Effects of estradiol on spatial learning, hippocampal cytochrome P450 19, and estrogen alpha and beta mRNA levels in ovariectomized female mice

The brain is an important target organ for peripherally synthesized estrogen but it also has its own steroid biosynthesis producing estrogen from testosterone catalyzed by the aromatase enzyme. This study examined the effects of estrogen treatment in two spatial memory tasks, one-arm-baited radial arm maze and a position discrimination task in the T-maze in ovariectomized female mice. Hippocampal cytochrome P450 19 (encoding aromatase), and estrogen receptor alpha and beta gene expressions were also measured using real time quantitative polymerase chain reaction analysis. Estrogen (17beta-estradiol) was administered either tonically via s.c. minipellets or phasically via daily i.p. injections. In ovariectomized mice, the tonic estrogen decreased the number of reference memory errors in radial arm maze. Tonic estrogen treatment also up-regulated the expression of cytochrome P450 19 and estrogen receptors. In contrast, estrogen injections decreased the expression of cytochrome P450 19 and estrogen receptor alpha genes. The number of reference memory errors correlated negatively with estrogen receptor alpha expression. These findings indicate that peripheral estrogen levels affect neuronal estrogen synthesis by regulating the cytochrome P450 19 gene expression and also influence estrogen receptor alpha expression. The results also suggest that tonic rather than cyclic estrogen treatment might be more beneficial for cognitive functions.     

Sabcomeline (SB-202026), a functionally selective M1 receptor partial agonist, reverses delay-induced deficits in the T-maze

 Sabcomeline, (SB-202026 [R-(Z)-α-(methoxyimino)-1-azabicyclo [2.2.2] octane-3-acetonitrile]), a functionally selective muscarinic M₁ receptor partial agonist, was tested in rats trained to perform a delayed, reinforced alternation task in a T maze, a test of short-term spatial memory. For comparison the cholinesterase inhibitor tacrine (THA-9-amino-1,2,3,4-tetrahydroaminoacridine) and the non-selective muscarinic receptor agonist RS86 (2-ethyl-8-methyl-2,8 diazospiro [4.5]-decane-1,3-dione hydrobromide) were also tested and all three compounds were also compared using a conditioned taste aversion (CTA) task. Sabcomeline (0.001–1.0 mg/kg IP) significantly reversed the T-maze choice accuracy deficit induced by a 20-s delay at 0.03 and 0.1 mg/kg. RS86 (0.1–3.0 mg/kg IP) reversed the deficit at 1.0 mg/kg and THA (0.1–3.0 mg/kg IP) had no effect at any dose. All three compounds induced conditioned taste aversion with minimum effective doses (MED) of 0.3, 1.0 and 3.0 mg/kg, respectively. The results show that sabcomeline reverses delay induced deficits in T-maze choice accuracy in a rewarded alternation task at doses approximately 10 times lower than those required to induce conditioned taste aversion. RS86 was equipotent in both tests. These data support the findings of clinical studies which have shown that SB-202026 provides significant symptomatic improvement in patients with probable Alzheimer’s disease at doses which do not induce cholinergic side effects. Received: 19 August 1997 / Final version: 14 January 1998     

Memory impairments following basal forebrain lesions

The functional contribution of the nucleus basalis magnocellularis (NBM) and medial septal area (MSA) to memory was evaluated in 4 behavioral tasks. The tasks were postoperative acquisition of a win-stay spatial discrimination in a T-maze, a win-shift spatial discrimination on a radial arm maze, active avoidance in a shuttle box, and passive avoidance in a shuttle box. Bilateral lesions were made by injecting ibotenic acid (IBO) into the NBM or MSA. Control rats received operations in which no neurotoxin was injected. When compared to controls, rats with lesions in either the NBM or MSA had significantly impaired choice accuracy in the T-maze and radial maze tasks, took significantly fewer trials to reach criterion in the acquisition, but not the retention of an active avoidance task, and significantly more trials to reach criterion in the passive avoidance task. The results show that equivalent behavioral changes are obtained from lesions in the NBM and MSA in tasks that vary in their type of motivation, reinforcement, response-reinforcement contingency, and response. These behavioral changes suggest that the NBM and MSA may both be involved in memory.     

Ketamine affects memory consolidation: differential effects in T-maze and passive avoidance paradigms in mice

The effects of ketamine, an N-methyl-D-aspartate (NMDA) antagonist, on memory in animals have been limited to the sub-anesthetic dose given prior to training in previous studies. We evaluated the effects of post-training anesthetic doses of ketamine to selectively manipulate memory consolidation, and the effect of pre-retention sub-anesthetic doses of ketamine on memory retrieval in passive avoidance and T-maze tasks in mice. Repeated post-training anesthetic doses of ketamine impaired the consolidation of memory in the T-maze but not in passive avoidance paradigms. This impairment was not permanent but diminished 1-2 days after ketamine withdrawal. Sub-anesthetic post-training doses of ketamine (5 mg/kg) had no effect on memory consolidation, and larger doses (10, 20 and 50 mg/kg) did not influence the retrieval of memory in the T-maze. The data suggest that repeated anesthetic doses of ketamine block NMDA receptors and affect memory consolidation. Moreover, NMDA mechanisms antagonized by ketamine appear to be selectively involved in spatial (T-maze) memory mechanisms but may not be necessary for non-spatial (passive avoidance) memory consolidation.     

The N-methyl-d-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats

NMDA receptor (NMDAR) activity has been strongly implicated in both in vitro and in vivo learning models and the decline in cognitive function associated with aging and is linked to a decrease in NMDAR functional expression. GLYX-13 is a tetrapeptide (Thr-Pro-Pro-Thr) which acts as a NMDAR receptor partial agonist at the glycine site. GLYX-13 was administered to young adult (3 months old) and aged (27-32 months old) Fischer 344 X Brown Norway F1 rats (FBNF1), and behavioral learning tested in trace eye blink conditioning (tEBC), a movable platform version of the Morris water maze (MWM), and alternating t-maze tasks. GLYX-13 (1 mg/kg, i.v.) enhanced learning in both young adult and aging animals for MWM and alternating t-maze, and increased tEBC in aging rats. We previously showed optimal enhancement of tEBC in young adult rats given GLYX-13 at the same dose. Of these learning tasks, the MWM showed the most robust age related deficit in learning. In the MWM, GLYX-13 enhancement of learning was greater in the old compared to the young adult animals. Examination of the induction of long-term potentiation (LTP) and depression (LTD) at Schaffer collateral-CA1 synapses in hippocampal slices showed that aged rats showed marked, selective impairment in the magnitude of LTP evoked by a sub-maximal tetanus, and that GLYX-13 significantly enhanced the magnitude of LTP in slices from both young adult and aged rats without affecting LTD. These data, combined with the observation that the GLYX-13 enhancement of learning was greater in old than in young adult animals, suggest that GLYX-13 may be a promising treatment for deficits in cognitive function associated with aging.     

Cycloheximide produces adult-like retention deficits of prior learning in infant mice

Utilizing a dosage of cycloheximide which was found to inhibit cerebral protein synthesis by almost 90% after injection, separate groups of 13-day-old mice received either cycloheximide or saline followed by 0 (control), 15, or 25 training trials in a discriminated shock-escape T-maze. Twenty-four hr later, each mouse was treated with cycloheximide or saline and tested for retention by an additional 25 trails in the T-maze. As reflected by correct choice-point turns, the results suggest that whereas salinetreated mice demonstrated reliable retention of prior learning, cycloheximide treated mice exhibited memory impairment; cycloheximide per se had no effect on performance during either original training or retest. A final experiment indicated that this memory impairment was not due to cycloheximide's general debilitating side effects at the time of retention testing. Taken together, these data suggest that protein synthesis inhibition during training impaired consolidation and/or retrieval processes involved in memory. The biochemical and behavioral effects following cycloheximide injection in 13-14-day-old mice in the present study parallel those reported with adult animals and lend indirect support to the hypothesis that the 24-hr memory capacity exhibited by these young mice reflects the early functioning of those processes involved in adult long-term memory.     

Anxiolytic effects of repeated treatment with an essential oil from Lippia alba and (R)-(-)-carvone in the elevated T-maze

Lippia alba (Mill.) N.E. Brown (Verbenaceae) is widely used in different regions of Central and South America as a tranquilizer. The plant''s anxiolytic properties, however, merit investigation. The present study evaluated the effects of repeated daily (14 days) intraperitoneal (ip) treatment with an essential oil (EO) from a chemotype of L. alba (LA, chemotype II, 12.5 and 25 mg/kg; N = 6-8) and (R)-(-)-carvone (25 mg/kg; N = 8-12), the main constituent of this chemotype, on male Wistar rats (weighing 250 g at the beginning of the experiments) submitted to the elevated T-maze (ETM). The ETM allows the measurement of two defensive responses: inhibitory avoidance and one-way escape. In terms of psychopathology, these responses have been related to generalized anxiety and panic disorder, respectively. Treatment with the EO impaired ETM avoidance latencies, without altering escape, in a way similar to the reference drug diazepam (P < 0.05) (avoidance 2: control = 84.6 ± 35.2; EO 12.5 mg/kg = 11.8 ± 3.8; EO 25 mg/kg = 14.6 ± 2.7; diazepam = 7 ± 2.1). (R)-(-)-carvone also significantly altered this same response (P < 0.05; avoidance 1: control = 91.9 ± 31.5; carvone = 11.6 ± 1.8; diazepam = 8.1 ± 3.3). These results were not due to motor changes since no significant effects were detected in an open field. These observations suggest that LA exerts anxiolytic-like effects on a specific subset of defensive behaviors that have been implicated in generalized anxiety disorder, and suggest that carvone is one of the constituents of LA responsible for its action as a tranquilizer.     

Mescaline action on “memory decay” and “problem solving” behavior in the rat

1. The modifications of behavior caused in the rat by a chronic oral administration of mescaline have been studied in three experimental situations.

2. In the staircase maze mescaline accelerated the spontaneous decay on the conditioned reflex (memory decay) during the period without daily training.Only the results observed at 30 mg/kg/day of mescaline were statistically significant.

3. In a T maze two lateral alleys closed by two swinging doors, 30 mg/kg/day of mescaline increased the time spent in opening the first door. When the two doors of the lateral alleys were closed with a latch, mescaline 30 mg/kg/day, caused an increase in the time spent by the rat in opening the doors.

4. Mescaline caused an increase in food consumption. The increase at 30 mg/kg/day is statistically significant.