CA1 Long-term Potentiation Research Articles

Cholinergic Activity Enhances Hippocampal Long-Term Potentiation in CA1 during Walking in Rats

Long-term potentiation (LTP) at the basal-dendritic synapses of CA1 pyramidal cells was induced by a single 200 Hz stimulation train (0.5-1 sec duration) in freely behaving rats during one of four behavioral states: awake-immobility (IMM), walking, slow-wave sleep (SWS), and rapid eye movement sleep (REM). Field EPSPs generated by basal-dendritic excitation of CA1 were recorded before and up to 1 d after the tetanus. After a tetanus during any behavioral state, basal-dendritic LTP was >170% of the baseline for the first hour after the tetanus and decayed to approximately 120% 1 d after. LTP induced during walking was significantly larger than that induced during IMM, SWS, or REM, which had similar LTP magnitudes. To test the hypothesis that septohippocampal cholinergic activity enhanced LTP during walking as compared with IMM, rats were either pretreated with muscarinic cholinergic antagonist scopolamine or injected with IgG192-saporin in the medial septum to selectively lesion cholinergic septohippocampal neurons. Pretreatment with scopolamine decreased the LTP induced during walking but did not affect that induced during IMM, such that the difference between the LTP induced during walking and IMM was abolished after scopolamine. Rats injected with IgG192-saporin showed no difference in the LTP induced during walking and IMM, and scopolamine did not reduce the LTP during walking. In contrast, sham-lesion rats showed larger LTP induced during walking than IMM, and the LTP induced during walking was attenuated by scopolamine. This is the first demonstration of an enhancement of hippocampal LTP by physiologically activated cholinergic inputs.

Modification of hippocampal neurogenesis and neuroplasticity by social environments

Synaptic plasticity and neurogenesis in the brain are affected by environmental stimuli. The present study was designed to investigate the effects of social environments on learning and memory, neurogenesis, and neuroplasticity. Twenty-two-day-old rats were housed in isolation or in groups for 4 or 8 weeks and injected intraperitoneally with bromodeoxyuridine to detect proliferation among progenitor cells. The animals were also tested for learning in a water maze and for hippocampal CA1 long-term potentiation in vivo and in vitro. The results show that the number of newborn neurons in the dentate gyrus and the learning in a water maze decreased significantly in rats reared in isolation for 4 or 8 weeks, as compared with grouped controls. Induction of long-term potentiation in the CA1 area of rat hippocampus in vivo and in vitro was also significantly reduced by isolation. Furthermore, the effects of isolation rearing on spatial learning, hippocampal neurogenesis, and long-term potentiation could be reversed by subsequent group rearing. These findings demonstrated that social environments can modify neurogenesis and synaptic plasticity in adult hippocampal regions, which is associated with alterations in spatial learning and memory.

Two organizational effects of pubertal testosterone in male rats: transient social memory and a shift away from long-term potentiation following a tetanus in hippocampal CA1

The organizational role of pubertal androgen receptor (AR) activation in synaptic plasticity in hippocampal CA1 and in social memory was assessed. Earlier data suggest pubertal testosterone reduces adult hippocampal synaptic plasticity. Four groups were created following gonadectomy at the onset of puberty: rats given testosterone; rats given testosterone but with the AR antagonist flutamide, present during puberty; rats given testosterone at the end of puberty; and rats given cholesterol at the end of puberty. A tetanus normally inducing long-term potentiation (LTP) was used to stimulate CA1 in the urethane-anesthetized adults during the dark phase of their cycle. Social memory was assessed prior to electrophysiology. Social memory for a juvenile rat at 120 min was seen only in rats not exposed to AR activation during puberty. Pubertal AR activation may induce the reduced social memory of male rats. Early CA1 LTP occurred following tetanus in rats with no pubertal testosterone. Short-term potentiation occurred in rats exposed to pubertal testosterone. Unexpectedly, rats with pubertal AR activation developed long-term depression (LTD). The same pattern was seen in normal male rats. Lack of LTP during the dark phase is consistent with other data on circadian modulation of CA1 LTP. No correlations were seen among social memory scores and CA1 plasticity measures. These data argue for two organizational effects of pubertal testosterone: (1) CA1 synaptic plasticity shifts away from potentiation toward depression; (2) social memory is reduced. Enduring effects of pubertal androgen on limbic circuits may contribute to reorganized behaviors in the postpubertal period.

Activation of PI3-Kinase Is Required for AMPA Receptor Insertion during LTP of mEPSCs in Cultured Hippocampal Neurons

Hippocampal CA1 homosynaptic long-term potentiation (LTP) is expressed specifically at activated synapses. Increased insertion of postsynaptic α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs) appears to be crucial for CA1 LTP. However, the mechanism underlying AMPAR insertion during LTP remains largely unknown. We now report that phosphatidylinositol 3-kinase (PI3K) is complexed with AMPARs at synapses and activated by selective stimulation of synaptic N-methyl-D-aspartate (NMDA) receptors. Activation of the AMPAR-associated PI3K is required for the increased cell surface expression of AMPARs and LTP. Thus, our results strongly suggest that the AMPAR-PI3K complex may constitute a critical molecular signal responsible for AMPAR insertion at activated CA1 synapses during LTP, and consequently, this lipid kinase may serve to determine the polarity of NMDA receptor-dependent synaptic plasticity.

The transient depression of hippocampal CA1 LTP induced by chronic intermittent ethanol exposure is associated with an inhibition of the MAP kinase pathway.

Using electrophysiological and biochemical approaches, we investigated the effects of chronic, intermittent ethanol (CIE) treatment on activation of the mitogen activated protein kinase (MAPK), also known as extracellular signal regulated protein kinase 1 and 2. In hippocampal slices taken from control rats, brief high-frequency stimulation to Schaffer collateral fibers induced a large post-tetanic potentiation (PTP) in the CA1 region that decayed to stable long-term potentiation (LTP) of field extracellular postsynaptic potentials. Western blot analyses showed that phosphorylation of MAPK was increased during PTP and returned to baseline levels during LTP. In slices from the rats removed immediately from CIE treatment, PTP and MAPK activation during the PTP was significantly less than that observed in control slices and LTP was absent. In slices from rats subjected to 1 day withdrawal from CIE treatment, both the reduction in MAPK phosphorylation during PTP and the impairment of PTP and LTP were still evident. Recovery of PTP and partial recovery of LTP was observed in slices obtained from 5-day withdrawn rats. However, MAPK activation during PTP was still attenuated significantly. Interestingly, MAPK activation was enhanced significantly during LTP in 5-day withdrawn rats as well as the sensitivity to MAPK inhibitor PD 098059. In addition to these changes in HFS-induced MAPK activation, we also observed a significant reduction in the basal phosphorylation of MAPK in slices removed from rats immediately after CIE treatment. These results implicate the MAPK signal transduction pathway as a potential cellular target of ethanol. Alterations in MAPKs could play an important role in the alcohol-induced changes in synaptic plasticity associated with the effects of alcohol abuse on learning and memory processes.

Inhibition of l-type voltage dependent calcium channels causes impairment of long-term potentiation in the hippocampal CA1 region in vivo

Long-term potentiation (LTP), in the hippocampal CA1 region is dependent on postsynaptic calcium influx. It is generally accepted that calcium influx occurs via activation of the NMDA receptor channel complex. However, studies in vitro using a high-frequency stimulus protocol (≥200 Hz) demonstrated previously an NMDA receptor-independent form of LTP that is dependent upon activation of L-type voltage-dependent calcium channels (VDCCs). Here we have investigated a role for L-type VDCCs in LTP in vivo. Two structurally different, L-type VDCC blockers, verapamil (1, 3 and 10 mg/kg) and diltiazem (1, 10 and 20 mg/kg), depressed the induction of LTP in a dose-dependent manner. Increased activation of L-type VDCCs by Bay K 8644, an L-type agonist, however, did not enhance LTP. The NMDA receptor antagonist d-AP5 (5 and 20 mM injected i.c.v) impaired, but failed to block fully LTP in vivo. A reduced level of LTP could still be recorded following co-administration of verapamil and d-AP5. The level of LTP recorded was similar to that observed in the presence of either verapamil (10 mg/kg) or d-AP5 alone. These results suggest that activation of the NMDA receptor/channel and L-type VDCCs are involved in the induction of LTP in area CA1 in vivo. However, it appears that activation of other receptor/channels may also play a role in this form of LTP.

Adenylyl cyclase-dependent form of chemical long-term potentiation triggers translational regulation at the elongation step

The persistent maintenance of long-term potentiation requires both messenger RNA and protein synthesis. While there is mounting evidence for an active role of protein synthesis in hippocampal long-term potentiation, the nature of mechanisms underlying its regulation has not yet been established. We used a previously described chemical long-term potentiation protocol [J Neurosci 19 (1999) 2500] to address the hypothesis that signaling mechanisms, involved in long-lasting long-term potentiation, directly regulate protein synthesis. Chemical long-term potentiation is an N-methyl- d-aspartate receptor-dependent form of plasticity, which relies on both synaptic activity, in the form of spontaneous bursting induced by high concentrations of K + and Ca 2+, and cyclic AMP/adenylyl cyclase signaling. We found that chemical long-term potentiation in CA1 of the mouse hippocampus lasts for at least 3 hours and requires both messenger RNA and protein synthesis. However, surprisingly de novo total protein synthesis was paradoxically decreased at 1 hour after long-term potentiation induction. Consistent with the decrease in total protein synthesis in potentiated CA1, phosphorylation of eukaryotic elongation factor 2 was increased and is likely responsible for inhibition of translation at the elongation step. Increased phosphorylation of eukaryotic elongation factor 2 was dependent on coincident cyclic AMP/adenylyl cyclase activation and synaptic activity and required N-methyl- d-aspartate receptor activation. Despite the inhibition in total protein synthesis, the level of the immediate early gene protein Arc (activity regulated cytoskeleton-associated protein) increased at 1 hour after chemical long-term potentiation induction. Taken together, the results suggest that regulation at the elongation step of protein synthesis contributes to persistent forms of long-term potentiation.

Nicotine enhances the depressive actions of A beta 1-40 on long-term potentiation in the rat hippocampal CA1 region in vivo.

Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity used as a cellular model of memory. Beta amyloid (A beta) is involved in Alzheimer's disease (AD), a neurode-generative disorder leading to cognitive deficits. Nicotine is also claimed to act as a cognitive enhancer. A beta is known to bind with high affinity to the alpha 7-nicotinic acetylcholine receptor (nAChR). Here we have investigated the effect of intracerebroventricular (i.c.v.) injection of the endogenous peptide A beta 1-40 on LTP in area CA1 of urethananesthetized rats. We also examined the effect of A beta 12-28 (i.c.v.), which binds with high affinity to the alpha 7-nAChR and the specific alpha 7-nAChR antagonist methyllycaconitine (MLA) on LTP. We found that A beta 12-28 had no effect on LTP, whereas MLA depressed significantly LTP, suggesting that activation of the alpha 7-nAChR is a requirement for LTP. Within the in vivo environment, where other factors may compete with A beta 12-28 for binding to alpha 7-nAChR, it does not appear to modulate LTP. To determine if the depressive action of A beta 1-40 on LTP could be modulated by nicotine, these agents were also co-applied. Injection of 1 or 10 nmol A beta 1-40 caused a significant depression of LTP, whereas nicotine alone (3 mg/kg) had no effect on LTP. Co-injection of nicotine with A beta 1-40 1 h prior to LTP induction caused a further significant depression of LTP compared with A beta 1-40 alone. These results demonstrate that nicotine enhances the deficit in LTP produced by A beta 1-40. This then suggests that nicotine may exacerbate the depressive actions of A beta on synaptic plasticity in AD.

B-adrenergic modulation of in vivo long-term potentiation in area CA1 and its role in spatial learning in rats

Activation of beta-adrenoceptors in area CA1 of the hippocampus facilitates in vitro long-term potentiation (LTP) in this region. However, it is unclear if in vivo LTP in area CA1 and hippocampus-dependent learning are subjected to beta-adrenergic regulation. To address this question, we investigated the effects of the beta-adrenergic agonist L-isoproterenol or antagonist DL-propranolol on in vivo LTP of area CA1 and the spatial learning in Morris water maze. In the presence of L-isoproterenol (through local infusion into area CA1), the theta-pulse stimulation with the parameter of 10 Hz, 150 pulses/train, 1 train, a frequency weakly modifying synaptic strength, induced a robust LTP, and this effect was blocked when DL-propranolol was co-administered. By contrast, the theta-pulse stimulation with the parameter of 5 Hz, 150 pulses/train, 3 trains, a frequency strongly modifying synaptic strength, induced a significantly smaller LTP when DL-propranolol was administered into area CA1. Accordingly, DL-propranolol impaired the spatial learning in the water maze when infused into area CA1 20 min pretraining. Compared with control rats, the DL-propranolol-treated rats showed significantly slower learning in the water maze and subsequently exhibited poor memory retention at 24-h test. These results suggest that beta-adrenoceptors in area CA1 are involved in regulating in vivo synaptic plasticity of this area and are important for spatial learning.

Dependence on morphine leads to a prominent sharing among the different mechanisms of long-term potentiation in the CA1 region of rat hippocampus

Here, we examined chronic exposure to morphine to determine if this treatment shifted LTP mechanism in the CA1 field in vitro. Long-term potentiation (LTP) of population spikes induced by a 200 Hz θ pattern primed bursts (PBs) stimulation. Verapamil was used to isolate NMDA-dependent LTP. In control slices, a 200 Hz tetanus induced a compound potentiation, consisted of two pharmacologically separable components: nmdaLTP and vdccLTP. LTP in slices taken from morphine dependent rats was completely abolished by either APV or verapamil. These data suggest that morphine dependence in rats does not interfere with the induction and maintenance of hippocampal CA1 LTP. While in control rats both NMDA and voltage-dependent Ca 2+ channel (VDCC) antagonists must have been used concurrently to prevent the induction of LTP, in morphine-dependent rats, each of the antagonist could prevent the LTP induction suggesting a tighter coupling between these two calcium influx regulating processes.

Role for P2X Receptors in Long-Term Potentiation

ATP receptors participate in synaptic transmission and intracellular calcium signaling in the hippocampus by providing a component of the excitatory input to CA1 pyramidal neurons. The activation of P2X purinoreceptors generates calcium influx that does not require cell depolarization, but this response desensitizes at increased rates of stimulation. Here we show that inhibition of P2X receptors dramatically facilitates the induction of long-term potentiation (LTP). High-frequency stimulation (HFS) (1 sec) induced LTP in CA1, whereas brief HFS (0.2 sec) caused only short-term potentiation. However, when P2X receptors were inhibited by PPADS (pyridoxal phosphate-6-azophenyl-2'-4'-disulphonic acid) or desensitized by the nonhydrolyzable ATP analog alpha,beta-methyleneATP, brief HFS reliably induced LTP. Inhibition of P2X receptors had no facilitatory effect on LTP when NMDA receptors were blocked. We hypothesized that P2X receptors affect the threshold for LTP by altering Ca2+-dependent inactivation of NMDA receptors. In isolated pyramidal CA1 neurons and hippocampal slices, activation of P2X receptors did cause inhibition of NMDA receptor-mediated current. We suggest that, by controlling the background calcium and thus the activity of NMDA receptors at low firing frequencies, P2X receptors act as a dynamic low-frequency filter so that weak stimuli do not induce LTP.

Reelin and ApoE Receptors Cooperate to Enhance Hippocampal Synaptic Plasticity and Learning

Two apolipoprotein E (apoE) receptors, the very low density lipoprotein (VLDL) receptor and apoE receptor 2 (apoER2), are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. In the adult brain, Reelin is expressed by GABA-ergic interneurons, suggesting a potential function as a modulator of neurotransmission. ApoE receptors have been indirectly implicated in memory and neurodegenerative disorders because their ligand, apoE, is genetically associated with Alzheimer disease. We have used knockout mice to investigate the role of Reelin and its receptors in cognition and synaptic plasticity. Mice lacking either the VLDL receptor or the apoER2 show contextual fear conditioning deficits. VLDL receptor-deficient mice also have a moderate defect in long term potentiation (LTP), and apoER2 knockouts have a pronounced one. The perfusion of mouse hippocampal slices with Reelin has no effect on baseline synaptic transmission but significantly enhances LTP in area CA1. This Reelin-dependent augmentation of LTP is abolished in VLDL receptor and apoER2 knockout mice. Our results reveal a role for Reelin in controlling synaptic plasticity in the adult brain and suggest that both of its receptors are necessary for Reelin-dependent enhancement of synaptic transmission in the hippocampus. Thus, the impairment of apoE receptor-dependent neuromodulation may contribute to cognitive impairment and synaptic loss in Alzheimer disease.

Effects of Win 55,212-2 on hippocampal CA1 long-term potentiation in experiments controlled for basal glutamatergic synaptic transmission

Cannabinoids, the active components of marijuana, are presumed to affect memory by an action on long-term potentiation. However, these molecules also reduce hippocampal glutamatergic neurotransmission. To distinguish the two activities, we studied the effects of the synthetic cannabinoid (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtalenylmethanone (Win 55,212-2, 10 μM) on CA1 hippocampal responses generated by the activation of two independent pathways, one of which was potentiated with a tetanic stimulation. The results of the study show the following: (a) the drug does not affect long-term potentiation provided that the responses are compared to those obtained in the unpotentiated control pathway; (b) Win 55,212-2 increases post-tetanic potentiation.

Syndecan-3-Deficient Mice Exhibit Enhanced LTP and Impaired Hippocampus-Dependent Memory

Syndecan-3 (N-syndecan) is a transmembrane heparan sulfate proteoglycan expressed predominantly in the nervous system in a developmentally regulated manner. Syndecan-3 has been suggested to play a role in the development and plasticity of neuronal connections by linking extracellular signals to the regulation of the cytoskeleton. To study its physiological functions, we produced mice deficient in syndecan-3 by gene targeting. The mutant animals are healthy, are fertile, and have no apparent defects in the structure of the brain. We focused on characterizing the functions of the hippocampus, a brain area where expression of syndecan-3 is prominent in adults. Mice lacking syndecan-3 exhibited an enhanced level of long-term potentiation (LTP) in area CA1, while basal synaptic transmission and short-term plasticity were similar to those in wild-type animals. Further, the mutant mice were not responsive to the syndecan-3 ligand heparin-binding growth-associated molecule, which inhibits LTP in area CA1 in wild-type animals. Behavioral testing of the syndecan-3-deficient mice revealed impaired performance in tasks assessing hippocampal functioning. We suggest that syndecan-3 acts as an important modulator of synaptic plasticity that influences hippocampus-dependent memory.

Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents

Leptin is well known to be involved in the control of feeding, reproduction and neuroendocrine functions through its action on the hypothalamus. However, leptin receptors are found in brain regions other than the hypothalamus (including the hippocampus and cerebral cortex) suggesting extrahypothalamic functions. We investigated hippocampal long-term potentiation (LTP) and long-term depression (LTD), and the spatial-memory function in two leptin receptor-deficient rodents (Zucker rats and db/db mice). In brain slices, the CA1 hippocampal region of both strains showed impairments of LTP and LTD; leptin (10 −12 M) did not improve these impairments in either strain. These strains also showed lower basal levels of Ca 2+/calmodulin-dependent protein kinase II activity in the CA1 region than the respective controls, and the levels did not respond to tetanic stimulation. These strains also showed impaired spatial memory in the Morris water-maze test (i.e. longer swim-path lengths during training sessions and less frequent crossings of the platform’s original location in the probe test. From these results we suggest that the leptin receptor-deficient animals show impaired LTP in CA1 and poor spatial memory due, at least in part, to a deficiency in leptin receptors in the hippocampus.

The Role of Extracellular Regulated Kinases I/II in Late-Phase Long-Term Potentiation

Extracellular regulated kinases (ERKI/II), members of the mitogen-activated protein kinase family, play a role in long-term memory and long-term potentiation (LTP). ERKI/II is required for the induction of the early phase of LTP, and we show that it is also required for the late phase of LTP in area CA1 in vitro, induced by a protocol of brief, repeated 100 Hz trains. We also show that ERKI/II is necessary for the upregulation of the proteins encoded by the immediate early genes Zif268 and Homer after the induction of LTP in the dentate gyrus by tetanic stimulation of the perforant path in vivo or by BDNF stimulation of primary cortical cultures. To test whether the induction of persistent synaptic plasticity by stimuli such as BDNF is associated with nuclear translocation of ERKI/II, we expressed enhanced green fluorescent protein (EGFP)-ERKII in PC12 cell lines and primary cortical cultures. In both preparations, we observed translocation of EGFP-ERKII from the cytoplasm to the nucleus in cells exposed to neurotrophic factors. Our results suggest that the induction of late LTP involves translocation of ERKI/II to the nucleus in which it activates the transcription of immediate early genes. The ability to visualize the cellular redistribution of ERKII after induction of long-term synaptic plasticity may provide a method for visualizing neuronal circuits underlying information storage in the brain in vivo.

Different calcium sources are narrowly tuned to the induction of different forms of LTP.

The essential role of calcium in the induction of long-term potentiation (LTP) has been well established. In particular, calcium influx via the N-methyl-D-aspartate (NMDA) receptor (NMDAR) is important for LTP induction in many pathways. However, the specific roles of other calcium sources in hippocampal LTP are less clear. The aim of the present study was to determine the appropriate conditions and extent to which non-NMDAR Ca(2+) sources contribute to the induction of different forms of LTP in area CA1 of hippocampal slices. Increasing numbers of theta-burst trains (1, 4, and 8 TBS) induced LTP of increasing magnitude and persistence. Inhibition of ryanodine receptors caused inhibition of weak LTP induced by 1 TBS, but had no effect on more robust forms of LTP. Inhibition of IP3 receptors inhibited moderate LTP induced by 4 TBS, but had no effect when 1 TBS or 8 TBS were used. Inhibition of L-type voltage-dependent Ca(2+) channels inhibited strong LTP induced by 8 TBS, but had no effect on weaker forms of LTP. These results show that different Ca(2+) sources have different thresholds for activation by TBS trains. Furthermore, each Ca(2+) source appears to be tuned to the induction of a different form of LTP. Such tuning could reflect an important link between different LTP induction and maintenance mechanisms.

The role of extracellular regulated kinases I/II in late-phase long-term potentiation.

Extracellular regulated kinases (ERKI/II), members of the mitogen-activated protein kinase family, play a role in long-term memory and long-term potentiation (LTP). ERKI/II is required for the induction of the early phase of LTP, and we show that it is also required for the late phase of LTP in area CA1 in vitro, induced by a protocol of brief, repeated 100 Hz trains. We also show that ERKI/II is necessary for the upregulation of the proteins encoded by the immediate early genes Zif268 and Homer after the induction of LTP in the dentate gyrus by tetanic stimulation of the perforant path in vivo or by BDNF stimulation of primary cortical cultures. To test whether the induction of persistent synaptic plasticity by stimuli such as BDNF is associated with nuclear translocation of ERKI/II, we expressed enhanced green fluorescent protein (EGFP)-ERKII in PC12 cell lines and primary cortical cultures. In both preparations, we observed translocation of EGFP-ERKII from the cytoplasm to the nucleus in cells exposed to neurotrophic factors. Our results suggest that the induction of late LTP involves translocation of ERKI/II to the nucleus in which it activates the transcription of immediate early genes. The ability to visualize the cellular redistribution of ERKII after induction of long-term synaptic plasticity may provide a method for visualizing neuronal circuits underlying information storage in the brain in vivo.

L-AP3 blocks rises in intracellular calcium associated with hippocampal CA1 LTP.

The involvement of type I metabotropic glutamate receptors in hippocampal CA1 long-term potentiation (LTP) depends on the applied tetanic stimulation protocol. Activation of these receptors may cause an elevation of intracellular calcium via the formation of the second messenger inositol triphosphate (IP3) and subsequent intracellular calcium release. It has been shown that the type I metabotropic receptors antagonist L-2-amino-3-phosphonopropionate (L-AP3) blocks CA1 LTP. Combining dendritic calcium and field potential measurements in CA1 hippocampal area, we found that L-AP3 did not affect single calcium transients but reduced the calcium changes evoked by a single tetanus, preventing the long-lasting calcium enhancements associated with CA1 LTP. These findings suggest that the formation of this type of LTP requires calcium release from IP3-sensitive stores.

Chronic morphine treatment alters endogenous opioid control of hippocampal mossy fiber synaptic transmission.

Synaptic adaptations are thought to be an important component of the consequences of drug abuse. One such adaptation is an up-regulation of adenylyl cyclase that has been shown to increase transmitter release at several inhibitory synapses. In this study the effects of chronic morphine treatment were studied on mossy fiber synapses in the guinea pig hippocampus using extracellular field potential recordings. This opioid-sensitive synapse was chosen because of the known role of the adenylyl cyclase cascade in the regulation of glutamate release. Long-term potentiation (LTP) at the mossy fiber synapse was enhanced after chronic morphine treatment. In control animals, opioid antagonists increased LTP but had no effect in morphine-treated guinea pigs. In contrast, the long-lasting depression of transmission induced by a mGluR agonist and CA1 LTP were not altered. Chronic morphine treatment neither caused tolerance to mu- and kappa-receptor-mediated inhibition at the mossy fiber synapse nor modified total hippocampal dynorphin levels. The results suggest that the phasic inhibition of glutamate transmission mediated by endogenous opioids is reduced after chronic exposure to morphine.