Susan B. Weinberger

Opioid receptors are involved in an NMDA receptor-independent mechanism of LTP induction at hippocampal mossy fiber-CA3 synapses ☆

Long-term potentiation (LTP) of mossy fiber responses in area CA3 of the rat hippocampus in vivo is blocked by naloxone, an opioid receptor antagonist, in a stereospecific and dose-dependent manner. LTP of commissural afferents to the same population of CA3 pyramidal cells is not attenuated by naloxone. This suggests that opioid receptors are involved in a mechanism of LTP induction that is specific to mossy fiber synapses, and that endogenous opioid receptors are involved in a mechanism of LTP induction that is specific to mossy fiber synapses, and that endogenous opioid peptides, presumably released as a result of mossy fiber stimulation, may be necessary for the induction of mossy fiber LTP. The naloxone sensitivity is limited to the induction phase of LTP, since naloxone does not reverse previously established LTP. These data suggest that LTP at the mossy fiber-CA3 synapse constitutes an NMDA receptor-independent, opioid receptor-dependent, form of hippocampal synaptic plasticity.

Enkephalins and learning and memory: a review of evidence for a site of action outside the blood-brain barrier.

A series of studies indicate that enkephalins exert dramatic influences on learning and memory in rats and mice, when studied with conditioning tasks that are both negatively and positively motivated. Pharmacological analysis of these enkephalin actions on conditioning suggests that the [leu]enkephalin acts through a delta opioid receptor which is located outside the blood-brain barrier. Control studies indicate that enkephalins do not simply affect the performance of a conditioned response through actions on shock sensitivity or locomotor activity. Characterization of the peripheral enkephalin mechanism that affects behavior suggests an action through an enzymatic system that controls the concentrations of enkephalin present at its receptors in the periphery. This enzymatic mechanism is sensitive to experience, since its activity changes following conditioning, which suggests that it may be a regulatory mechanism for behavior.

How to Increase and Decrease the Strength of Memory Traces: The Effects of Drugs and Hormones

Publisher Summary This chapter discusses how drugs and hormones influence memory. A fundamental observation in this area of research is that drugs and hormones make memories both stronger and weaker. Interestingly, research suggests that most drugs and hormones do not affect the memory trace directly but instead, they influence modulatory systems that in turn regulate associative strength. These ideas are elaborated in this chapter. However, before considering how drugs affect memory, the nature of the memory trace itself must be discussed first. Memory traces are physical entities within organisms. Scientists agree that memory involves the functional connection of neurons. The major issues discussed in this chapter are, firstly, memories most likely are stored in networks of neurons, called cellular assemblies. The strength of memories is influenced by exercise and by activation of modulatory mechanisms. Secondly, the importance of an experienced event is conveyed to an organism by the strength of the UCS or by the hormonal response associated with the experience. Third, manipulating either the strength of the UCS or the dose of the drug or hormonal treatment often produces a U-shaped dose-response function, which is the hallmark of a modulatory system. Fourth, the Principle of Substitution describes the finding that the UCS and the hormonal response, as mimicked by exogenous administration of a hormone, can substitute for each other to produce equivalent associative strength. Finally, the effects of drugs and hormones on memory are in accord with well-established principles of pharmacology, including the observation of dose—response relationships, competitive antagonism and antagonist effects that are the opposite of effects produced by agonists.

Differences in one-way active avoidance learning in mice of three inbred strains

DBA/2J, C57BL/6J, and C3H/HeJ mice were given 10 one-way avoidance training trials per day, using an unconditioned stimulus intensity that provided equivalent motivation for learning to mice of all three strains, and were found to differ in their abilities to learn and retain the response. DBA/2J mice acquired the response in fewer days than did the mice of the other two strains, although C57BL/6J mice eventually reached a level of performance similar to that of DBA/2J mice. Both the rate of acquisition and the level at which avoidance performance stabilized were significantly lower in C3H/HeJ, than in DBA/2J or C57BL/6J, mice. In addition, DBA/2J mice showed a significantly greater task retention from one testing day to the next than did C57BL/6J or C3H/HeJ mice.

Behavioral assessment of forgetting in aged rodents and its relationship to peripheral sympathetic function.

Observation of age-related memory deficits in rodents is often dependent on the behavioral task used to assess these changes, rather than being universal to all memories. A review of studies using aversively-motivated multiple trial training paradigms suggests that the apparent acquisition deficits common to older animals may instead be due to a confounding tendency of these animals to behavioral rigidity or perseveration. Data obtained using single trial training paradigms, such as the one-trial passive avoidance task, indicate that young and old rodents can learn tasks with equal facility, that retention in young and old animals is similar at short training-testing intervals, but that retention is impaired in aged animals at longer training-testing intervals. We suggest that the adrenal medulla, a peripheral source of catecholamines, secretes catecholamines that act outside the blood-brain barrier to modulate memory processes. Further, we review evidence suggesting that the ability of the adrenal medulla to respond to the stresses of footshock during aversively-motivated training are impaired in aged rodents, and that this impairment may contribute to the rapid forgetting observed in senescent animals.

Further characterization of the in vitro hydrolysis of [Leu]- and [Met]enkephalin in rat plasma : HPLC-ECD measurement of substrate and metabolite concentrations

Hydrolysis of [Leu]- and [Met]enkephalin was determined in whole rat plasma in vitro by using HPLC-ECD to measure Tyr, Tyr-Gly and Tyr-Gly-Gly formation. Although [Leu]- and [Met]enkephalin did not differ in Tyr or Tyr-Gly accumulation, the amount of Tyr-Gly-Gly resulting from [Met]enkephalin hydrolysis was greater than that resulting from [Leu]enkephalin hydrolysis, and [Met]enkephalins half-life in plasma was slightly shorter than that of [Leu]enkephalin. By comparing metabolite formation in the presence and absence of peptidase inhibitors with high selectivity for their respective enzymes, these studies demonstrated that aminopeptidase M and angiotensin converting enzyme are the major peptidases that hydrolyze enkephalins in rat plasma.

Plasma uptake and in vivo metabolism of [Leu]enkephalin following its intraperitoneal administration to rats

To understand better how [Leu]enkephalin (LE) acts to modulate learning and memory in rats, the plasma uptake, disappearance, and metabolism of LE were investigated following its intraperitoneal administration. Concentrations of [3H]-LE and its radioactive metabolites were determined by thin layer chromatography in plasma samples withdrawn from rats at various times after injection of peptide. As measured in rats receiving an IP injection of a dose of LE (3 micrograms/kg) that impairs active avoidance conditioning, the LE was very rapidly metabolized, with greater than 95% of plasma [3H] in the form of metabolites by 1 min after injection. Despite this rapid metabolism, low but measurable quantities of intact LE were detectable in plasma at all sampling times. Consistent with a greater potency of D-Ala2-[D-Leu5]enkephalin (DADLE) than of LE in modulating avoidance conditioning, DADLE was less rapidly metabolized than was LE following its IP administration. The metabolism of DADLE and LE in vivo was more rapid than it was in plasma in vitro, suggesting a role for membrane bound enzymes in the metabolism of IP-administered enkephalins. The data demonstrate that, despite a rapid hydrolysis of LE in vivo, sufficient LE is present in plasma following IP administration of a behaviorally active dose to support a role of circulating intact LE in the modulation of avoidance conditioning.

Enkephalin hydrolysis in plasma is highly correlated with escape performance in the rat.

A very high correlation was found in rats between latency to escape on the first trial of an active avoidance task and the rate at which [leu]enkephalin is hydrolyzed in plasma. In addition, the rate of [leu]enkephalin hydrolysis is significantly altered following the first training trial. The results suggest that a regulatory enzyme system exists for [leu]enkephalin in plasma and that this system may be important for modulating behavior.

Decreased locomotor activity produced by repeated, but not single, administration of murine-recombinant interferon-gamma in mice

A single treatment with murine-recombinant interferon-gamma (murIFN-gamma; 30 micrograms/mouse), whether evaluated immediately after, or four hrs after, intraperitoneal injection, does not alter open field activity levels. On the other hand, repeated murIFN-gamma administration (30 micrograms/mouse/day for 5 days) results in decreased spontaneous locomotor activity and an increase in body weight.

Enkephalin hydrolysis by mouse plasma in vitro

Hydrolysis of [Leu]- and [Met]enkephalin was determined in samples of pooled whole mouse plasma in vitro by using HPLC-ECD to measure accumulation of Tyr-containing metabolites. More Tyr-Gly-Gly accumulated from [Met]enkephalin than from [Leu]enkephalin hydrolysis, and [Met]enkephalins half-life in mouse plasma was approximately half that of [Leu]enkephalin. Comparisons of metabolite formation in the presence versus the absence of inhibitors with high selectivity for various peptidases demonstrated that a bestatin-sensitive aminopeptidase, presumably aminopeptidase M, as well as enkephalinase and angiotensin converting enzyme, participate in the hydrolysis of enkephalin in mouse plasma.