogue DDAVP facilitated avoidance latencies irrespective of the time of administration. Vasopressin and related peptides exert a long term effect on avoidance behavior. However, DGAVP and AVP-(5-9) facilitated passive avoidance behavior at the 24, 48, and 72 hr retention test if administered immediately after the learning trial. If injection was postponed till 15 hr after the learning trial, passive avoidance behavior was facilitated at the 24 hr retention test only.(ABSTRACT TRUNCATED AT 250 WORDS)     

d-Amphetamine: disruptive effects on the long-term store of memory and proactive facilitatory effects on learning in inbred mice.

Male, C57BL/6J mice were given two daily trials on an appetitively-motivated successive brightness discrimination maze problem; they then received daily intraperitoneal injections of saline or d-amphetamine for 5 days. When trained again in the maze, mice in all d-amphetamine groups tended to display impaired retention: retention was significantly impaired in the 2.0 mg/kg group. Naive mice were treated exactly as were the pretrained mice except that they received no initial maze training prior to drug treatments. Mice in all naive d-amphetamine groups tended to display enhanced acquisition of the maze problem: acquisition was significantly enhanced in the 1.0 mg/kg groups. These results could not be explained as effects of d-amphetamine on attentional, motivational or other performance factors.     

Tolerance to ethanol's effects on operant performance in rats: role of number and pattern of intoxicated practice opportunities

Acquisition and retention of tolerance to ethanol's rate-decreasing effects on operant performance were examined in rats which received a 52-day regimen of ethanol or saline injections prior to and/or after each daily session. Eight groups of rats differed on: (a) number of days with intoxicated practice (pre-session ethanol); (b) intermittent (spaced) or daily (massed) intoxicated practice; and (c) post-session ethanol or saline on nonintoxicated practice days. Massed practice groups were given their presession saline days prior to their pre-session ethanol days. Ethanol dose-effect tests were given prior to, during, and after the chronic injection regimen. Under both spaced and massed practice conditions, the magnitude of tolerance developed increased directly with the number of pre-session ethanol days, even when absolute ethanol exposure was constant. No group showed complete tolerance loss. The post-session ethanol supplements (a) facilitated tolerance development in spaced practice groups and tolerance loss in massed practice groups, (b) blocked ethanol's low dose rate-increasing effects, and (c) produced an acute withdrawal-like performance disruption the next day. The results suggest that both intoxicated practice and practice during acute ethanol withdrawal influence the acquisition and retention of compensatory behaviors during ethanol tolerance development.     

Scopolamine in rats impairs acquisition but not retention in a 14-unit T-maze

To follow up a previous report noting that scopolamine impaired acquisition performance of young rats in a shock-motivated 14-unit T-maze, the present study assessed the effects of muscarinic antagonism on retention aspects of the same task. The broader objective was to further the investigation of possible defects in cholinergic neurotransmission that might underlie the age-related impairements previously observed in this task. Young (3-month) male F-344 rats were given preliminary training to criterion in one-way active avoidance in a straight runaway. Then on the first day of complex maze training, each rat received 5 acquisition (AQ) trials followed by a second 10-trial retention (RET) session conducted the following day. Subjects were assigned to one of eight groups receiving an intraperitoneal injection of either scopolamine hydrochloride (1.0 mg/kg) or saline as follows: (a) 30 min prior to training on the first day (PRE-AQ); (b) 30 min prior to training on both the first and second day (PRE-AQ-RET); (c) immediately after completing the trial on the first day (POST-AQ); (d) 30 min prior to testing on the second day (PRE-RET). Dependent measures included errors, alternation errors, run time, number of shocks, and total shock received. On the first day of maze training, all performance measures except for alternation errors were significantly higher for the two acquisition groups (PRE-AQ and PRE-AQ-RET) compared to all other groups which did not differ significantly. While on the second day the PRE-AQ group recovered on all measures to levels comparable to other groups, the PRE-AQ-RET group remained impaired throughout training on all performance measures and appeared to maintain an alternation strategy for maze acquisition. Retention aspects of this task appeared unaffected as none of the other groups differed significantly in performance. Thus, further evidence of a scopolamine-induced cognitive impairment in acquisition of this task was noted but was manifested only when given throughout training. These results suggest that the dose of scopolamine used impaired encoding processes while leaving storage and retrieval mechanisms intact.     

Post-learning ethanol effects on a water-finding task in rats

Ethanol's post-training facilitation of memory was examined using a latent learning paradigm known as the "water-finding task." Rats were assigned to one of two ethanol groups (E0.75 g/kg or E1.5 g/kg) or to a control group (saline) and individually placed in a novel open field containing a drinking tube. Following this exposure, subjects were immediately administered intraperitoneal (IP) injections of either the saline or ethanol and 48 hours later, re-introduced to the field. Initial latencies to contact the tube each time were recorded. A linear regression analysis of trial 2 latencies regressed onto trial 1 latencies indicated a statistically significant effect of ethanol on the relation between initial and subsequent latencies. Though the control rats' trial 2 latencies were completely random with respect to their previous speeds (rSAL = -0.07), the ethanol rats' trial 2 latencies were positively correlated with initial speeds (rE0.75 = 0.35, rE1.5 = 0.67). These results suggest that under conditions of post-training ethanol, trial 2 behavior is more similar to, or controlled by, trial 1 behavior and are consistent with the argument that, under certain training and testing contexts, ethanol can come to exert control over a response's recurrence.     

Testing cyclic AMP mediation of memory: Reversal of α-methyl-p-tyrosine-induced amnesia

Treatments that increased intracellular cyclic 3, 5 adenosine monophosphate (cAMP) levels following catecholamine depletion caused by -methyl-p-tyrosine (AMPT) provided a prophylactic effect against AMPT-induced amnesia. This effect gives evidence that cAMP mediated the formation of memory. In Experiment I, the phosphodiesterase inhibitor papaverine (50 mg/kg), immediately after a one-trial acquisition task, functionally increased cAMP levels and prevented amnesia 3 h after treatment with AMPT (200 mg/kg) for New Zealand A strain (NZ/A) mice tested in a step-through passive avoidance apparatus. Retention test latencies 72 h later were significantly higher for animals that received only saline and for animals that received AMPT and papaverine than for animals that received AMPT and saline (the amnesic group). In a similar task (Experiment II), mice that received an intracerebroventricular injection of either 5 or 10 g dibutyryl cAMP immediately after acquisition and 3 h after AMPT administration showed significantly higher retention test latencies than animals that received AMPT and saline. The AMP plus 10 g dibutyryl cAMP group showed facilitated performance even compared to the saline plus saline group.     

Working memory deficits induced by single but not repeated exposures to domoic acid.

Single injections of domoic acid, given either intraperitoneally to mice or directly into the hippocampal formation of rats, have been shown to impair learning on the place version of the Morris water maze task and the eight arm radial maze task. The present study was designed to test whether both single and repeated exposures of intraperitoneally administered domoic acid (1.0 or 2.0 mg/kg) impair spatial working memory in mice on a delayed matching-to-sample task. DBA strain mice were given a series of four injections over a 7-day period consisting of either saline or one of two doses of domoic acid. During the 18 days of testing, each subject was given one trial per day consisting of one information run, followed by three test runs. On non-alternation days (days in which the correct response was the same as the preceding day) the saline injected group significantly outperformed the single injection 2.0 mg/kg domoic acid group. This indicates that domoic acid-treated animals were incapable of forming a memory that persisted for 24 h and hence were less able to utilize the prior day's experience. However, the repeated exposure groups did not perform as poorly on non-alternation days than the single exposure groups, indicating that domoic acid may affect multiple mechanisms involved in memory consolidation.     

Effect of lysine vasopressin on pentylenetetrazol-induced retrograde amnesia in rats

Lysine vasopressin (1 microgram/rat SC) administered 1 hr prior to either the acquisition trial or 24 hr retention trial facilitated passive avoidance retention. Amnesia was produced when a single 50 mg/kg (IP) injection of pentylenetetrazol was given immediately following the passive avoidance acquisition trial. A single injection of lysine vasopressin (1 microgram/rat SC) administered 1 hr prior to either the acquisition trial or 24 hr retention trial antagonized the amnesia.     

Alleviation of anisomycin-induced amnesia by pre-test treatment with lysine-vasopressin

Amnesia in mice for a passive avoidance response induced by anisomycin injection immediately after training was reversed by 40 micrograms of lysine-vasopressin given one hour before testing. Control groups receiving non-contingent shock instead of training were used to demonstrate that the effects of vasopressin were due to memory of shock received in a particular place, rather than non-specific suppression of locomotion. The effects of vasopressin on retention were not mimicked by either pentylenetetrazol or epinephrine suggesting that the enhanced latencies were probably not the result of increases in fear or arousal. These data support the hypothesis that the retrieval of memory can be facilitated by vasopressin. The possibility of a relationship between the effects of vasopressin and those of catecholamine manipulations on memory is discussed.     

Effects of scopolamine on acquisition of passive avoidance

Summary Scopolamine was tested for effects on acquisition of a passive-avoidance problem. First mice were given four trials 24 hours apart on a step-off apparatus. Various dose levels of the drug were studied. For one group the drug was injected i.p. 20 minutes prior to each trial, in the other immediately after. Doses of 5.0 mg/kg and higher greatly interfered with the acquisition of the response, but only when injected prior to the trial. These results failed to indicate any direct effect of the drug on the learning process. The only time the drug affected the behavior was when the animal was under its influence at the time of testing.A second experiment was conducted in which mice were trained as before but pre-injection of 5.0 mg/kg of scopolamine was used. However, the mice were injected with the drug on only some of the trials. In all, six groups were studied, and their performance compared with a group that had received scopolamine on all trials and with one that received saline on all trials. When the data were examined for evidence of dissociation, it was clear that it was not present. Further analysis showed that animals which had learned, as indicated by their performance on the early trials conducted when they were not drugged, failed to show evidence of memory when given additional trials after being drugged. This outcome clearly indicated that a major effect of scopolamine was on the performance of the animal. Also, animals which had received 1 or 2 trials while drugged and given additional trials in the nondrugged state, showed a rapid increase in latency on succeeding trials equal that of animals which had not been drugged at all.These results, in light of other research, indicate that the effect of scopolamine on this type of learning task does not appear to be through a modification of the consolidation process.A preliminary report of Experiment I was made at the Southeastern Psychological Association Annual Meeting in Atlanta, Georgia, April, 1967. Supported by NIMH Grant No. MH 12770-01 to the senior author.     

Dissociation of the anti-punishment activities of chlordiazepoxide and atropine using two heterogeneous passive avoidance tasks

The effects of chlordiazepoxide and atropine on the acquisition of passive avoidance learning in rats were compared in two superficially similar but theoretically distinct forms of the step down task in an attempt to dissociate behaviourally the disinhibiting effects of these two classes of drug. In a discrete trial procedure both chlordiazepoxide and atropine significantly retarded acquistion; on retention testing under saline treatment alone, the initial chlordiazepoxide group showed no change in behaviour while the initial atropine group showed a facilitation. In a continuous trial procedure, however, atropine but not chlordiazepoxide produced an increase in the total number of step downs; despite this, these groups showed acquisition at similar rates, though learning was not shown on retention testing under saline alone. These results enabled the two classes of drug to be distinguished. The nature of the heterogeneity between the two test paradigms is discussed, and results interpreted in terms of possible differential drug effects on punishment and escape components of the tasks.     

Pharmacology of sucrose-reinforced place-preference conditioning: effects of naltrexone

Two experiments investigated the role of the opioid system in sucrose-reinforced conditioned place preferences (CPPs) in rats. Experiment 1 examined the effects of a general opioid antagonist, naltrexone, on the expression of a CPP acquired in the absence of the drug. Subjects were trained to associate one compartment of a two-compartment chamber with sucrose and the other compartment with water. Rats displayed a preference for the sucrose-associated compartment in a choice test without sugar or water available following vehicle saline treatment. Naltrexone doses of 2.5 and 5.0 mg/kg reduced this preference for the sucrose-associated compartment. Experiment 2 examined the effects of naltrexone on the acquisition as well as the expression of CPPS. Different groups of rats received daily injections of either saline, 0.1, 1.0, or 5.0 mg/kg of naltrexone prior to each training session, and then these groups were given a choice test for the CPP after saline or naltrexone injections. Although naltrexone treatment attenuated the expression of CPPs in each group relative to saline treatment, there were no group differences during these tests in the magnitude of the preferences. Moreover, all groups displayed equal acquisition of CPPs despite the fact that naltrexone dose dependently decreased sucrose intake during the training phase. Together, the results indicate that the opioid system modulates the expression but not the acquisition of sucrose-reinforced CPPs.     

Contingent tolerance to the disruptive effects of alcohol on the copulatory behavior of male rats.

Sexually active male rats received five 30-min copulation tests with sexually receptive females, one every 4 days. One group of rats received alcohol (1 g/kg, IP) 45 min before, and an equivalent volume of saline 45 min after, each test; a second group received saline before and alcohol after each test; and a third, control group received saline both before and after. Four days after the last of the five tolerance-development trials, each rat received an injection of alcohol (1 g/kg, IP) 45 min before a copulation test so that the development of tolerance in the three groups could be compared. Tolerance to the disruptive effects of alcohol on mount, intromission, and ejaculation latencies, and on the duration of the postejaculatory interval was found to be significantly greater in the rats injected with alcohol before each copulation test than it was in the rats in the other two groups. These results constitute the first experimental evidence that tolerance develops to the disruptive effects of alcohol on male sexual behavior, and they support the theory that tolerance is an adaptive response to the disruptive effects of drugs on concurrent patterns of neural activity, rather than to drug exposure per se.     

Memory retention: effect of prolonged cholinergic stimulation in mice

The fundamental hypothesis that drugs may affect memory processing by prolonging transmitter action was tested by extending the time of drug action, using repeated administrations of the cholinergic agonist, arecoline hydrobromide (ARE). The ARE was injected intracerebroventricularly into mice immediately after training (T-maze footshock avoidance) and at 90-min intervals thereafter, for a total of 1, 2, or 3 injections. The results indicate that 1 injection had no effect whereas 3 successive injections significantly improved memory retention test performance. The results confirm the hypothesis being tested; six control groups ruled out other plausible interpretations of the results.