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Biomedical subjects

G F Koob

Publications and source records attributed to G F Koob.

At least 19 recordsLinked to original sources
PubMed2005

Epipregnanolone and a novel synthetic neuroactive steroid reduce alcohol self-administration in rats.

This study was designed to compare the effects of several neuroactive steroids with varying patterns of modulation of gamma-aminobutyric acid (GABA)(A) and NMDA receptors on operant self-administration of ethanol or water. Once stable responding for 10% (w/v) ethanol was achieved, separate test sessions were conducted in which male Wistar rats were allowed to self-administer ethanol or water following pre-treatment with vehicle or one of the following neuroactive steroids: (3beta,5beta)-3-hydroxypregnan-20-one (epipregnanolone; 5, 10, 20 mg/kg; n=12), (3alpha,5beta)-20-oxo-pregnane-3-carboxylic acid (PCA; 10, 20, 30 mg/kg n=10), (3alpha,5beta)-3-hydroxypregnan-20-one hemisuccinate (pregnanolone hemisuccinate; 5, 10, 20 mg/kg; n=12) and (3alpha,5alpha)-3-hydroxyandrostan-17-one hemisuccinate (androsterone hemisuccinate; 5, 10, 20 mg/kg; n=11). The effect of the 3beta-epimer of PCA, (3beta,5beta)-20-oxo-pregnane-3-carboxylic acid (10, 20, 30 mg/kg; n=9), on ethanol self-administration was also examined. The compounds were administered using a Latin-square design 45 min prior to the weekly test sessions. The effects of the 30 mg/kg dose of the steroidal hemisuccinates on ethanol intake were also examined 5 min after administration of these drugs. Both epipregnanolone and PCA attenuated ethanol self-administration. However, neither of the hemisuccinate compounds significantly altered this behavior. The steroidal hemisuccinates (30 mg/kg; n=7) were also tested 5 min before behavior testing and had no effect on ethanol intake 5 min after administration. The 3beta-epimer of PCA also failed to alter ethanol intake. None of the test compounds altered water intake. In electrophysiological studies, the effects of PCA and androsterone hemisuccinate on evoked GABA(A) receptor-mediated inhibitory postsynaptic currents (GABA(A)-IPSCs) was examined in brain slices of the amygdala. PCA had a stimulatory effect at concentrations of 5 and 25 muM. Androsterone hemisuccinate had no agonist activity. The ability of epipregnanolone and PCA to alter ethanol intake appears to be related to different inhibitory actions of these compounds on either GABA(A) or NMDA receptors, respectively. Thus, dual modulation of these systems by selected neuroactive steroids may offer potential for modifying the reinforcing effects of alcohol.

Amygdala↗
PubMed2004

A non-invasive gating device for continuous drug delivery that allows control over the timing and duration of spontaneous opiate withdrawal.

Opiate dependence in laboratory animals is commonly induced by two methods: (1) subcutaneous (s.c.) insertion of morphine pellets, and (2) daily injections of increasing doses of opiates. While both of these methods reliably induce opiate dependence, they do not allow one to discontinue, and subsequently reestablish steady state opiate plasma levels with minimal invasive procedures. We developed an "ON-OFF" gating device for repeatedly and non-invasively turning ON or OFF opiate delivery by standard osmotic minipumps. The reliability of this "device" was tested utilizing naloxone (NAL)-precipitated somatic signs of withdrawal, and body mass index (BMI) as measures of withdrawal. Rats were implanted with osmotic minipumps equipped with the gating device, containing heroin (2.66 mg per day). Three days after surgery, somatic signs of withdrawal were precipitated every 48 h by NAL (0.3mg/kg), with minipumps gated ON or OFF. For BMI, spontaneous withdrawal was repeatedly (three times) induced by turning OFF and ON the gating devices every 48 h. Body weights were measured every 4h from 06:00 to 22:00 h daily. Results show that NAL precipitated intense somatic signs of withdrawal when gating devices were ON. This effect was almost abolished when gating devices were OFF. BMI rapidly decreased after the gating devices were turned OFF with maximum weight loss occuring 12 h post-OFF position, and gradually returning to baseline values after gating devices were turned back ON. These results demonstrate the validity of the "ON-OFF" gating device for non-invasively and repeatedly inducing physical dependence to opiates over a prolonged time.

Analysis of Variance↗
PubMed2002

Effect of bilateral 6-hydroxydopamine lesions of the medial forebrain bundle on reaction time.

Overt symptoms of Parkinson's disease do not manifest themselves until there is a substantial loss of the dopaminergic nigrostriatal projection. However, as neuroprotective strategies are developed, it will be essential to detect the disease in its preclinical phase. Performance on conditioned reaction time tasks is known to be impaired by extensive 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway. However, the effect of smaller lesions on a reaction time task has not been systematically assessed. We, therefore, used this test to examine behavioral deficits as a function of striatal dopamine loss. When injected at doses that produced striatal DA depletion <50%, 6-hydroxydopamine infused in the medial forebrain bundle produced no reliable impairment in the reaction time task. Higher doses producing > or = 60% DA depletion in the striatum produced a decrease in the percent correct responding throughout the 5 week testing period and akinetic deficits expressed by an increase in delayed responding. In addition, larger DA depletions (> or = 95%) profoundly altered motor control with decreases in percent correct responses, increases in delayed responses and increases in reaction time. These results suggest that reaction time may be a relatively sensitive measure of preclinical or subtle deficits, although it might be even more useful in quantitating the severity of depletion once overt deficits or symptoms appear and has the advantage of measuring such deficits over time to follow recovery of function. Furthermore since reaction time deficits required extensive loss of dopamine, these results are consistent with a predominant role of extrasynaptic dopamine in the mediation of relatively skilled motor tasks.

Adrenergic Agents↗
PubMed2001

Time-dependent induction of anxiogenic-like effects after central infusion of urocortin or corticotropin-releasing factor in the rat.

RATIONALE: Corticotropin-releasing factor (CRF) and urocortin (Ucn) belong to the CRF-related family, share a high degree of structural homology and bind to CRF receptors. However, compared with CRF, Ucn was shown to display either weaker or similar anxiogenic-like effects in vivo. OBJECTIVE: To compare the anxiogenic-like responses of rats injected intracerebroventricularly (ICV) with different doses of either rat/human CRF (r/hCRF) or rat Ucn (rUcn) at different intervals after injection. METHODS: Rats were tested on three validated paradigms of emotional behavior [i.e. elevated plus-maze (EPM), defensive withdrawal (DW) and conflict test (CT)] 5 and 30 min after treatment. RESULTS: In the EPM test only r/hCRF, but not rUcn, produced anxiogenic-like effects at the dose of 1.0 microg, when the peptides were injected 5 min before testing. At 30 min after injection, both peptides caused a significant reduction of open arms exploration, rUcn being effective at 0.01 microg. In the DW test both peptides were equally potent in decreasing the exploratory behavior and increasing the time spent in the chamber at the dose of 1.0 microg when tested 30 min after injection. In the CT both rUcn (0.25-1.0 microg) and r/hCRF (0.75-1.0 microg) decreased significantly the responding in the punished component. However, rUcn reduced food responding also in the unpunished component possibly due to its powerful anorectic activity. CONCLUSIONS: Comparison of anxiogenic-like activities of r/hCRF and rUcn at doses up to 1.0 microg revealed striking differential effects that depended on the time of testing after ICV peptide injection, and on the paradigm of anxiety used. These results suggest that the onset of r/hCRF and rUcn actions related to behavioral responses to anxiety is likely to depend on brain peptide-specific mechanisms including binding properties to CRF-receptors, differential distribution to specific functional brain sites and the distribution and effectiveness of binding-protein interactions.

Animals↗
PubMed2001

Hypothalamic paraventricular nucleus injections of urocortin alter food intake and respiratory quotient.

Corticotropin releasing hormone (CRH) acts on the central nervous system to alter energy balance and influence both food intake and sympathetically-mediated thermogenesis. CRH is also reported to inhibit food intake in several models of hyperphagia including neuropeptide Y (NPY)-induced eating. The recently identified CRH-related peptide, urocortin (UCN), also binds with high affinity to CRH receptor subtypes and decreases food intake in food-deprived and non-deprived rats. The present experiment characterized further the feeding and metabolic effects of UCN by examining its impact after direct injections into the paraventricular nucleus (PVN) of the hypothalamus. In feeding tests (n=8), UCN (50-200 pmol) was injected into the PVN at the onset of the dark cycle and food intake was measured 1, 2 and 4 h postinjection. In separate rats (n=8), the metabolic effects of UCN were monitored using an open circuit calorimeter which measured oxygen consumption (V(O2)) and carbon dioxide production (V(CO2)). Respiratory quotient (RQ) was calculated as V(CO2)/V(O2). UCN suppressed feeding at all times studied and reliably decreased RQ within 30 min of infusion. Additional work examined the effect of UCN (50-100 pmol) pretreatment on the feeding and metabolic effects of NPY. NPY, injected at the start of the dark period, reliably increased 2 h food intake. This effect was blocked by PVN UCN administration. Similarly, UCN blocked the increase in RQ elicited by NPY alone. These results suggest that UCN-sensitive mechanisms within the PVN may modulate food intake and energy substrate utilization, possibly through an interaction with hypothalamic NPY.

Animals↗
PubMed2001

Functional interaction between opioid and cannabinoid receptors in drug self-administration.

The present study was designed to explore the relationship between the cannabinoid and opioid receptors in animal models of opioid-induced reinforcement. The acute administration of SR141716A, a selective central cannabinoid CB1 receptor antagonist, blocked heroin self-administration in rats, as well as morphine-induced place preference and morphine self-administration in mice. Morphine-dependent animals injected with SR141716A exhibited a partial opiate-like withdrawal syndrome that had limited consequences on operant responses for food and induced place aversion. These effects were associated with morphine-induced changes in the expression of CB1 receptor mRNA in specific nuclei of the reward circuit, including dorsal caudate putamen, nucleus accumbens, and septum. Additionally, the opioid antagonist naloxone precipitated a mild cannabinoid-like withdrawal syndrome in cannabinoid-dependent rats and blocked cannabinoid self-administration in mice. Neither SR141716A nor naloxone produced any intrinsic effect on these behavioral models. The present results show the existence of a cross-interaction between opioid and cannabinoid systems in behavioral responses related to addiction and open new strategies for the treatment of opiate dependence.

Animals↗
PubMed2001

Performance-enhancing effects of CRF-BP ligand inhibitors.

Intracerebroventricular (i.c.v.) administration of corticotropin-releasing factor (CRF) peptide fragments with low affinity for CRF receptors reportedly improves cognitive performance without producing anxiety. These compounds are hypothesized to act by displacing endogenous peptide from the CRF-binding protein (CRF-BP). To test this hypothesis, the present study determined whether the performance-enhancing potency of CRF fragments was related to their affinity for the CRF-BP. Rank ordering of the optimal doses of these compounds for facilitating spatial navigation corresponded to their affinity for the CRF-BP. i.c.v. pretreatment with performance-enhancing doses of r/h CRF(1-41)-OH (5 micrograms) or r/h CRF(6-33) (25 micrograms) did not increase emotionality. These findings replicate the dissociability of the cognition- and anxiety-related effects of CRF-related compounds and suggest that CRF fragments facilitate performance via the CRF-BP.

Animals↗
PubMed2001

A second-generation vaccine protects against the psychoactive effects of cocaine.

The effects of immunization with the second-generation cocaine immunoconjugate GND-keyhole limpet hemocyanin (KLH) or with the anti-cocaine mAb GNC92H2 were assessed in a model of acute cocaine-induced locomotor activity. After i.p. administration of cocaine small middle dotHCl (15 mg/kg), rats were tested in photocell cages, and stereotypy was rated to determine preimmunization drug response (baseline). Experimental animals were subjected to an immunization protocol with GND-KLH or treated with the mAb GNC92H2. Rats were then challenged with systemic cocaine, and their locomotor responses were again measured. Active immunization with GND-KLH produced a 76% decrease in the ambulatory measure (crossovers) in the experimental group and a 12% increase in the control group compared with baseline values. Also, stereotypic behavior was significantly suppressed in the vaccinated animals. Decreases in both measures were seen in the experimental group on two subsequent challenges. The maximum effect was observed at the time of the second challenge with a dramatic 80% decrease in crossovers. Treatment with GNC92H2 resulted in a 69% decrease in crossovers compared with baseline. This effect persisted across two additional challenges over 11 days with decreases of 46--47%. In contrast, the control group showed increases of up to 28%. Significant differences between groups were observed in the stereotypic measure in all three challenges. The results indicate that these immunopharmacotherapeutic agents have significant cocaine-blockade potential and therefore may offer an effective strategy for the treatment of cocaine abuse.

Animals↗
PubMed2001

Drug addiction: functional neurotoxicity of the brain reward systems.

Drug addiction is a chronic relapsing brain disorder characterized by a compulsion to take a drug with loss of control over drug intake. The hypothesis under discussion here is that chronic drug use produces long-lasting dysfunctions in neurons associated with the brain reward circuitry, and this "functional neurotoxicity" of drugs of abuse leads to vulnerability to relapse and continued drug dependence. Several sources of reinforcement are associated with various components of the drug addiction cycle and much progress has been made in identifying the midbrain-basal forebrain neural elements involved in the positive reinforcing effects of drugs of abuse and more recently in the neural elements involved in the negative reinforcement associated with drug addiction. Key elements for the acute reinforcing effects of drugs of abuse include a macrostructure in the basal forebrain called the extended amygdala that contains parts of the nucleus accumbens and amygdala and involves key neurotransmitters such as dopamine, opioid peptides, serotonin, GABA, and glutamate. Withdrawal from drugs of abuse is associated with subjective symptoms of negative affect and dysregulation of brain reward systems involving some of the same neurochemical systems implicated in the acute reinforcing effects of drugs of abuse. In addition, the functional toxicity of acute withdrawal is accompanied by recruitment of the brain stress neurotransmitter system corticotrophin-releasing factor. During more prolonged abstinence, post-acute withdrawal, evidence is accumulating of continued dysregulation of the neural systems associated with drug reinforcement and stress, regulation that may represent more subtle but persistent functional neurotoxic effects of chronic drug use and could be responsible for long-lasting vulnerability to relapse. Such functional neurotoxicity could be hypothesized to lead to a change in set point for drug reward that may represent an allostatic state contributing to vulnerability to relapse and re-entry into the addiction cycle. Elucidation of the specific neuropharmacological changes contributing to this prolonged functional neurotoxicity will be the challenge of future research on the neurobiology of drug addiction.

Journal Article↗
PubMed2001

Both GABA(B) receptor agonist and antagonists decreased brain stimulation reward in the rat.

The present experiments were designed to determine the role of GABA(B) receptor function on brain stimulation reward. Using a discrete-trial current-intensity threshold procedure, dose-effect functions were generated for the GABA(B) receptor agonist CGP 44532 (0-1.0 mg/kg, s.c.) and the GABA(B) receptor antagonists CGP 56433A (0-10.0 mg/kg, s.c.) and CGP 51176 (0-300.0 mg/kg, s.c.) on brain reward thresholds in rats. The GABA(B) receptor antagonists CGP 56433A and CGP 51176 were used also to examine interaction effects with the GABA(B) receptor agonist CGP 44532 on reward thresholds. Administration of the highest doses of both the GABA(B) receptor agonist and antagonists elevated reward thresholds. Thus, both the agonist and antagonists used induced a reward decrement when administered separately. In addition, the co-administration of either of the two receptor antagonists with the agonist induced an additive effect on thresholds, rather than blocking the agonist-induced threshold elevations. These results suggest that activation of GABA(B) receptors modulates intracranial self-stimulation behavior in a complex fashion, possibly through differential effects of GABA(B) agonists and antagonists on pre- and post-synaptic GABA(B) receptors.

Animals↗
PubMed2001

Neurosteroids in learning and memory processes.

The discovery that neurosteroids could be synthesized de novo in the brain independent from the periphery and display neuronal actions led to great enthusiasm for the study of their physiological role. Pharmacological studies suggest that neurosteroids may be involved in several physiological processes, such as learning and memory. This chapter summarizes the effects of the administration of neurosteroids on learning and memory capabilities in rodents and in models of amnesia. We address the central mechanisms involved in mediating the modulation of learning and memory processes by neurosteroids. In this regard, the neurosteroid-modulated neurotransmitter systems, such as gamma-aminobutyric acid type A, N-methyl-D-aspartate, and cholinergic and sigma opioid systems, appear to be potential targets for the rapid memory alteration actions of neurosteroids. Moreover, given that some neurosteroids affect neuronal plasticity, this neuronal change could be involved in the long-term modulation of learning and memory processes. To understand the role of endogeneous neurosteroids in learning and memory processes, we present some physiological studies in rodents and humans. However, the latter do not successfully prove a role of endogenous neurosteroids in age-related memory impairments. Finally, we discuss the relative implication of a given neurosteroid vs its metabolites. For this question, a new approach using the quantitative determination of traces of neurosteroids by mass spectrometry seems to have potential for examining the role of each neurosteroid in discrete brain areas in learning and memory alterations, as observed during aging.

Animals↗
PubMed2001

A dopamine partial agonist and antagonist block amphetamine self-administration in a progressive ratio schedule.

A recently characterized class of compounds, dopamine partial agonists, have been suggested as potential therapeutic candidates for pharmacological intervention in psychostimulant addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are thought to behave as functional antagonists in conditions of high dopaminergic tone, and as agonists in conditions of low receptor occupancy by dopamine. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the D2 receptor subtype, on intravenous self-administration of amphetamine in a progressive ratio schedule and to compare it with the effects produced by the dopamine D2 antagonist eticlopride and the dopamine D2 full agonist quinpirole. Terguride at the doses of 0.2 and 0.4 mg/kg i.p. significantly decreased the maximum number of responses delivered for a single injection of amphetamine ("breaking point"), an effect similar to that produced by the antagonist eticlopride (0.01-0.1 mg/kg s.c.). In contrast, administration of quinpirole (0.1-1 mg/kg s.c.) did not significantly modify the breaking point for amphetamine responding. Also, terguride dose-dependently increased responding for amphetamine self-administration on a continuous reinforcement schedule. These data further confirm the effects of terguride on psychostimulant self-administration and indicate that under these conditions partial dopamine agonists act as functional dopamine receptor antagonists.

Amphetamine↗
PubMed2001

Opiate withdrawal-induced fos immunoreactivity in the rat extended amygdala parallels the development of conditioned place aversion.

Low doses of naloxone have been shown to affect the motivational aspects of opiate withdrawal in morphine-dependent rats. Conditioned place aversion to opiate withdrawal is one of the most sensitive of motivational indices of opiate withdrawal and is thought to be mediated by the basal forebrain. Expression of the transcription factor Fos is known to increase during opiate withdrawal, but its presence during low-dose antagonist-precipitated withdrawal has not previously been established. In order to determine if there is a relationship between withdrawal-induced neuronal activity and conditioned place aversion, immunocytochemical localization of Fos was examined in the basal forebrain of opiate-dependent animals receiving one of several doses of naloxone (0, 3.25, 7.5, 15, 30, or 1000 microg/kg). In separate groups of opiate-dependent animals, naloxone doses of 3.25 - 30 microg/kg were paired with a specific chamber in a single-pairing conditioned place aversion paradigm. Significant increases in both immunocytochemical detection of Fos and conditioned place aversion were seen at doses >/= 7.5 microg/kg. The shell of the nucleus accumbens and central nucleus of the amygdala were most sensitive to low doses, thus supporting the hypothesis that the extended amygdala plays a role in opiate-induced condition place aversion.

Amygdala↗
PubMed2001

Drug addiction, dysregulation of reward, and allostasis.

This paper reviews recent developments in the neurocircuitry and neurobiology of addiction from a perspective of allostasis. A model is proposed for brain changes that occur during the development of addiction that explain the persistent vulnerability to relapse long after drug-taking has ceased. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in the compulsive use and loss of control over drug-taking. The development of addiction recruits different sources of reinforcement, different neuroadaptive mechanisms, and different neurochemical changes to dysregulate the brain reward system. Counteradaptive processes such as opponent-process that are part of normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. Allostasis from the addiction perspective is defined as the process of maintaining apparent reward function stability by changes in brain reward mechanisms. The allostatic state represents a chronic deviation of reward set point and is fueled not only by dysregulation of reward circuits per se, but also by the activation of brain and hormonal stress responses. The manifestation of this allostatic state as compulsive drug-taking and loss of control over drug-taking is hypothesized to be expressed through activation of brain circuits involved in compulsive behavior such as the cortico-striatal-thalamic loop. The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and relapse.

Animals↗
PubMed2001

Anxiogenic-like effects limit rewarding effects of cocaine in balb/cbyj mice.

Previous studies have reported intravenous cocaine self-administration behavior in several strains of mice with the exception of BALB/cByJ, a strain considered a mouse model of high emotional reactivity. The present experiments further investigated acquisition of self-administration in BALB/cByJ mice using a low dose and a habituation session. Following evidence of an initial drug-seeking behavior, we observed a progressive decline of intravenous self-administration. Pretreatment with diazepam (0.5 mg/kg, IP), reinstated cocaine-maintained responding. To test the hypothesis that injections directly into a reward-relevant brain region might support consistent cocaine-seeking behavior, BALB/cByJ mice implanted in the nucleus accumbens (NAc) or the caudate-putamen nucleus (CPu) were trained to discriminate between the arm enabling a microinjection of cocaine (30 pmol/50 nl or 150 pmol/50 nl) and the neutral arm of a Y-maze. Only NAc subjects exhibited a spatial discrimination toward the cocaine-reinforced arm and the D2 antagonist, sulpiride (50 mg/kg, IP) eliminated intra-NAc cocaine self-administration. However, after several days of cocaine self-injection, animals developed an approach/avoidance-like behavior between the start box and the reinforced arm. This behavior was suppressed by systemic diazepam (1 mg/kg, IP) pretreatment. We conclude that: (1) medio-ventral NAc is involved both in the rewarding (via a D2 dopaminergic mechanism) and aversive effects of cocaine in mice; and (2) anxiolytic pretreatment (diazepam) indirectly enhanced the reinforcing properties of cocaine in BALB/cByJ, suggesting that emotionality can act as a protective mechanism against stimulant abuse.

Animals↗
PubMed2001

Dopamine partial agonist reverses amphetamine withdrawal in rats.

Decreased motivation to work for a natural reward is a sign of amphetamine withdrawal and is thought to be associated with hypofunction of the mesolimbic dopamine system. During withdrawal from repeated amphetamine administration, rats showed reduced responding for a sweet solution in a progressive ratio schedule. Repeated systemic treatment with terguride (0.2 and 0.4 mg/kg, i.p.) twice daily during the first four days of amphetamine withdrawal reversed the decrease in responding for the sweet solution. These results suggest that dopamine partial agonists, possibly due to their agonistic-like actions under these conditions, are a potential therapeutic approach for the acute withdrawal stage of the amphetamine addition cycle.

Amphetamine↗
PubMed2001

Steroid structure and pharmacological properties determine the anti-amnesic effects of pregnenolone sulphate in the passive avoidance task in rats.

Pregnenolone sulphate (PREGS) has generated interest as one of the most potent memory-enhancing neurosteroids to be examined in rodent learning studies, with particular importance in the ageing process. The mechanism by which this endogenous steroid enhances memory formation is hypothesized to involve actions on glutamatergic and GABAergic systems. This hypothesis stems from findings that PREGS is a potent positive modulator of N-methyl-d-aspartate receptors (NMDARs) and a negative modulator of gamma-aminobutyric acid(A) receptors (GABA(A)Rs). Moreover, PREGS is able to reverse the amnesic-like effects of NMDAR and GABA(A)R ligands. To investigate this hypothesis, the present study in rats examined the memory-altering abilities of structural analogs of PREGS, which differ in their modulation of NMDAR and/or GABA(A)R function. The analogs tested were: 11-ketopregnenolone sulphate (an agent that is inactive at GABA(A)Rs and NMDARs), epipregnanolone ([3beta-hydroxy-5beta-pregnan-20-one] sulphate, an inhibitor of both GABA(A)Rs and NMDARs), and a newly synthesized (-) PREGS enantiomer (which is identical to PREGS in effects on GABA(A)Rs and NMDARs). The memory-enhancing effects of PREGS and its analogs were tested in the passive avoidance task using the model of scopolamine-induced amnesia. Both PREGS and its (-) enantiomer blocked the effects of scopolamine. The results show that, unlike PREGS, 11-ketopregnenolone sulphate and epipregnanolone sulphate failed to block the effect of scopolamine, suggesting that altering the modulation of NMDA receptors diminishes the memory-enhancing effects of PREGS. Moreover, enantioselectivity was demonstrated by the ability of natural PREGS to be an order of magnitude more effective than its synthetic enantiomer in reversing scopolamine-induced amnesia. These results identify a novel neuropharmacological site for the modulation of memory processes by neuroactive steroids.

Amnesia↗