Joe L. Martinez

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.

Age-related memory deficits in rats and mice: Enhancement with peripheral injections of epinephrine

Epinephrine peripherally administered to rats and mice immediately following avoidance and/or appetitive training enhances later memory retention in both young and old animals. These findings suggest a possible involvement of peripheral adrenergic systems in memory dysfunctions which accompany aging.

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.

Opioid receptor-dependent long-term potentiation at the lateral perforant path-CA3 synapse in rat hippocampus

The involvement of opioid receptors in the induction of long-term potentiation (LTP) was investigated in the lateral and medial perforant path projections to area CA3 of the hippocampus in anesthetized rats. The opioid receptor antagonist naloxone (10 nmol), applied to the hippocampal CA3 region 10 min prior to tetanization, blocked the induction lateral perforant path-CA3 LTP induced by high-frequency stimulation. By contrast, LTP induction in medial perforant path-CA3 was not attenuated by a 10 nmol quantity of naloxone. (+)-Naloxone (10 nmol), the inactive stereoisomer of naloxone, was without effect on the induction of lateral perforant path-CA3 LTP. Naloxone applied 1 h following LTP induction did not reverse established lateral perforant path-CA3 LTP, indicating that opioid receptors are involved in the induction but not the maintenance of LTP in this pathway. LTP of medial perforant path responses developed immediately, while LTP of lateral perforant path responses was slow to develop. The latter pattern is similar to the time course of the development of LTP observed at the mossy fiber-CA3 synapse and suggests that lateral and medial perforant path synapses may use distinct mechanisms of both induction and expression of LTP. These data extend previous findings demonstrating opioid receptor-dependent mechanisms of LTP induction at both the mossy fiber-CA3 synapse and the lateral perforant path-dentate gyrus synapse. We suggest that lateral perforant path and mossy fiber synapses may utilize similar, opioid receptor-dependent, mechanisms of LTP induction and expression.

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.

Arginine Vasopressin, Stress, and Memory

Arginine vasopressin (AVP) has been shown to have several non-renal actions including the potentiation of learned avoidance behavior in rats and improvement in cognitive functioning in humans. Research in our laboratory has confirmed these behavioral effects in rats using both peripheral and central injection of AVP. We have begun to examine the physiological basis for these effects. Peripheral administration of a vasopressor AVP antagonist reversed the prolongation of extinction produced by peripherally administered AVP in both active and passive avoidance, but also reversed the aversive unconditioned effects of AVP. However, central administration of the vasopressor AVP antagonist reversed peripheral effects of AVP only at doses shown to act peripherally to reverse vasopressor effects of AVP. An osmotic stress in doses known to liberate endogenous AVP mimicked the behavioral effects of exogenously administered AVP, and this stress effect was reversed by the AVP antagonist. These results support our hypothesis of separate but parallel AVP systems in the pituitary and brain with a role in behavioral adaptation to certain types of stress.

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.

Modification of place preference conditioning in mice by systemically administered [Leu]enkephalin

[Leu]enkephalin (300 micrograms/kg, i.p.) induced either a positive or negative conditioned place preference response in mice depending on whether the animals were trained against or towards their initial preference. Induction of a positive preference (300 micrograms/kg) was partially blocked by simultaneous addition of methylnaloxonium (10 mg/kg, i.p.), an opioid antagonist that does not readily cross the blood-brain barrier; methylnaloxonium alone (3 or 10 mg/kg) had no effect on the place preference response. The results indicate that [Leu]enkephalin treatment reverses the initial preference of the animal regardless of training, and that some aspect of the [Leu]enkephalin effect on place preference conditioning is mediated by peripheral opioid receptors. These findings challenge the notion that place preference conditioning is a simple measure of opioid reward.

Post-reactivation cocaine administration facilitates later acquisition of an avoidance response in rats

We previously demonstrated that cocaine administered immediately prior to a reactivation episode comprised of re-exposure to selected features of the original fear-conditioning session alters subsequent memory retrieval or reconsolidation. In the present study we determined that, similar to pre-reactivation administration, post-reactivation administration of cocaine also alters memory retrieval or reorganization, as measured by subsequent conditioned performance. The dose-response function for this effect of cocaine was U-shaped; maximal enhancement of subsequent avoidance performance was produced by a 7.5 mg/kg i.p. dose of cocaine. Because a dose of lidocaine equimolar to the effective cocaine dose was found not to alter subsequent conditioned performance, the effect of cocaine on memory processing most likely is not attributable to its local anesthetic properties.

Cocaine and amphetamine facilitate retention of jump-up responding in rats

The effects of cocaine and d-amphetamine administration on the acquisition of an automated jump-up active avoidance task were examined in two separate experiments. On days 1 and 2, male Sprague-Dawley rats received one escape-only training trial, followed immediately by the intraperitoneal injection of cocaine, amphetamine, or saline. On day 3, subjects received eight escape/avoidance trials. The posttraining administration of cocaine (2.75 and 5.55 mg/kg) and amphetamine (0.3 and 1.0 mg/kg) on days 1 and 2 facilitated jump-up avoidance performance on day 3. Importantly, both cocaine and amphetamine enhanced learning and memory under experimental conditions that allowed for drug-free training and testing.