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

Bruin Research Bulletin, Vol. 33, pp. 17-24, 1994 Printed in the USA. All rights reserved.

0361-9230/94 $6.00 + .OO Copyright 0 1993 Peqamon Press Ltd.

Opi~id Receptor-dependent Long-term Potentiation at the Lateral Perforant Path-CA3 Synapse in Rat Hippocamp~s ANETTE

BREINDL,

BRIAN E. DERRICK,’ SUSAN B. RODRIGUEZ AND JOE L. MARTINEZ, JR.

Department of Psychology, University of CaliJornia,Berkeley, CA 94120 Received 23 February 1993; Accepted 27 May 1993 BREINDL, A., 8. E. DERRICK, S. B. RODRIGUEZ AND J. L. MARTINEZ, JR. Opioidr~~tQr-dependentlong-rerm~te~iati~n at the lateralperfirant path-CA3 synapse in rat hippocampus. BRAIN RES BULL 33( 1) 17-24, 1994.-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 pertorant path-CA3 LTP induced by high-frequency stimulation. By contrast, LTP induction in medial perforant path-CA3 was not attenuated by a IO 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 indu~ion 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 Iateral 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 r~ptor-de~ndent, mechanisms of LTP induction and expression. Long-term potentiation Dentate gyrus

Hippocampus

Perforant path

Naloxone

LONG-TERM potentiation (LTP) is a long-lasting increase in synaptic efficacy that follows delivery of a brief hip-fr~uency train. LTP was first observed in the hippocampus (4) and has since been demonstrated at all synapses of the hippocampal trisynaptic circuit ( 1,3,18), as well as in various limbic structures (26) and in neocortex (28). Recently, the monosynaptic perforant path projection to area CA3 was extensively characterized (33) and this projection is reported to display LTP (34). The perforant path can be divided into a lateral and a medial component on the basis of both cytoarchitectonic (14,27) and physiological (23,24) methods. The lateral perforant path is further distinguished from its medial counterpart in that only lateral perforant path afferents contain pro-enkephalin-derived opioid peptides (12). At their dentate gyrus synapses the lateral and medial perforant path utilize distinct m~hanisms for LTP induction; induction of LTP in the lateral perforant path is blocked by antagonists of opioid receptors (5), while the induction of LTP in the medial perforant path is blocked by antagonists of the NMDA glutamate receptor (6).

Opioid receptor

CA3

However, the receptor mechanisms of LTP at the medial and lateral perforant path projections to area CA3 have not been elucidated. The aim of the present study was to determine if LTP induction in the perforant path projections to hippocampal area CA3 display sensitivity to the opioid receptor antagonist naloxone. METHOD

Subjects Adult male Sprague-Dawley rats (350-400 g, Simonsen Labs, Gilroy, CA) were housed individually in accordance with NIH guidelines, with free access to food and water, and maintained on a 12L: 12D cycle (lights on 0700 h). All animal use procedures were approved by the Animal Care and Use Committee at the University of California, Berkeley. Ex~grimen~ Design

For surgery, animals were anesthetized by IP injection of 5060 mg/kg of sodium pentobarbital; booster injections of 25-30

’ Requests tor reprints should be addressed to Brian E. Derrick, 3210 Tolman Hall, University of California, Berkeley, CA 94720.

17

BREINDL

Dentate

EPSP

of Angular

1.

.

vs.

Bundle

B

Depth Stimulation

Medial

J :m.

.

.

Perforant

Path

.. 8,m8 4

mm .

.m . . .

AA

2.6

ET AL.

3.0 Depth

.mm .m .

.

.

.

3.4 (mm)

FIG. 1.(A) Dentate EPSP versus depth of angular bundle stimulation. Plot of field EPSP slope (a) and peak amplitude (m) of responses evoked in dentate gyms as the stimulating electrode traversed the medial and lateral aspects of the angular bundle. Dorsal-ventral depths that were chosen to evoke medial or lateral perforant path-CA3 responses are denoted by arrows. (B) Representative dentate gyrus responses evoked by stimulation of medial and lateral perforant paths. Calibration: 0.5 mV, 5 msec.

mg/kg were given every hour to maintain a surgical level of anesthesia. Body temperature was maintained at 37°C with a heating pad. The head was mounted in a stereotaxic frame and skin and fascia were reflected to expose the skull. Holes were drilled through the skull 8.1 mm posterior and 4.4 mm lateral to bregma for placement of the stimulating electrode in the angular bundle, and 3.5 mm posterior and both 1.9 and 3.0 mm lateral to bregma for placement of the recording electrodes in the dentate gyrus and area CA3, respectively. For each animal, medial or lateral perforant path responses were first obtained in the dentate gyrus. When recording from the dentate granule cell layer, it is possible to distinguish field potentials elicited from the lateral versus the medial perforant path by their different rise times (24). The medial perforant path synapses are more proximal to the cell bodies of the dentate granule cells than are the lateral perforant path synapses, and thus stimulation of the medial perforant path produces larger evoked field potentials with a faster rise time than does stimulation of the lateral perforant path. While lowering the stimulating electrode, it is possible to see a transition in both the slope and time to peak of the evoked response as the electrode is moved dorsally between these two pathways in the angular bundle. It is also possible to see a similar transition in field potentials when the recording electrode is placed in the CA3 region. However, the differences are not as pronounced as they are in the dentate granule cell layer because the distance of the medial versus the lateral perforant path synapses from the current source near the CA3 pyramidal cell bodies is not as great as the distance of the medial vetsus the lateral perforant path synapses from the current source near the dentate granule cell bodies; thus, transition between the media1 and the lateral aspects of the perforant path is more obvious when observed in the dentate gyrus. The monopolar recording electrode, consisting of Tefloncoated nichrome wire (0.062 mm diameter; Medwire, Chicago, IL) was referenced to a screw in the skull. Evoked responses were amplified on a Grass P3 series AC preamplifier, filtered at

0.1 Hz to 1 KHz, digitized (10,000 Hz), and stored for off-line analysis using commercially available software (Brainwave Systems, Thornton, CO). The recording electrode was first lowered approximately 3.0 mm from the brain surface to the dentate granule cell layer while monitoring for injury-induced unit discharges in areas CA I and dentate. Evoked responses were then elicited by constant current stimulation (50-300 PA, 0.1-0.35 msec) delivered to the recording electrode by a Grass P350 stimulator through a Grass stimulus isolation unit. The stimulating electrode, comprised of twisted Teflon-coated nichrome wires, then was lowered into the angular bundle. The optimal depth for the stimulating electrode was determined by eliciting evoked potentials in the dentate granule layer while the stimulating electrode was being lowered. Both rise time (slope) and response peak were used to determine whether the medial or lateral perforant path was being stimulated. In agreement with previous reports (6,24), the field potentials we observed in the dentate gyrus showed a gradual decrease in slope and peak latency as the stimulating electrode traversed the angular bundle (See Fig. 1). The average electrode depth was 2.6 mm + 0.3 mm from the surface of the brain for the medial perforant path and 3.4 mm + 0.4 mm for the lateral perforant path. LTP was induced in only one pathway in each animal. Once a maximal medial or lateral perforant path response was found in the dentate gyrus, the recording electrode was moved to 3.5 mm AP and 3.0 mm ML and lowered approximately 3 mm into the CA3 region (25). The optimal depth coordinate for the recording electrode was determined both acoustically, by listening for the typical injury-induced unit discharges of the CA3 pyramidal cells, and visually, by observing the evoked waveforms while lowering the electrode through the cell body layer of area CA3. Moving the electrode through the hippocampus to the pyramidal layer of area CA3 gave characteristic responses: a negative field potential that was maximal between CA 1 and CA3 layers and that phase-reversed on penetration of the CA3 pyramidal layer (See Fig. 2A).

OPIOID RECEPTOR-DEPENDENT

19

LTP

A

DG Medial

Pwforant

Path

hhxd

Perforant

\

Path

C Medial

Lateral

Pet-for-ant

Perforant

path-CA3

path-CA3

PIG. 2. Representative traces ofperforant path responses evoked in area CA3 of hippocampus. (A) Laminar profile of lateral periorant path responses recorded as the e&rode was fowesedto the CA3 pyramidal ceil layer. (B) Representative responses evoked in dentate gyms (broken traces) and area CA3 (solid traces) following stimulation of medial (left) and lateral (right) perforant path. Note that the onset and the peak of the population spikes of CA3 responses precede those occurring in responses evoked in the detttate gyrus. Calibration: 0.5 Mv, 5 msec. (C) Demonstration that medial and lateral petforant path-CA3 responsesfollow high-frequency (60 Hz) stimulation. Calibration: 0.5 mV, IO msec.

Our initial studies verified the monosynaptic nature of medial and lateral perforant path-CA3 responses. Perforant path-CA3 responses had onsets of 2-3 msec and a time-to-peak of about 6 msec for the medial perforant path and 7 msec for the lateral perforant path. Perforant path-CA3 responses had onsets that were simultaneous with, or that slightiy preceded, evoked responses observed in the dentate, and perforant path-CA3 responses displayed population spikes that preceded the onset and peak of population spikes recorded in the dentate gyrus (see Fig. 2B), as observed previously in the rabbit (33). Both medial and

lateral per&rant path-CA3 responses followed hip-fr~uency trains of stimuli delivered at 50-60 Hz (See Fig. 2C). Together these data indicate that the responses we obtained were monosynaptic medial or lateral petforant path responses elicited locally in area CA3. Once characteristic responses were obtained in area CA3, the stimulating current was adjusted to give a field EPSP that was 50% of the maximum response. In all cases, the intensity necessary for eliciting a 50% maximal response was below threshold for ehciting population spikes both in area CA3 and the dentate

20

gyrus; evoked responses were elicited using this current intensity at 20 s intervals. Following collection of at least 20 min of baseline evoked responses, drug or the lactated Ringer’s vehicle was applied through a 29-gauge stainless steel cannula adjacent to the recording electrode. The tip of the electrode protruded 0.5 mm below the tip of the cannula, permitting drug delivery to the stratum radiatum/lacunosum-moleculare of the CA3 layer. One ~1 of lactated Ringer’s vehicle, or either 10 nmol naloxone or 10 nmol (+)-naloxone dissolved in 1 ~1 of vehicle, was then pressure-ejected over 5 min at a rate of 0.2 &min. Ten minutes were. allowed for the drug to disperse; during this time period evoked responses were recorded once every 20 s. Ten min after completion of drug delivery, the animal was given a conditioning train consisting of five, lOO-msec trains at a frequency of 100 Hz, with an intertrain interval of 20 s. To ensure stimulation of the minimum number of afferents necessary to achieve cooperativity, which is necessary for LTP induction in perforant path projections to the dentate (22), the stimulation intensity for the high-frequency train was increased to give a response to test pulses which was 75% of the maximal amplitude. Following delivery of the conditioning trains, evoked responses were elicited every 20 s for 1 h using the current intensity that elicited a 50% maximal response. In studies of the effect of naloxone on established perforant path LTP, 10 nmol naloxone dissolved in 1 ~1 lactated Ringer’s vehicle was applied 1 h after delivery of the conditioning trains at a rate of 0.20 &min. Evoked responses were then collected every 20 s for an additional 15 min. In the initial studies assessing the characteristics of perforant path-CA3 responses, correct stereotaxic coordinates for electrode placements were verified histologically. In subsequent drug studies, correct electrode placement was verified by stereotaxic coordinates, acoustic localization of dentate and CA3 cell layers, and characteristics of the evoked response. In addition, electrode placement was verified histologically in approximately 20% of the animals. Correct placement of the electrode in the CA3 pyramidal layer was observed in 100% of these animals. Data Analysis

To assess whether LTP induction was altered by either naloxone or (+)-naloxone, the 10% trimmed mean ( 11)of the EPSP slopes of every third responses evoked at 20-s intervals was calculated for the period between 55 and 60 min following delivery of the conditioning trains. This value was divided by the 10% trimmed mean of the five responses evoked at 60-s intervals (i.e., every third response) just prior to drug injection to give the percent change in EPSP slope that resulted from delivery of conditioning trains in the presence of drug or vehicle. The 10% trimmed mean of the slope of the five responses evoked at 60-s intervals just prior to the tetanizing train (5 min after the end of drug injection) was also divided by the mean of the preinjection slope to give the percent change in EPSP slope that resulted from drug or vehicle delivery. The effect of naloxone on established lateral perforant path-CA3 LTP was determined by comparing the trimmed mean of the EPSP slope measured between 55 and 60 min after delivery of conditioning trains with the trimmed mean of the EPSP slope measured between 5 and 10 min after application of naloxone. A comparison of treatment effects was made using an overall analysis of variance (ANOVA). Planned single-&comparisons were made using the error term of the overall analysis (17), to assess the effects of naloxone and (+)-naloxone on LTP induction in each pathway. To assess the effects of naloxone on established

BREINDL

ET AL.

lateral perforant path-CA3 LTP, the EPSP slopes measured before and after application of naloxone were compared using a dependent t test.

RESULTS

Efect oJ‘Naloxone on Evoked Medial und Lateral Pe$orant Path-CA3 Responses und LTP

Neither naloxone nor (+)-naloxone, in quantities of 10 nmol, altered significantly EPSP slopes of CA3 responses evoked by stimulation of the medial or lateral perforant path (See Table 1). Delivery of conditioning trains to the medial or lateral perforant path following application of Ringer’s vehicle resulted in LTP of the perforant path responses (See Fig. 3). By contrast, application of a 10 nmol quantity of naloxone, a quantity that we have found to block mossy fiber-CA3 LTP, attenuated significantly the increases of the EPSP slopes of lateral perforant path-CA3 responses as compared to either the Ringer’s vehicle, F( 1, 7) = 10.83, p < 0.02) or (+)-naloxone, F( 1, 7) = 8.84, p < 0.05. By contrast, the 10 nmol quantity of naloxone did not attenuate medial perforant path LTP but it produced a nonsignificant increase in the mean magnitude of medial perforant path-CA3 LTP (F(I, 7) = 0.96, p > 0.05; Figs. 4 and 5). The effect of naloxone on established lateral perforant path LTP was assessed by applying naloxone 1 h after LTP induction. The 10 nmol quantity of naloxone, which blocked induction of LTP in lateral perforant path-CA3 responses, did not change the magnitude of EPSP slopes measured between 6 and 10 min after application of naloxone (magnitude of lateral perforant path-CA3 LTP at 1 h = 32% f 4%, magnitude of LTP after delivery of naloxone = 35% f 11%; t = 0.34, p > 0.05). The time course of LTP for the l-h period following delivery of conditioning trains to Ringer’s vehicle-treated animals is shown in Fig. 3. LTP of the EPSP slopes of medial perforant path-CA3 responses develops rapidly and remains relatively stable (Fig. 3A), which is typical of LTP in NMDA receptordependent afferent systems to area CA3 (9,lO). By contrast, the EPSP slope of lateral perforant path-CA3 responses, although displaying significant initial increases following delivery of conditioning trains, evidenced a further gradual increase in evoked response magnitude over the hour following tetanization (Fig. 3B).

TABLE EFFECT

Pathway and Treatment Medial

1

OF NALOXONE ON PERFORANT EVOKED WITH LOW FREQUENCY

perforant

PATH-CA3 RESPONSES STIMULATION

B Change in EPSP Slope

n

5.20 +_ 5.3 17.00 f 10.6

5 4

2.75 +_ 5.3 4.00 + 3.10 -4.25 + 8.87

4 5 4

path

Ringer’s Naloxone (10 nmol) Lateral perforant path Ringer’s Naloxone (10 nmol) (+) Naloxone (10 nmol)

Responses were evoked using low-frequency (0.05 Hz) stimulation. Each value represents the mean (+- SEM) percent change in perforant

path-CA3 field EPSP slopes measured between 5 and 10 min following drug application. Within each pathway, no significantdifferencesin EPSP slopes following any of the experimental treatments were observed.

OPIOID RECEPTOR-DEPENDENT

21

LTP

a

a

Medial

-20

Perforant

0

40

20 Time

b

Path-CA3

Loterol

Perforont

,

,

60

(minutes)

Path-CA3

x 0

cl

160

El e

140

0 ;

120

pq

d

, -20

,

0

20 Time

,

, 40

(

, 60

(minutes)

FIG. 3. Comparison of the time course of medial (A) and lateral (B) perforant path-CA3 LTP. Each point represents the mean percent change from averaged pre-tetanization baseline of medial or lateral perforant path-CA3 responses collected at I min intervals (i.e., every third response; n = 4 for medial, n = 5 for lateral). Note that near maximal LTP develops rapidly in medial perforant path responses and remains relatively stable for at least 1 h, while LTP in the lateral perforant path continues to increase over the I h observation period. DISCUSSION

The present study indicates that the induction of LTP in lateral perforant path-CA3 responses is blocked by a 10 nmol quantity of naloxone in a stereospecific manner. By contrast, LTP induction in the medial perforant path projection to area CA3 is not attenuated by the same quantity of naloxone. Naloxone, in quantities effective in blocking the induction of lateral perforant path LTP (10 nmol), was not effective in reversing established LTP. In addition to their differential sensitivity to naloxone, lateral and medial perforant path-CA3 responses exhibit distinct time courses with respect to LTP onset. Medial perforant path synapses display potentiation that is established rapidly and remains stable for at least 1 h, whereas lateral perforant path LTP is slow to develop and continues to increase in amplitude for at least 1 h following induction.

Although it was shown previously that the perforant path projection to area CA3 displays LTP (34) these prior studies did not differentiate between lateral and medial perforant path responses. The data presented here suggest that, as for the mossy fiber-CA3 synapse, LTP induction in the enkephalinergic lateral perforant path is dependent on the activation of opioid receptors, presumably by endogenous opioid peptides. These results parallel those reported for the perforant path-dentate gyrus synapse (5,7,32). These latter two groups of investigators report that LTP of lateral but not medial perforant path-dentate gyrus responses is blocked by naloxone. In addition, as was observed in the present study at the lateral perforant path-CA3 synapse, naloxone is ineffective in reversing established LTP at lateral perforant path-dentate gyrus synapses (5).

22

BREINDL

ET AL.

0.35 A

0

E \

> A

0.25

a

10

20

30

40

50

60

70

80

90

MINUTES FIG. 4. Plot of field EPSP slopes (mV/msec) for lateral perforant path responses evoked at 1 min intervals in representative animals before and after delivery of high-frequency stimulation at 30 min. Either Ringer’s vehicle (m) or a 10 nmol quantity of naloxone (A) was applied at 20 min. The induction of LTP of lateral perforant path-CA3 responses was blocked by naloxone. Inset shows representative traces of lateral perforant path-CA3 responses 20 min before, and I h following, tetanization in an animal receiving Ringer’s vehicle.

It is possible that a single opioid receptor-mediated process may underlie LTP induction in opioidergic projections to the hippocampus. Previous studies (6) indicate that LTP of the EPSP component of lateral perforant path-dentate gyrus responses, which is sensitive to naloxone, is insensitive to the NMDA receptor antagonist AP5, suggesting that NMDA receptors do not play a role in LTP induction in this pathway. This is similar to the pattern of antagonist sensitivity observed with LTP induction at the mossy fiber-CA3 synapse, which is sensitive to the opioid receptor antagonist naloxone (9,10,2 1) but insensitive to NMDA receptor antagonists (13). These findings suggest that LTP at lateral perforant path-dentate and mossy fiber-CA3 synapses may use a similar, opioid receptordependent, mechanism for LTP induction. This mechanism also could be operative in the lateral perforant path projection to area CA3. However, mossy fiber LTP is sensitive primarily to mu opioid receptor antagonists (1 l), while LTP at the lateral perforant path-dentate synapse is sensitive to both mu (3 1) and possibly delta (7) opioid receptor antagonists. Although this could suggest that there are several opioid receptor-dependent mechanisms of LTP induction in the hippocampus, a thorough comparison of the dose-response functions for various opioid receptor-selective antagonists on lateral perforant path-dentate gyrus LTP has not been conducted. It therefore remains to be determined whether perforant path responses in both area CA3

and the dentate are preferentially blocked by mu opioid receptor antagonists, and whether LTP induction in the lateral perforant path-CA3 synapse is insensitive to NMDA receptor antagonists. The present data suggest that, in addition to their differing mechanisms of LTP induction, media1 and lateral perforant path afferents to area CA3 may use distinct mechanisms of LTP maintenance. While LTP in media1 perforant path afferents displays an immediate onset and remains relatively stable, LTP of lateral perforant path responses continues to increase for at least 1 h. That these afferents display dissimilar LTP time courses suggests that they may use distinct mechanisms of both LTP induction and LTP expression, and therefore that they may display distinct forms of LTP. Interestingly, the gradual increase in LTP observed in lateral perforant path-CA3 responses is similar to the time course of LTP development that is observed at the mossy fiber-CA3 synapse (9). By contrast, LTP at the commissural/associatiom&CA3 synapse, which is sensitive to NMDA receptor antagonists ( 13) shows a rapid and stable increase following tetanization (9). LTP in this latter pathway has a similar time course to that of LTP observed at the medial perforant path-CA3 synapse, which also is sensitive to NMDA receptor antagonists (8). These data, taken together with previous reports (9,10), suggest that the opioid receptor-dependent LTP that is observed at lateral perforant path-CA3 and mossy fiber-CA3

OPIOID

RECEPTOR-DEPENDENT

23

LTP

Medial

Latera I Perforant

60

-

40

-

20

-

Perforant

Path-CA3

Path-CA3

O0.1 Ringers

10

NLX

10 (+> NLX

(nmol)

Ringer’s

NLX (nmol)

FIG. 5. Summary of the effects of naioxone and (+)-naloxone on perforant path LTP. Each bar represents the mean percent increase in the field EPSP slope in lateral or medial perforant path-CA3 responses measured 1h following delivery of conditioning trains. Naloxone significantly blocked LTP induction in the lateral perforant path, compared to both Ringer’s vehicle and (f)-naloxone treatment. By contrast, naloxone was without effect on LTP induction in medial perforant path (*p < 0.05).

synapses may use similar mechanisms of both induction and expression. The cellular mechanisms by which opioid receptors contribute to the induction of LTP in the mossy fibers and the lateral perforant pathway are not yet known. Naloxone could block LTP induction at these synapses by several different mechanisms. For example, the opioid peptide-mediated blockade of GABAergic inhibition is suggested to facilitate postsynaptic depolarization. Because a critical level of postsynaptic depolarization is necessary for LTP induction (20), the blockade of the disinhibitory effects of endogenous opioid peptides by naloxone could prevent achievement of adequate postsynaptic depola~zation. Alternatively, if LTP at lateral perforant path synapses is similar to that observed at the mossy fiber-CA3 synapse, then it is likely that opioid receptors play another, perhaps direct, role in lateral perforant path LTP induction, because the role of opioid receptors in LTP induction at the mossy fiber-CA3 synapse appears to be independent of opioid peptide effects on GABAergic inhibition (9,10,30). Although the mechanisms by which opioid receptors contribute to LTP induction at mossy fiber-CA3 synapses are not yet known, it is suggested either that mu opioid receptors may, via presynaptic actions, contribute to calcium

influx (11 f, or that mu opioid receptors may initiate the activation of specific second messenger/protein kinase systems such as cyclic AMP (16) or protein kinase C (15) at pre- or postsynaptic sites. The opioid receptor-dependent mechanism of LTP induction is observed in at least three afferent systems to the hippocampa1 formation: the lateral perforant path projection to the dentate gyrus, the lateral perforant path projection to area CA3, and the mossy fiber projection to area CA3 (510). Opioid receptor-dependent LTP appears to be a fundamental and widespread mechanism of LTP induction within the hippocampal formation. Because the mossy fibers and the lateral perforant path together comprise the majority of the inputs relaying information originating from entorhinal cortex to the hippocampus proper, opioid receptor activation appears to be the predominant mechanism underlying LTP induction in afferent projection systems conveying information from cortex to hippocampus. In addition, several common properties are observed in the induction and expression of LTP in opioidergic afferents, including a slowly developing potentiation, a sensitivity to the opioid receptor antagonist naioxone, and, in the pathways that have been studied to date, an insensitivity to NMDA receptor antagonists. Thus the

24

BREINDL

available data suggest that a unitary, opioid receptor-dependent form of LTP is shared by opioidergic hippocampal afferents.

ET AL.

ACKNOWLEDGEMENTS

Supported by DA05374 to B. E. D., DA04195 to J. L. M. and the Rennie Fund of the University of California.

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