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The demonstration that the neurosteroid pregnenolone sulfate (PREGS) is active on memory function at both the physiological and pharmacological levels led to us examining in detail the effects of the steroid on spatial working memory by using a two-trial recognition task in a Y-maze, a paradigm based on the natural drive in rodents to explore a novel environment. Dose-response studies in young male adult Sprague-Dawley rats and Swiss mice, after the postacquisition intracerebroventricular injection of steroid, showed an U-inverted curve for memory performance and indicated a greater responsiveness in rats compared with mice. Remarkably, the synthetic (؊) enantiomer of PREGS not only also displayed promnesiant activity, but its potency was 10 times higher than that of the natural steroid. Intracerebroventricular coadministration experiments with DL-2-amino-5-phosphonovaleric acid, a competitive selective antagonist of the N-methyl-D-aspartate receptor, abolished the memory-enhancing effect of PREGS, but not that of the PREGS enantiomer, evoking enantiomeric selectivity at the N-methyl-D-aspartate receptor and͞or different mechanisms for the promnestic function of the two enantiomers.spatial memory ͉ Y-maze ͉ N-methyl-D-aspartate receptor ͉ 2-amino-5-phosphovaleric acid ͉ rodents S teroids found in the brain, of peripheral origin or locally synthesized (neurosteroids), are known to exert modulatory actions on several functions in the central nervous system. Among them, the neurosteroid pregnenolone sulfate (3␤-hydroxy-5-pregnen-20-one sulfate, PREGS) has been well described as a potent steroidal enhancer of learning and memory processes in rodents (1-6). Of particular interest is the physiological role of PREGS in the hippocampus, which was recently demonstrated for the preservation of age-related spatial memory loss (4). With regards to the mechanism(s) underlying the promnestic action of this endogenous steroid, it is most likely occurring by regulating neurotransmitter receptor function [particularly ␥-aminobutyric acid type A (GABA A ) and N-methyl-D-aspartate (NMDA) receptor activities] in several brain regions (2,3,(7)(8)(9)(10)(11)(12)(13).Particularly relevant to the work here on enantiomeric steroids are the structure-activity data that have demonstrated a marked stereoselectivity for steroid regulation of neurotransmitter receptor function. For example, the endogenous 3␣-hydroxy ring A-reduced steroids, such as the neurosteroid allopregnanolone (3␣-hydroxy-5␣-pregnan-20-one), display potent positive-allosteric modulation of GABA A receptors (14-16) that may explain their anesthetic, anxiolytic, hypnotic, and anticonvulsant effects in animals (17). Conversely, epiallopregnanolone and pregnanolone, the respective 3␤-and 5␤-hydroxy-diastereomers of allopregnanolone (diastereomers having the opposite configuration at only one of multiple chiral centers, in this case at C-3 or C-5, also are known as epimers) are ineffective in potentiating GABA A receptors (18). Cognate evidence for a direct interaction betwe...

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Although it is known that panic attacks are triggered by the cholecystokinin fragment CCK4, the specific involvement of peripheral or central cholecystokinin CCK receptors in various adaptive processes such as emotion, memory and anxiety has yet to be demonstrated. With this aim, we have investigated the biochemical and pharmacological effects resulting from the administration of BC264, a highly potent and selective CCK-B agonist able to cross the blood-brain barrier. Very low doses of BC264 (microg/kg i.p.), increased the exploration of animals submitted to an unknown territory but were devoid of anxiogenic properties in the elevated plus maze. BC264 increased locomotion and rearings of rats newly placed in an open field and improved their spontaneous alternation in a Y-maze. The use of vagotomized animals showed that the increased alternation induced by BC264 did not require an intact vagus nerve, unlike the locomotor activation. These behavioural effects, prevented by the prior i.p. administration of the CCK-B antagonist L-365,260 but not by the CCK-A antagonist L-364,718, were shown to depend on dopaminergic systems, since they were blocked by D1 (SCH23390, 25 microg/kg i.p.) or D2 (sulpiride, 50 or 100 mg/kg i.p.) antagonists. In addition, bilateral perfusion in freely moving rats of BC264 at pharmacologically active doses, using a newly designed microdialysis system, was found to increase the extracellular levels of DA, DOPAC and HVA in the anterior part of the nucleus accumbens. These results show that activation of CCK-B receptors by BC264 does not produce anxiogenic-like effects but appears to improve motivation and attention, whereas other CCK-B agonists such as BocCCK4 induce anxiogenic responses. Several explanations, including the existence of different sub-sites of the CCK-B receptor, could account for these differential effects.

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1 The hypothesis of the existence of two CCK B receptor subsites, CCK B1 and CCK B2 corresponding probably to di erent coupling states of CCK B receptors, was studied by measuring grooming behaviour in rats. 2 The B1 receptor agonist, BC197 (300 mg kg 71 , i.p.) produced a 45 ± 50% decrease in grooming activity, which was prevented by both the CCK B receptor antagonists CI-988 (20 mg kg 71 i.p.) and L-365,260 (200 mg kg 71 , i.p.). 3 In contrast, 3, 10 and 30 mg kg 71 , i.p., of the potent B2 receptor agonist, BC264, enhanced grooming (150 ± 190%). This e ect was prevented by previous injection of 75 mg kg 71 of L-365,260 while higher doses (200 mg kg 71 , i.p.) produced only a partial antagonism. Moreover, CI-988 (20 mg kg 71 , i.p.), showed an opposite e ect in potentiating the responses induced by BC264. However, 200 mg kg 71 of CI-988 tended to suppress the increase of grooming induced by BC264. 4 The e ects of BC264 were prevented by the D 1 receptor (SCH 23390) and D 2 receptor (sulpiride) antagonists, while those of BC197 were only antagonized by sulpiride, emphasizing the existence of a link between peptidergic (CCK) and dopaminergic systems. 5 This study brings additional evidence for the existence of the two CCK B receptor subsites and suggests that particular attention should be focused on the selectivity of CCK B receptor agonists, notably to explain the fact that some compounds such as Boc-CCK4 induce anxiogenic-like e ects while others, including BC264, are devoid of these e ects.

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