Formalin pain increases the concentration of serotonin and its 5-hydroxyindoleacetic acid metabolite in the CA1 region of hippocampus.

BACKGROUND AND THE PURPOSE OF THE STUDY: The hippocampal formation is involved in nociception. Prenatal serotonin depletion results in a significant decrease in the concentration of nociceptive sensitivity during the second phase of behavioral response in the formalin test. METHODS: A microdialysis probe was inserted via a guide cannula into the right CA1 region of the hippocampus. Extracellular serotonin (5HT) and its 5- hydroxyindoleacetic acid (5HIAA) metabolite overflow were collected every 10 min during the formalin test and measured by HPLC with electrochemichal detector. RESULTS: Compared to the sham group, formalin injection in the hind paw of the rat significantly increased 5HT after 10, 30, 40, and 50 min and increased 5HIAA after 10, 30, 40, 50, and 60 min collection time periods in hippocampal dialysate. (n=6 for each group at each sampling time). In the formalin treated rats serotonin and 5HIAA concentrations increased in the biphasic pattern in concert with the first and second phases of formalin pain. CONCLUSION: The hippocampal formation might be involved in the processing of nociceptive information and serotonin-related mechanisms in the hippocampus may play a role in the biphasic behavioral responses to formalin noxious stimulation.

The role of adenosine A(1) receptors in mediating the inhibitory effects of low frequency stimulation of perforant path on kindling acquisition in rats.

Low frequency stimulation (LFS) has an inhibitory effect on rapid perforant path kindling acquisition. In the present study the role of adenosine A(1) and A(2A) receptors in mediating this inhibitory effect was investigated. Rats were kindled by perforant path stimulation using rapid kindling procedures (12 stimulations per day). LFS (0.1 ms pulse duration at 1 Hz, 200 pulses, and 50-150 muA) was applied to the perforant path immediately after termination of each rapid kindling stimulation. 1,3-Dimethyl-8-cyclopenthylxanthine (CPT; 50 muM), a selective A(1) antagonist and ZM241385 (ZM, 200 muM), a selective A(2A) antagonist were daily microinjected into the lateral ventricle 5 min before kindling stimulations. LFS had an inhibitory effect on kindling development. Pretreatment of animals with CPT reduced the inhibitory effect of LFS on kindling rate and suppressed the effects of LFS on potentiation of population EPSP during kindling acquisition. In addition, CPT was able to antagonize the effects of LFS on kindling-induced increase in early (10-50 ms intervals) and late (300-1000 ms intervals) paired pulse depression. ZM pretreatment had no effect on antiepileptogenic effects of LFS in kindling acquisition. In addition, LFS prevented the kindling-induced elevation of cyclic AMP (cAMP) levels in kindled animals. Based on these results, we suggest that the antiepileptogenic effects of LFS on perforant path kindling might be mediated through activation of adenosine A(1), but not A(2A) receptors. Moreover, modulation of cAMP levels by LFS may potentially be an important mechanism which explains the anticonvulsant effects of LFS in kindled seizures.

Administration of corticosterone after memory reactivation disrupts subsequent retrieval of a contextual conditioned fear memory: dependence upon training intensity.

Reactivation of stabilized memories returns them to a labile state and causes them to undergo extinction or reconsolidation processes. Although it is well established that administration of glucocorticoids after training enhance consolidation of contextual fear memories, but their effects on post-retrieval processes are not known. In this study, we first asked whether administration of corticosterone after memory reactivation would modulate subsequent expression of memory in rats. Additionally, we examined whether this modulatory action would depend upon the strength of the memory. We also tested the effect of propranolol after memory reactivation. Adult male Wistar rats were trained in a fear conditioning system using moderate (0.4 mA) or high shock (1.5 mA) intensities. For reactivation, rats were returned to the chamber for 90 s 24h later. Immediately after reactivation, rats were injected with corticosterone (1, 3 or 10mg/kg) or vehicle. One, 7 and 14 days after memory reactivation, rats were returned to the context for 5 min, and freezing behavior was scored. The findings indicated that corticosterone when injected after memory reactivation had no significant effect on recall of a moderate memory, but it impaired recall of a strong memory at a dose of 3mg/kg. Propranolol (5mg/kg) given after the reactivation treatment produced a modest impairment that persisted over three test sessions. Further, the results showed that corticosterone, but not propranolol deficit was reversed by a reminder shock. These findings provide evidence that administration of glucocorticoids following memory reactivation reduces subsequent retrieval of strong, but not moderate, contextual conditioned fear memory likely via acceleration of memory extinction. On the other hand, propranolol-induced amnesia may result from blockade of reconsolidation process. Further studies are needed to determine the underlying mechanisms.

Offsetting of aberrations associated with seizure proneness in rat hippocampus area CA1 by theta pulse stimulation-induced activity pattern.

Epileptiform activity induces long term aberrations in hippocampal network functions. This study was conducted in pentylenetetrazol (PTZ) -kindled rats to examine offsetting of aberrations associated with seizure proneness in hippocampus area CA1 by theta pulse stimulation (TPS: 5 Hz trains for 3 min) -induced activity pattern. In hippocampal slices from both control and kindled rats, the field excitatory postsynaptic potentials (fEPSP) and population spikes (PS) were simultaneously recorded through electrodes in the apical dendrites and stratum pyramidale, respectively. The following changes in kindled vs. control slices were observed. The fEPSP needed to be greater to produce the PS recorded in the cell body layer. The fEPSP was reduced by paired stimuli whereas the PS amplitude was increased. TPS selectively depressed the PS in a lasting fashion, and shifted the fEPSP slope and the PS amplitude relation toward what was observed in controls. Both the fEPSP and PS were increased by paired stimuli at 60 min after TPS application. The lasting depressive effect of TPS on the PS amplitude was converted into facilitation by adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (CPX). Potentiation of the PS amplitude by TPS in the presence of CPX was blocked by an N-methyl-d-aspartate receptor antagonist AP5. We hypothesize that the extracellular adenosine spillover, acting through adenosine A1 receptors, during TPS-induced activity pattern could trigger a homeostatic process for correcting network imbalances caused by epileptiform activity.

Naloxone improves impairment of spatial performance induced by pentylenetetrazol kindling in rats.

The role of endogenous opioid peptides in impairment of spatial performance due to epileptogenesis was examined. Animals were kindled by repeated injections of pentylenetetrazol (PTZ) (40 mg/kg, i.p.) in the presence or absence of the opioid receptor antagonist naloxone. Naloxone in different doses (1, 5 and 10 mg/kg, i.p.) was applied 30 min before each PTZ injection. Behavioral testing was assessed 24 h and 10 days after the last injection in separate groups of animals using Morris water maze. Our results showed that PTZ-induced kindling produced a significant impairment of spatial learning and memory as compared with controls and this effect was not due to the aftereffect of repeated seizures. Naloxone pretreatment in the course of kindling had no effect on seizures development, however it caused an improvement of spatial learning and memory performance in kindled rats. It is likely that the long-lasting changes in neuronal responsiveness associated with kindling led to a defect in the processing of spatial information. These data suggest that endogenous opioid peptides released in the hippocampus during kindling are at least in part responsible for impairment of spatial performance in kindled animals.

The role of galanin receptors in anticonvulsant effects of low-frequency stimulation in perforant path-kindled rats.

Low-frequency stimulation (LFS) has antiepileptogenic effects on kindled seizures. In the present study, the role of galanin receptors in the inhibitory effect of LFS on perforant path kindling acquisition was investigated in rats. Animals were kindled by perforant path stimulation in a rapid kindling manner (six stimulations per day). LFS (0.1 ms pulses at 1 Hz, 600 pulses, and 80-150 microA) was applied immediately after termination of each kindling stimulation. M35 (0.5 and 1.0 nM per site), a nonselective galanin receptor antagonist and M871 (1.0 microM per site), a selective galanin receptor type 2 (GalR2) antagonist, were daily microinjected into the dentate gyrus before starting the stimulation protocol. The expression of GalR2 in the dentate gyrus was also investigated using semi-quantitative RT-PCR. Application of LFS significantly retarded the kindling acquisition and delayed the expression of different kindled seizure stages. In addition, LFS significantly reduced the increment of daily afterdischarge duration during kindling development. Intra-dentate gyrus microinjection of both M35 and M871 significantly prevented the inhibitory effects of LFS on kindling parameters. During the focal kindled seizure stages (1-3) M871 had no significant effect. However, during generalized seizure stages (4 and 5), M871 had the same effect as M35. Semi-quantitative RT-PCR also showed that after kindling acquisition, the GalR2 mRNA level decreased in the dentate gyrus but application of LFS prevented this decrease. Obtained results show that activation of galanin receptors by endogenous galanin has a role in mediating the inhibitory effect of LFS on perforant path-kindled seizures. This role is exerted through GalR1 during focal- and through GalR2 during generalized-kindled seizures.

Microinjection of ritanserin into the dorsal hippocampal CA1 and dentate gyrus decrease nociceptive behavior in adult male rat.

Prenatal 5HT depletion causes a significant decrease in the level of nociceptive sensitivity during the second phase of the formalin test behavioral response. These experiments were designed to test whether blocking 5HT2A/2c receptors in the CA1 region of the hippocampus and dentate gyrus would decrease nociceptive behaviors induced by a peripheral noxious stimulus formalin as an animal model of unremitting human being. The 5HT2A/2c receptor antagonist ritanserin (2, 4 and 8 microg/0.5 microl) was injected into the CA1 area and dentate gyrus of behaving rats 5 min before subcutaneous injection of formalin irritant. Nociceptive behaviors in both phases of the formalin test were significantly decreased by ritanserin (4 and 8 microg/0.5 microl) and ritanserin had no effect at 2 microg/0.5 microl. These results support the hypothesis that the hippocampal formation may modify the processing of incoming nociceptive information and that 5HT2A/2c receptor-sensitive mechanisms in the hippocampus may play a role in nociception and/or the expression of related behaviors.

Oct4 transcription factor in conjunction with valproic acid accelerates myelin repair in demyelinated optic chiasm in mice.

Multiple sclerosis is a demyelinating disease with severe neurological symptoms due to blockage of signal conduction in affected axons. Spontaneous remyelination via endogenous progenitors is limited and eventually fails. Recent reports showed that forced expression of some transcription factors within the brain converted somatic cells to neural progenitors and neuroblasts. Here, we report the effect of valproic acid (VPA) along with forced expression of Oct4 transcription factor on lysolecithin (LPC)-induced experimental demyelination. Mice were gavaged with VPA for one week, and then inducible Oct4 expressing lentiviral particles were injected into the lateral ventricle. After one-week induction of Oct4, LPC was injected into the optic chiasm. Functional remyelination was assessed by visual-evoked potential (VEP) recording. Myelination level was studied using FluoroMyelin staining and immunohistofluorescent (IHF) against proteolipid protein (PLP). IHF was also performed to detect Oct4 and SSEA1 as pluripotency markers and Olig2, Sox10, CNPase and PDGFRα as oligodendrocyte lineage markers. One week after injection of Oct4 expressing vector, pluripotency markers SSEA1 and Oct4 were detected in the rims of the 3rd ventricle. LPC injection caused extensive demyelination and significantly delayed the latency of VEP wave. Animals pre-treated with VPA+Oct4 expressing vector, showed faster recovery in the VEP latency and enhanced myelination. Immunostaining against oligodendrocyte lineage markers showed an increased number of Sox10+ and myelinating cells. Moreover, transdifferentiation of some Oct4-transfected cells (GFP+ cells) to Olig2+ and CNPase+ cells was confirmed by immunostaining. One-week administration of VPA followed by one-week forced expression of Oct4 enhanced myelination by converting transduced cells to myelinating oligodendrocytes. This finding seems promising for enhancing myelin repair within the adult brains.

Epileptogenic insult causes a shift in the form of long-term potentiation expression.

The relationship between epilepsy, modeled here by pentylenetetrazol kindling, and learning deficits, modeled here by long-term potentiation (LTP), was studied. The field excitatory postsynaptic potentials and population spikes (PS) were recorded from strata radiatum and pyramidale, respectively, in urethane-anesthetized rat dorsal hippocampus CA1 area upon stimulation of Schaffer collaterals. To induce LTP, a 100 Hz primed-burst stimulation protocol was used. Experiments were carried out at approximately 30 days after the last pentylenetetrazol dose. The effects of voltage dependent calcium channel blocker verapamil and N-methyl-D-aspartate receptor antagonist MK-801 on LTP expression were examined. Tetanic stimulation elicited both field excitatory postsynaptic potential LTP and PS LTP in control animals, and LTP-induction of the PS in control animals was attenuated by MK-801, but not by verapamil. By contrast, kindled rats showed LTP of the PS only. MK-801 reduced the extent of potentiation of PS amplitude and verapamil inhibited the PS amplitude potentiation, completely. The results suggest that seizure induction modifies mechanisms underlying LTP induction and causes a shift in the form of LTP expression. The pentylenetetrazol-kindling-induced increase in PS LTP is sensitive to verapamil and not to MK-801 and therefore primarily dependent on activation of voltage dependent calcium channels rather N-methyl-D-aspartate receptors. Kindling may lead to a shift in synaptic plasticity thresholds much like the shift that occurs during aging, and such alterations may contribute to deficits in learning and memory.

Responsiveness of vascular alpha1-adrenoceptors of diabetic rat knee joint to phenylephrine in acute inflammation.

In diabetic angiopathy, responsiveness of alphal-adrenoceptors in blood vessels increases. The aim of this study was to investigate the vasoconstrictor response of knee joint blood vessels to phenylephrine (a 1-adrenoceptor agonist) in diabetes and acute inflammation. Acute knee joint inflammation was induced by the intraarticular injection of a 3% kaolin/3% carrageenan suspension. Diabetes was induced by the intravenous injection of alloxan (70 mg/kg). Male albino rats weighing 70 to 90 g each were divided into the following 4 groups: untreated controls, diabetic, inflammatory, and diabetic inflammatory. The blood flow of the knee joint was measured using the laser Doppler flowmetry (LDF) technique. Vasoconstriction of the articular microvascular was measured in response to the topical application of different concentrations (10(-7) to 10(-3) mol) phenylephrine. The results of this study show that (a) increased knee joint diameter and circumference due to inflammation and the knee joint basal blood flow were significantly lower in diabetic than in control rats; (b) the responsiveness of alphal-adrenoceptors decreased in kaolin/carrageenan-induced acute inflammation; (c) carrageenan-induced acute inflammation did not decrease the responsiveness of alphal-adrenoceptors in diabetic rats. We conclude that diabetes inhibits the reductive effect of acute inflammation on the responsiveness of alpha1-adrenoceptors in rats.

Do Ca2+ channels share NMDA receptors in plasticity of synaptic transmission in the rat visual cortex?

We examined the involvement of Ca2+ channels in LTP of responses in rat visual cortex slices. Stimulating layer IV, field potentials including EPSP1 and EPSP2 from layer II/III were recorded. L-type Ca2+ channel blocker nifedipine did not have a considerable effect on LTP of the responses. T-type Ca2+ channel blocker Ni2+ decreased potentiation of EPSP1 and almost blocked that of EPSP2. Effect of visual experience on the function of the channels is also considered. These results indicate that T-type Ca2+ channels play a real role in stable LTP of EPSP2. Also the function of the channels was almost the same in dark and light reared visual cortices.

Differential effect of dark rearing on long-term potentiation induced by layer IV and white matter stimulation in rat visual cortex.

In the earlier work, we showed that primed-burst stimulation (PBs) is an effective protocol to induce long-term potentiation (LTP) in layer II/III of adult rat visual cortex in vitro. In the present study, we investigated effects of dark rearing on potentiation of layer II/III responses to stimulation of layer IV or the underlying white matter in the visual cortex in vitro. Long-term potentiation was induced by PBs applied to white matter or layer IV of the cortex in light and dark reared rats. Regardless of the stimulation site, layer II/III field potentials consisted of two components. In general, the latency of responses in dark reared rats was shorter than that in light reared ones. Whereas PBs of layer IV produced LTP of two components in both the groups, that of white matter induced an appreciable potentiation of the second component in both groups and the first component only in dark reared rats. These results indicate that PBs of either white matter or layer IV can gain access to the modifiable synapses that are related to the second component of layer II/III responses in light and dark reared visual cortex, but accessibility of the modifiable synapses that are related to first component depends on the tetanization site. The dark rearing enhances accessibility of the modifiable synapses that are related to the first component following PBs of the white matter. It is suggested that the immaturity of inhibitory circuits and/or better function of excitatory ones in the visual cortex of dark reared rats may contribute to the enhanced accessibility of the first component.

The ability of hippocampal CA1 area for induction of long-term potentiation is persistently reduced by prior treatment with cysteamine: an in vitro study.

Using field potential recording in the CA1 region of hippocampal slices from rats injected with cysteamine (200 mg/kg, s.c.), changes in activity and plasticity of Schaffer collateral-CA1 pyramidal cell synapses were examined. Extracellular field potential recording prior to and following either theta-pattern primed bursts (PBs), perfusion with low Mg(2+) or with high Ca(2+), indicated long-term potentiation (LTP) of population spikes amplitude (PSA). The extent of LTP of PSA was significantly lower in cysteamine-treated rats. It is concluded that cysteamine can entail lasting modifications in susceptibility of hippocampal CA1 for synaptic plasticity induced by tetanus. Similarly, disability in function of CA1 synapses can be traced by other protocols of LTP induction. The relevancy of the results to the facilitatory role of endogenous somatostatin in the function of Schaffer collateral-CA1 pyramidal cell synapses is also discussed.

Long-term potentiation as an electrophysiological assay for morphine dependence and withdrawal in rats: an in vitro study.

Using a long-term potentiation (LTP) method, we attempted to establish an electrophysiological assay for morphine dependence and withdrawal in rats in vitro. The field excitatory postsynaptic potential (fEPSP) and orthodromic population spikes (OPS) were recorded from stratums radiatum and pyramidale, respectively, of area CA1 following stimulation of Schaffer collaterals in control and morphine-dependent slices. To induce LTP, a 100 Hz primed-burst stimulation protocol was used. Although morphine exposure had excitatory effects on control slices, namely, an increase in the amplitude of primary population spikes (PSs) and appearance of extra PSs, slices taken from dependent rats demonstrated tolerance to morphine. LTP of the fEPSP was not changed in slices from dependent animals although dependent slices did show an enhanced OPS LTP compared to control ones, which was attenuated by morphine exposure. In the presence of morphine, naloxone caused a withdrawal phenomenon; apparent as a robust enhanced OPS LTP in dependent slices. So we propose morphine-naloxone withdrawn slices as a suitable in vitro withdrawal-like model. Such an in vitro preparation could provide a convenient practical experimental tool for examination of the probable molecular and cellular mechanisms involved in withdrawal states.

Morphine tolerance and dependence in the nucleus paragigantocellularis: single unit recording study in vivo.

In this study, a single unit activity was recorded in the nucleus paragigantocellularis (PGi), located in the rostral ventrolateral medulla of anesthetized, morphine-dependent rats. The spontaneous activity of PGi neurons was significantly decreased by administration of morphine (10 mg/kg; i.p.) in sham-operated, control and morphine-dependent rats. However, in PGi neurons of morphine-dependent rats, the firing rate decreased significantly less than those of sham-operated and control ones. There was also significant enhancement of spontaneous activity of PGi neurons for 30 min following administration of naloxone (2 mg/kg; s.c.) in morphine-dependent rats as an opiate withdrawal-induced activation of PGi neurons. The results indicated the occurrence of morphine tolerance and dependence in the PGi and/or elsewhere which appeared in PGi unit activity. The findings are consistent with the hypothesis that during morphine withdrawal, there is an increase in unit activity of the PGi afferents to the nucleus locus coeruleus (LC) or an increased release of excitatory transmitter from their nerve terminals in the LC.

Examination of persistent effects of repeated administration of pentylenetetrazol on rat hippocampal CA1: evidence from in vitro study on hippocampal slices.

The early and long-lasting effects of pentylenetetrazol-kindling on hippocampal CA1 synaptic transmission were investigated. Experiments were carried out in the hippocampal slices from control and kindled rats at two post-kindling periods, i.e. 48-144 h (early phase) and 30-33 days (long-lasting phase). Field potentials, i.e. population excitatory postsynaptic potential (pEPSP) and population spike (PS) were recorded at the stratum pyramidale following stimulation of the stratum radiatum. Kindling-induced changes in synaptic transmission were assessed by stimulus-response functions and paired-pulse responses. The results showed that 48-144 h after kindling, the PS amplitude in the CA1 of kindled slices enhanced, and a second PS appeared compared to control slices. But at 30-33 days after kindling, the pEPSP slope in the CA1 of kindled slices enhanced without any change in the PS compared with those in the control slices. Evaluation of paired-pulse responses showed a significant reduction in paired-pulse inhibition for PS 48-144 h after kindling and a significant increase in paired-pulse inhibition for pEPSP 30-33 days after kindling. Our results suggest that pentylenetetrazol-kindling is accompanied by enhanced excitability and a reduction of paired-pulse inhibition in hippocampal CA1. The increased paired-pulse inhibition one month after kindling, may be interpreted as an adaptive process to cope with subsequent seizures.

Chronic in vivo morphine administration facilitates primed-bursts-induced long-term potentiation of Schaffer collateral-CA1 synapses in hippocampal slices in vitro.

In this study, the effects of chronic morphine administration (20-30 days) on long-term potentiation (LTP) were investigated at the Schaffer collateral-CA1 pyramidal cell synapses of the rat hippocampal slices. Orthodromic population spike (OPS) amplitude and delay (peak latency) were measured as indices of increase in synaptic efficacy. The amounts of LTP of OPS delay and LTP of OPS amplitude were higher in slices from dependent rats. Perfusion of slices from control and dependent rats with morphine containing ACSF and delivering tetanic stimulation, showed that short-term presence of morphine could not mimic the LTP enhancing effects of chronic morphine administration, however, attenuated the amount of LTP of OPS amplitude in slices of dependent rats. This study supports the hypothesis that the susceptibility of CA1 synapses to plastic changes increases by chronic, not acute exposure to morphine and suggests that a withdrawal phenomenon might be an underlying mechanism for the observed augmented LTP of OPS amplitude in slices of dependent rats.

Repeated administration of pentylenetetrazol alters susceptibility of rat hippocampus to primed-burst stimulation: evidence from in vitro study on CA1 of hippocampal slices.

The effectiveness of theta pattern primed-bursts (PBs) on development of primed-burst (PB) potentiation was investigated in hippocampal CA1 of pentylenetetrazol-kindled rats. Experiments were carried out in the hippocampal slices from control and kindled rats at two post-kindling periods, i.e., 48-144 h (early phase) and 30-33 days (long-lasting phase). Field potentials (population excitatory post-synaptic potential, pEPSP) were recorded at stratum radiatum following stimulation of the stratum fibers. theta pattern primed-bursts were delivered to stratum radiatum and PB potentiation was assessed. The results showed that 48-144 h after kindling, PB potentiation in CA1 of kindled slices is significantly greater than control slices. In contrast, 30, 33 days after kindling PB potentiation was not observed and the pEPSP slope was depressed after PBs delivery, which lasted at least 60 min. Our results suggest that shortly after kindling, PB potentiation can be more readily induced while one month later, it is more difficult ot elicit. These findings may help to explain the behavioral deficits seen with the kindling model of epilepsy.

Intraperitoneal and intraamygdala N(6)-cyclohexyladenosine suppress hippocampal kindled seizures in rats.

Effects of intraperitoneal and intraamygdala N(6)-cyclohexyladenosine (CHA), a selective adenosine A(1) receptor agonist, and 1,3-dimethyl-8-cyclopentylxanthine (CPT), a selective adenosine A(1) receptor antagonist, were examined in fully hippocampal kindled rats. Intraperitoneal administration of CHA (0. 25, 0.5 and 1 mg/kg) decreased hippocampal secondary afterdischarge duration (SAD) and amygdala afterdischarge duration (ADD). Only the 1 mg/kg dose induced a significant increase in latency to stage 4. Intraperitoneal administration of CPT (0.25, 0.5 and 1 mg/kg) induced a significant increase in stage 5 duration, hippocampal SAD and ADD. Pretreatment of animals with CPT (1 mg/kg), antagonized effects of CHA on seizure parameters. Intraamygdala microinfusion (1 microl over 2 min) of CHA (5 nM-1 mM) significantly reduced hippocampal SAD and amygdala ADD. These effects were antagonized by intraamygdala CPT (1 microM). Results obtained suggest that in hippocampal kindled rats, amygdala may be regarded as a relay point for AD propagation specially in recruit activity of the hippocampus.

Augmentation of LTP induced by primed-bursts tetanic stimulation in hippocampal CA1 area of morphine dependent rats.

The effects of chronic morphine administration on the development of Long-term potentiation (LTP) were investigated at the Schaffer collateral-CA1 pyramidal cell synapses of the rat hippocampal slices using primed-bursts tetanic stimulation. Significant enhancement of orthodromic population spike (OPS) was found for all stimulus intensities after tetanic stimulation. OPS enhancement was greatest when tested with low to mid-range stimulus intensities (25 and 50 microA). There was also significant decrease in OPS delay. These responses were similar in slices from both control and morphine dependent rats. At all delivered stimulus intensities, the amount of LTP of OPS in slices from dependent rats was larger than that of control slices. However, these differences in LTP of OPS were significant at low stimulus intensities. These findings suggest that chronic morphine administration had induced changes in CA1 neurocircuitry which modulated synaptic plasticity during high frequency stimulation and appeared as augmented LTP.