Pairs of male rats were placed in a test box for 10 min and the time they spent in active social ... more Pairs of male rats were placed in a test box for 10 min and the time they spent in active social interaction was scored. Maximum active interaction was found when the rats were tested under low light in a box with which they were familiar. When the light level was increased or when the box was unfamiliar active social interaction decreased. 2 Exploration (time spent sniffing objects) decreased in the same way in relation to test conditions as did social interaction. As these decreased, defecation, and freezing increased. 3 Anosmic controls showed that the decrease in social interaction across test conditions could not be attributed to olfactory changes in the partner. 4 Chlordiazepoxide (5 mg/kg) given chronically prevented or significantly reduced the decrease in social interaction that occurred in undrugged rats as the light level or the unfamiliarity of the test box was increased. Controls showed that this effect could not be entirely attributed to chlordiazepoxide acting selectively to increase low levels of responding. 5 The effect of chronic chlordiazepoxide contrasts with its action when given acutely; in the latter case it has only sedative effects. 6 Whether this test can be used as an animal model of anxiety is discussed and this test is compared with existing tests of anxiety.
Two colonies of 12 male hooded rats were established for several months. Intruder rats were intro... more Two colonies of 12 male hooded rats were established for several months. Intruder rats were introduced into the colony, and agonistic encounters were observed for 18 min. Acute administration of chlordiazepoxide (5 mglkg) and lorazepam (.25 mglkg) to intruder rats had little effect on aggressive behavior. After 5 days of benzodiazepine administration to the intruders, there were fewer fights and less time was spent fighting. The residents directed fewer bites and aggressive behaviors toward the intruders. The intruders submitted less and initiated more interaction (both sniffing and agonistic behaviors) with the residents.
Benzodiazepines are the most widely prescribed psychotropic drugs and while the specific neural p... more Benzodiazepines are the most widely prescribed psychotropic drugs and while the specific neural pathways mediating their several therapeutic effects remain largely unknown, at least their initial site of action has been identified. For the last decade we have known that the central nervous system contains high affinity, stereospecific binding-sites for the benzodiazepines. These sites are found on a supramolecular complex with y-aminobutyric acid (GABA) receptors and with a chloride ionophore (channel across the cell membrane), which also has binding-sites for drugs such as the barbiturates . Recently there has been a growing appreciation that benzodiazepines induce dependence and that tolerance can occur to their behavioural effects. Although initially these phenomena were linked with long-term use, more recent evidence suggests that similar changes can be observed after short-term or even a single administration. This review covers both the clinical evidence and relevant experimental studies and attempts to explore the possible underlying mechanism(s). Although the precise mechanism is still unknown, we conclude that both rebound and withdrawal symptoms are reflections of a common dependence mechanism and also that tolerance is simply another manifestation of this same mechanism. We further conclude that the same underlying mechanism mediates the rebound phenomena and tolerance seen after short-term or acute benzodiazepine administration. 19 539 PSM n .
The ability of chronic treatment with imipramine (an antidepressant with anti-panic activity) to ... more The ability of chronic treatment with imipramine (an antidepressant with anti-panic activity) to antag onise the anxiogenic effects of 3 different compounds was investigated in the elevated plus-maze. The compounds chosen are likely to produce anxiety by activity at different sites in the central nervous system: yohimbine, by blocking the cu-adrenoceptor; FG 7142, by action at the p-carboline site on the GABA-benzodiazepine receptor complex and pentylenetetrazole, by acting at the picrotoxinin site on this complex. Administration of imipramine following 21 days pre-treatment did not produce a significant consistent anxiolytic effect alone and was unable to reverse the anxiety produced by any of the 3 anxiogenic compounds. Our results are discussed in terms of the nature of the anxiety produced by the anxiogenic drugs and the sensitivity of tests of anxiety to anti-panic agents.
This review discusses the effects of antidepressant drugs on behaviors that are changed during th... more This review discusses the effects of antidepressant drugs on behaviors that are changed during the clinical treatment of depression. We first consider whether there is a similar subjective state produced by antidepressant drugs that might be akin to the mood changes caused clinically by these drugs. We thus review the evidence that antidepressant drugs can produce a distinctive enough subjective state to serve as a discriminative stimulus, and then discuss the nature of the cue produced. Secondly, we discuss whether there is any evidence that antidepressants enhance the rewarding aspects of stimuli since this aspect of behavior is reported to change during the successful treatment of depression. In this section we review the effects on electrical brain stimulation, water and food intake, exploratory and social behaviors. Finally, because of the proposed role of stress in the aetiology of depression, we review the effects of antidepressants on the responses to acute and chronic stress.
The purpose of the present study was to determine the role of the 5-HT 1A receptors in the latera... more The purpose of the present study was to determine the role of the 5-HT 1A receptors in the lateral septum in the mediation of the anxiogenic effects of nicotine in the social interaction and elevated plus maze tests of anxiety in the rat. Bilateral infusion of (±)nicotine (4 and 8 mg) and of the 5-HT 1A receptor agonist 8-OH-DPAT (200 and 500 ng) into the lateral septum decreased the time spent in social interaction, indicating anxiogenic effects. The anxiogenic effect of 8-OH-DPAT (500 ng) was completely reversed by coadministration of a behaviourally inactive dose of the 5-HT 1A receptor antagonist, WAY 100635 (200 ng). The anxiogenic effect of the lower dose of (±)-nicotine (4 mg) was completely reversed by WAY 100635 (200 ng), but the reversal was only partial following administration of 8 mg nicotine. In a second test of anxiety, the elevated plus maze, lateral septal administration of 8-OH-DPAT (500 ng) and nicotine (4 mg) induced anxiogenic effects. In this test, the anxiogenic effect of nicotine (4 mg) was completely reversed by coadministration of WAY 100635 (200 ng). The effects of 8-OH-DPAT demonstrate that stimulation of 5-HT 1A receptors in the lateral septum has anxiogenic effects in two animal tests and that the anxiogenic effects of nicotine are mediated at least in part by these 5-HT 1A receptors.
The protective effects of acute and chronic diazepam administration (4 mg/kg) against seizures in... more The protective effects of acute and chronic diazepam administration (4 mg/kg) against seizures induced by pentylenetetrazole (PTZ) and picrotoxin were investigated. Considering the incidence of tonic-clonic convulsions, tolerance to the protective effects of diazepam was evident by day 5 if the mice were challenged with PTZ (120 mg/kg), by day 10 if the challenge was picrotoxin (8 mg/kg) and by day 20 if the challenge was PTZ (105 mg/kg). Diazepam retained its protective effects against tonic-clonic convulsions induced by PTZ (90 and 60 mg/kg) for 45 days, but the incidence of myoclonic jerks revealed tolerance after 5 days.
Pharmacology, Biochemistry and Behavior, May 1, 1996
FILE, S. E. Recent developments in anxiefy, stress, and depression. PHARMACOL BIOCHEM BEHAV 54(l)... more FILE, S. E. Recent developments in anxiefy, stress, and depression. PHARMACOL BIOCHEM BEHAV 54(l) 3-12, 1996. -Recent research in the development, analysis, and pharmacology of animal tests of state anxiety is discussed, including the use of responses to predator odours, the role of learning in modifying the anxiety measured in the plus-maze, and the roles
Changes in hormones of the hypothalamic-pituitary-adrenal (HPA) axis in patients suffering from a... more Changes in hormones of the hypothalamic-pituitary-adrenal (HPA) axis in patients suffering from anxiety and depressive disorders are reviewed, and the changes that occur when animals are exposed to test situations used preclinically to model anxiety or depression. The effects of exogenous administration of HPA hormones both clinically and in animal tests is discussed and the effects of clinically used anxiolytics and antidepressants on hormones of the HPA axis. The final section discusses stress-induced changes in the CNS.
SummaryTianeptine is a clinically effective anti-depressant with the unusual profile of increasin... more SummaryTianeptine is a clinically effective anti-depressant with the unusual profile of increasing 5-HT uptake, thereby decreasing the synaptic availability of 5-HT. In the social interaction test of anxiety in the rat, withdrawal from chronic diazepam treatment produced a significant anxiogenic response that was reversed by acute administration of tianeptine (2.5–10 mg/kg). These doses were without significant effect in the vehicle-treated rats. Exposure of rats to cat odour resulted in anxiogenic responses in the plus-maze and social interaction tests and in decreased exploration. These changes were not reversed by 5 days treatment with tianeptine (2.5–10 mg/kg). Thus, tianeptine may not he effective in all anxiety states, but could be particularly useful in treating patients withdrawn from benzodiazepines.
The effects of d-amphetamine (4 mglkg), scopolamine (1 mdkg), methylscopolamine (1 mdkg), and par... more The effects of d-amphetamine (4 mglkg), scopolamine (1 mdkg), methylscopolamine (1 mdkg), and parachlorophenylalanine (400 mg/kg) on exploration were studied in male rats at 16, 21, and 28 days of age. Amphetamine elicited stereotypy at all ages tested, reduced exploration (measured by the time spent head-dipping during a 10-min trial in a holeboard) from Day 21, but did not significantly increase rearing at the ages tested. (Reduced head-dipping, accompanied by stereotypy, is the pattern of results previously seen in adult rats with this dose of amphetamine.) An interesting difference emerged with scopolamine, which reduced head-dipping at all the ages tested, whereas in adults it produced an increase. The age-related difference in drug effects suggests that muscarinic pathways are functioning from Day 16, but that the system concerned with exploration functions differently in mature and immature rats. Both scopolamine and methylscopolamine reduced rearing which suggests that the change is due to peripheral actions of the drugs. Parachlorophenylalanine, which decreases serotonin levels, increased head-dipping, as it has been found to do in adult rats. Exploration in the rat, measured by the time spent head-dipping in a holeboard, increases considerably from Day 16 t o Day 28 (File, in press). Although the effects of drugs on exploration in adult rats have been widely studied little information is available about drug effects on exploration in immature rats. In the rat, central catecholaminergic neuronal systems are at least partially functioning at birth in that responses can be elicited to amphetamine (Campbell, Lytle,
ABSTRACT Using the social interaction test of anxiety we have shown that whereas in acute doses b... more ABSTRACT Using the social interaction test of anxiety we have shown that whereas in acute doses benzodiazepines have a sedative effect, with chronic (5 days) administration they have an anxiolytic (anxiety reducing) action. Corticotrophin (ACTH 1-24 ) has an anxiogenic action and when given in combination with benzodiazepines it can reverse their behavioural effects. The importance of 5-HT pathways is indicated by our findings: a) that chronic (5 days) administration of benzodiazepines reduces 5-HT turnover, whereas ACTH increases it; and b) that parachlorophenylalanine (an inhibitor of 5-HT synthesis) produces a behavioural profile similar to that seen with anxiolytic drugs. It is therefore suggested that ACTH exerts an anxiogenic action by acting on 5-HT pathways and that this effect can be counteracted by anxiolytic drugs. On the basis of our lesion studies we suggest that the 5-HT pathways ascending from the dorsal raphe nucleus might be of particular importance.
In general, hormone replacement therapy (HRT) has been found to improve memory in post-menopausal... more In general, hormone replacement therapy (HRT) has been found to improve memory in post-menopausal women. However, many women are either unable or unwilling to take HRT and, furthermore, there is evidence that long-term HRT may not convey memory benefits and may even lead to impaired frontal lobe function . There is therefore a need to evaluate alternative treatments and there has been considerable interest in the use of phytoestrogens in the menopause. However, their effects on cognitive function have received relatively little attention. Thirty-three post-menopausal women (51-65 years), who were not receiving HRT, were randomly allocated to soya supplements (Solgen, twice daily capsules, each containing 30 mg total phytoestrogen isoflavones) or placebo treatment. Neither the volunteers nor the experimenters were aware which treatment they had received. They were given a battery of cognitive tests before treatment began (baseline) and after 12 weeks. The women receiving the soya supplements showed a greater improvement in memory than did those receiving placebo, (episodic memory factor, MANOVA, treatment × day F(4,28)=4.5, p<0.02), measured by long-term recall of pictures (p<0.03), short-term story recall (p=0.06) and pattern recognition (p=0.10). The women receiving soya also showed significantly greater improvements than those receiving placebo capsules in 3 tasks reflecting frontal lobe function: mental flexibility (as shown by the speed at which they could learn rule reversals F(1,11)=11.9, p<0.003); planning (as shown by the speed at which they were able to complete this task, F(1,31)=4.2, P<0.05); and in sustained attention (as measured in PASAT, F(1,29)=6.2, P<0.02). These cognitive improvements resulting from soya supplements to post-menopausal women are similar to the benefits that we have previously found following administration of a supervised high soya diet to male and female students. Compared with those on a low soya diet both male and female students showed greater improvements in memory and mental flexibility . The cognitive effects of soya are most likely to be mediated by actions at the oestrogen [~-receptors in the hippocampus and frontal cortex, where the soya isoflavones act as full agonists.
Twenty-one outpatients attending Guy's Dental Hospital received intravenous midazolam prior t... more Twenty-one outpatients attending Guy's Dental Hospital received intravenous midazolam prior to the removal of at least one wisdom tooth. The patient's memory for material presented both before and after midazolam was assessed either whilst still in the drug-treated condition (midazolam+placebo) or in the drug-reversed condition (midazolam+flumazenil). There were no differences between the two retrieval conditions in the number of words or pictures correctly recalled or recognized and both groups showed significantly better memory for material presented prior to midazolam administration. In a word completion task both groups showed a significant and equal priming effect, in that they completed more words with those to which they had been previously exposed in a rating task. However, the groups differed significantly in the total number of words correctly completed, with the drug-reversed group completing more. The word completion task is a problem- solving task requiring retrieval from semantic memory. There was further evidence that midazolam might impair retrieval from semantic memory from the number of subjects making spelling errors; this was significantly greater in the midazolam group than in the midazolam+flumazenil group. Finally, free recall of the dental procedures was significantly different in the two retrieval conditions. The midazolam+flumazenil group remembered significantly more items, and this effect was particularly marked for patients who had all four wisdom teeth removed. Flumazenil significantly reversed the midazolam-induced decrease in tapping rate (an objective measure of sedation), significantly attenuated the reduction in self-rated anxiety and significantly increased shaking and trembling.
Pairs of male rats were placed in a test box for 10 min and the time they spent in active social ... more Pairs of male rats were placed in a test box for 10 min and the time they spent in active social interaction was scored. Maximum active interaction was found when the rats were tested under low light in a box with which they were familiar. When the light level was increased or when the box was unfamiliar active social interaction decreased. 2 Exploration (time spent sniffing objects) decreased in the same way in relation to test conditions as did social interaction. As these decreased, defecation, and freezing increased. 3 Anosmic controls showed that the decrease in social interaction across test conditions could not be attributed to olfactory changes in the partner. 4 Chlordiazepoxide (5 mg/kg) given chronically prevented or significantly reduced the decrease in social interaction that occurred in undrugged rats as the light level or the unfamiliarity of the test box was increased. Controls showed that this effect could not be entirely attributed to chlordiazepoxide acting selectively to increase low levels of responding. 5 The effect of chronic chlordiazepoxide contrasts with its action when given acutely; in the latter case it has only sedative effects. 6 Whether this test can be used as an animal model of anxiety is discussed and this test is compared with existing tests of anxiety.
Two colonies of 12 male hooded rats were established for several months. Intruder rats were intro... more Two colonies of 12 male hooded rats were established for several months. Intruder rats were introduced into the colony, and agonistic encounters were observed for 18 min. Acute administration of chlordiazepoxide (5 mglkg) and lorazepam (.25 mglkg) to intruder rats had little effect on aggressive behavior. After 5 days of benzodiazepine administration to the intruders, there were fewer fights and less time was spent fighting. The residents directed fewer bites and aggressive behaviors toward the intruders. The intruders submitted less and initiated more interaction (both sniffing and agonistic behaviors) with the residents.
Benzodiazepines are the most widely prescribed psychotropic drugs and while the specific neural p... more Benzodiazepines are the most widely prescribed psychotropic drugs and while the specific neural pathways mediating their several therapeutic effects remain largely unknown, at least their initial site of action has been identified. For the last decade we have known that the central nervous system contains high affinity, stereospecific binding-sites for the benzodiazepines. These sites are found on a supramolecular complex with y-aminobutyric acid (GABA) receptors and with a chloride ionophore (channel across the cell membrane), which also has binding-sites for drugs such as the barbiturates . Recently there has been a growing appreciation that benzodiazepines induce dependence and that tolerance can occur to their behavioural effects. Although initially these phenomena were linked with long-term use, more recent evidence suggests that similar changes can be observed after short-term or even a single administration. This review covers both the clinical evidence and relevant experimental studies and attempts to explore the possible underlying mechanism(s). Although the precise mechanism is still unknown, we conclude that both rebound and withdrawal symptoms are reflections of a common dependence mechanism and also that tolerance is simply another manifestation of this same mechanism. We further conclude that the same underlying mechanism mediates the rebound phenomena and tolerance seen after short-term or acute benzodiazepine administration. 19 539 PSM n .
The ability of chronic treatment with imipramine (an antidepressant with anti-panic activity) to ... more The ability of chronic treatment with imipramine (an antidepressant with anti-panic activity) to antag onise the anxiogenic effects of 3 different compounds was investigated in the elevated plus-maze. The compounds chosen are likely to produce anxiety by activity at different sites in the central nervous system: yohimbine, by blocking the cu-adrenoceptor; FG 7142, by action at the p-carboline site on the GABA-benzodiazepine receptor complex and pentylenetetrazole, by acting at the picrotoxinin site on this complex. Administration of imipramine following 21 days pre-treatment did not produce a significant consistent anxiolytic effect alone and was unable to reverse the anxiety produced by any of the 3 anxiogenic compounds. Our results are discussed in terms of the nature of the anxiety produced by the anxiogenic drugs and the sensitivity of tests of anxiety to anti-panic agents.
This review discusses the effects of antidepressant drugs on behaviors that are changed during th... more This review discusses the effects of antidepressant drugs on behaviors that are changed during the clinical treatment of depression. We first consider whether there is a similar subjective state produced by antidepressant drugs that might be akin to the mood changes caused clinically by these drugs. We thus review the evidence that antidepressant drugs can produce a distinctive enough subjective state to serve as a discriminative stimulus, and then discuss the nature of the cue produced. Secondly, we discuss whether there is any evidence that antidepressants enhance the rewarding aspects of stimuli since this aspect of behavior is reported to change during the successful treatment of depression. In this section we review the effects on electrical brain stimulation, water and food intake, exploratory and social behaviors. Finally, because of the proposed role of stress in the aetiology of depression, we review the effects of antidepressants on the responses to acute and chronic stress.
The purpose of the present study was to determine the role of the 5-HT 1A receptors in the latera... more The purpose of the present study was to determine the role of the 5-HT 1A receptors in the lateral septum in the mediation of the anxiogenic effects of nicotine in the social interaction and elevated plus maze tests of anxiety in the rat. Bilateral infusion of (±)nicotine (4 and 8 mg) and of the 5-HT 1A receptor agonist 8-OH-DPAT (200 and 500 ng) into the lateral septum decreased the time spent in social interaction, indicating anxiogenic effects. The anxiogenic effect of 8-OH-DPAT (500 ng) was completely reversed by coadministration of a behaviourally inactive dose of the 5-HT 1A receptor antagonist, WAY 100635 (200 ng). The anxiogenic effect of the lower dose of (±)-nicotine (4 mg) was completely reversed by WAY 100635 (200 ng), but the reversal was only partial following administration of 8 mg nicotine. In a second test of anxiety, the elevated plus maze, lateral septal administration of 8-OH-DPAT (500 ng) and nicotine (4 mg) induced anxiogenic effects. In this test, the anxiogenic effect of nicotine (4 mg) was completely reversed by coadministration of WAY 100635 (200 ng). The effects of 8-OH-DPAT demonstrate that stimulation of 5-HT 1A receptors in the lateral septum has anxiogenic effects in two animal tests and that the anxiogenic effects of nicotine are mediated at least in part by these 5-HT 1A receptors.
The protective effects of acute and chronic diazepam administration (4 mg/kg) against seizures in... more The protective effects of acute and chronic diazepam administration (4 mg/kg) against seizures induced by pentylenetetrazole (PTZ) and picrotoxin were investigated. Considering the incidence of tonic-clonic convulsions, tolerance to the protective effects of diazepam was evident by day 5 if the mice were challenged with PTZ (120 mg/kg), by day 10 if the challenge was picrotoxin (8 mg/kg) and by day 20 if the challenge was PTZ (105 mg/kg). Diazepam retained its protective effects against tonic-clonic convulsions induced by PTZ (90 and 60 mg/kg) for 45 days, but the incidence of myoclonic jerks revealed tolerance after 5 days.
Pharmacology, Biochemistry and Behavior, May 1, 1996
FILE, S. E. Recent developments in anxiefy, stress, and depression. PHARMACOL BIOCHEM BEHAV 54(l)... more FILE, S. E. Recent developments in anxiefy, stress, and depression. PHARMACOL BIOCHEM BEHAV 54(l) 3-12, 1996. -Recent research in the development, analysis, and pharmacology of animal tests of state anxiety is discussed, including the use of responses to predator odours, the role of learning in modifying the anxiety measured in the plus-maze, and the roles
Changes in hormones of the hypothalamic-pituitary-adrenal (HPA) axis in patients suffering from a... more Changes in hormones of the hypothalamic-pituitary-adrenal (HPA) axis in patients suffering from anxiety and depressive disorders are reviewed, and the changes that occur when animals are exposed to test situations used preclinically to model anxiety or depression. The effects of exogenous administration of HPA hormones both clinically and in animal tests is discussed and the effects of clinically used anxiolytics and antidepressants on hormones of the HPA axis. The final section discusses stress-induced changes in the CNS.
SummaryTianeptine is a clinically effective anti-depressant with the unusual profile of increasin... more SummaryTianeptine is a clinically effective anti-depressant with the unusual profile of increasing 5-HT uptake, thereby decreasing the synaptic availability of 5-HT. In the social interaction test of anxiety in the rat, withdrawal from chronic diazepam treatment produced a significant anxiogenic response that was reversed by acute administration of tianeptine (2.5–10 mg/kg). These doses were without significant effect in the vehicle-treated rats. Exposure of rats to cat odour resulted in anxiogenic responses in the plus-maze and social interaction tests and in decreased exploration. These changes were not reversed by 5 days treatment with tianeptine (2.5–10 mg/kg). Thus, tianeptine may not he effective in all anxiety states, but could be particularly useful in treating patients withdrawn from benzodiazepines.
The effects of d-amphetamine (4 mglkg), scopolamine (1 mdkg), methylscopolamine (1 mdkg), and par... more The effects of d-amphetamine (4 mglkg), scopolamine (1 mdkg), methylscopolamine (1 mdkg), and parachlorophenylalanine (400 mg/kg) on exploration were studied in male rats at 16, 21, and 28 days of age. Amphetamine elicited stereotypy at all ages tested, reduced exploration (measured by the time spent head-dipping during a 10-min trial in a holeboard) from Day 21, but did not significantly increase rearing at the ages tested. (Reduced head-dipping, accompanied by stereotypy, is the pattern of results previously seen in adult rats with this dose of amphetamine.) An interesting difference emerged with scopolamine, which reduced head-dipping at all the ages tested, whereas in adults it produced an increase. The age-related difference in drug effects suggests that muscarinic pathways are functioning from Day 16, but that the system concerned with exploration functions differently in mature and immature rats. Both scopolamine and methylscopolamine reduced rearing which suggests that the change is due to peripheral actions of the drugs. Parachlorophenylalanine, which decreases serotonin levels, increased head-dipping, as it has been found to do in adult rats. Exploration in the rat, measured by the time spent head-dipping in a holeboard, increases considerably from Day 16 t o Day 28 (File, in press). Although the effects of drugs on exploration in adult rats have been widely studied little information is available about drug effects on exploration in immature rats. In the rat, central catecholaminergic neuronal systems are at least partially functioning at birth in that responses can be elicited to amphetamine (Campbell, Lytle,
ABSTRACT Using the social interaction test of anxiety we have shown that whereas in acute doses b... more ABSTRACT Using the social interaction test of anxiety we have shown that whereas in acute doses benzodiazepines have a sedative effect, with chronic (5 days) administration they have an anxiolytic (anxiety reducing) action. Corticotrophin (ACTH 1-24 ) has an anxiogenic action and when given in combination with benzodiazepines it can reverse their behavioural effects. The importance of 5-HT pathways is indicated by our findings: a) that chronic (5 days) administration of benzodiazepines reduces 5-HT turnover, whereas ACTH increases it; and b) that parachlorophenylalanine (an inhibitor of 5-HT synthesis) produces a behavioural profile similar to that seen with anxiolytic drugs. It is therefore suggested that ACTH exerts an anxiogenic action by acting on 5-HT pathways and that this effect can be counteracted by anxiolytic drugs. On the basis of our lesion studies we suggest that the 5-HT pathways ascending from the dorsal raphe nucleus might be of particular importance.
In general, hormone replacement therapy (HRT) has been found to improve memory in post-menopausal... more In general, hormone replacement therapy (HRT) has been found to improve memory in post-menopausal women. However, many women are either unable or unwilling to take HRT and, furthermore, there is evidence that long-term HRT may not convey memory benefits and may even lead to impaired frontal lobe function . There is therefore a need to evaluate alternative treatments and there has been considerable interest in the use of phytoestrogens in the menopause. However, their effects on cognitive function have received relatively little attention. Thirty-three post-menopausal women (51-65 years), who were not receiving HRT, were randomly allocated to soya supplements (Solgen, twice daily capsules, each containing 30 mg total phytoestrogen isoflavones) or placebo treatment. Neither the volunteers nor the experimenters were aware which treatment they had received. They were given a battery of cognitive tests before treatment began (baseline) and after 12 weeks. The women receiving the soya supplements showed a greater improvement in memory than did those receiving placebo, (episodic memory factor, MANOVA, treatment × day F(4,28)=4.5, p<0.02), measured by long-term recall of pictures (p<0.03), short-term story recall (p=0.06) and pattern recognition (p=0.10). The women receiving soya also showed significantly greater improvements than those receiving placebo capsules in 3 tasks reflecting frontal lobe function: mental flexibility (as shown by the speed at which they could learn rule reversals F(1,11)=11.9, p<0.003); planning (as shown by the speed at which they were able to complete this task, F(1,31)=4.2, P<0.05); and in sustained attention (as measured in PASAT, F(1,29)=6.2, P<0.02). These cognitive improvements resulting from soya supplements to post-menopausal women are similar to the benefits that we have previously found following administration of a supervised high soya diet to male and female students. Compared with those on a low soya diet both male and female students showed greater improvements in memory and mental flexibility . The cognitive effects of soya are most likely to be mediated by actions at the oestrogen [~-receptors in the hippocampus and frontal cortex, where the soya isoflavones act as full agonists.
Twenty-one outpatients attending Guy's Dental Hospital received intravenous midazolam prior t... more Twenty-one outpatients attending Guy's Dental Hospital received intravenous midazolam prior to the removal of at least one wisdom tooth. The patient's memory for material presented both before and after midazolam was assessed either whilst still in the drug-treated condition (midazolam+placebo) or in the drug-reversed condition (midazolam+flumazenil). There were no differences between the two retrieval conditions in the number of words or pictures correctly recalled or recognized and both groups showed significantly better memory for material presented prior to midazolam administration. In a word completion task both groups showed a significant and equal priming effect, in that they completed more words with those to which they had been previously exposed in a rating task. However, the groups differed significantly in the total number of words correctly completed, with the drug-reversed group completing more. The word completion task is a problem- solving task requiring retrieval from semantic memory. There was further evidence that midazolam might impair retrieval from semantic memory from the number of subjects making spelling errors; this was significantly greater in the midazolam group than in the midazolam+flumazenil group. Finally, free recall of the dental procedures was significantly different in the two retrieval conditions. The midazolam+flumazenil group remembered significantly more items, and this effect was particularly marked for patients who had all four wisdom teeth removed. Flumazenil significantly reversed the midazolam-induced decrease in tapping rate (an objective measure of sedation), significantly attenuated the reduction in self-rated anxiety and significantly increased shaking and trembling.
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