Modulation of long-term potentiation in the rat hippocampus following cocaine self-administration

Long-lasting neuroadaptations that occur during drug use and remain after withdrawal are thought to contribute to the persisting and compulsive nature of drug addiction and relapse. At the molecular and cellular levels, mechanisms that have been implicated in the normal process of memory formation are increasingly being identified as potential contributors to the persistence of the addicted state. To investigate the effect of cocaine self-administration on synaptic plasticity, rats were allowed to self-administer 0.5 mg/kg/infusion cocaine or 0.9% NaCl during 90 min sessions for 15 consecutive days. These cocaine and saline self-administration subjects were then restricted to their home cages for 3, 30, or 100 days (3, 30, and 100 day cocaine/saline withdrawal groups) before the assessment of the induction and reversal of long-term potentiation (LTP) in the CA1 region of hippocampal slices. The magnitude of LTP was increased in the 3-day cocaine withdrawal group as compared with the 3-day saline withdrawal group, but this effect was short lived, as the 30-day cocaine and saline withdrawal groups exhibited similar LTP magnitudes. Interestingly, LTP was significantly decreased in the 100-day cocaine withdrawal group compared with the 100-day saline withdrawal group. These results support the hypothesis that the capacity for LTP is persistently altered after withdrawal from exposure to an addictive substance. In addition, this alteration can be differentially expressed such that depending upon the duration of the withdrawal period following the last drug exposure, LTP may be enhanced, unchanged, or suppressed.     

Calcium-induced long-term potentiation in the hippocampus

The effect of a transient increase in extracellular calcium concentration on the Schaffer collateral-commissural evoked excitatory postsynaptic potential and population spike responses of CAI pyramidal neurons was investigated using the rat in vitro hippocampal slice preparation. Brief exposure of slices (5-10 min) to twice the normal concentration of calcium (4 mM) induced a marked potentiation of both the excitatory postsynaptic potential and population spike that could persist for at least 3 h. No long-term changes were observed in either the presynaptic fiber volley of antidromically evoked CAI population spike, indicating that the potentiation could not be attributed to an increase in the number of fibers activated or a generalized increase in cellular excitability. The response of CAI pyramidal neurons to the iontophoretic application of L-glutamate in the apical dendritic zone was also unaffected after exposure to high calcium perfusate, suggesting a lack of alteration in membrane excitability or receptor sensitivity restricted to the region of synaptic input. In addition, total intracellular calcium content of individual slices, measured by atomic absorption spectrophotometry, was significantly increased for at least 1 h following return to the control medium. These data indicate that brief exposure of in vitro hippocampal slices to a high extracellular calcium concentration results in a long-term increase in synaptic efficacy which is similar in many respects to long-term potentiation induced by tetanic stimulation of hippocampal excitatory afferents. The results further suggest that the mechanisms underlying calcium-induced long-term potentiation may reside in presynaptic components and involve an enhanced transmitter release.     

Phorbol ester-induced synaptic potentiation differs from long-term potentiation in the guinea pig hippocampus in vitro

The relationship between the synaptic potentiations evoked by the protein kinase C activator phorbol-12,13-diacetate and by afferent tetanization has been examined in the CA1 region of the hippocampal slice preparation using extracellular recording. It has been found that the potentiation of the field excitatory postsynaptic potential produced by 1 microM phorbol ester does not affect the amount of long-term potentiation (LTP) that can be evoked by afferent tetanization, and vice versa. A dissociation between phorbol ester-induced and tetanus-induced potentiation is also indicated by the fact that only the former was associated with changes in paired-pulse facilitation. On the other hand, as previously described, higher concentrations (10 microM) of phorbol ester blocked the tetanus-induced potentiation. Since the total potentiation given by 10 microM phorbol ester and tetanization depended on the order of presentation of the potentiation-inducing stimuli, it appears that the blockade of LTP is, at least partly, independent of the phorbol ester-induced potentiation.     

Voltage-clamp analysis of synaptic inhibition during long-term potentiation in hippocampus

The excitatory synaptic response evoked by stimulating the mossy fiber synaptic input to hippocampal CA3 neurons in normally accompanied by concomitant feedforward or recurrent inhibition. The purpose of the present study was to determine whether a decrease in the inhibitory conductance of this mixed synaptic response contributes to the enhanced synaptic efficacy observed during long-term potentiation (LTP). Intracellular recordings were made from CA3 neurons of rat hippocampal brain slices. Current- and voltage-clamp measurements of the mixed excitatory/inhibitory evoked synaptic response were made, using a single-electrode clamp system. Outward and inward rectification were reduced, respectively, by intracellular injection and bath application of Cs+. Biophysical analysis of the evoked synaptic conductance sequence was performed before and 15 min to 1 h after inducing LTP. As expected, measurements made in the early part of the conductance sequence, which represents primarily the monosynaptic excitatory input, demonstrated an increase in the slope conductance during LTP. Measurements made later in the conductance sequence, when the excitatory component appeared to have declined to a negligible value, revealed no decrease in the slope conductance of the inhibitory component of the mixed response. We conclude that a decrease in the conductance associated with the inhibitory component of the mixed synaptic response plays little or no role in the increase in synaptic efficacy observed during LTP of this synaptic system.     

Noradrenergic enhancement of long-term potentiation at mossy fiber synapses in the hippocampus

1. We tested several hypotheses related to the modulation of long-term potentiation (LTP) by norepinephrine (NE) at the mossy fiber synapses in the rat hippocampal slice preparation using extracellular and intracellular recording techniques. 2. NE exerted frequency-dependent effects on mossy fiber synaptic transmission. It had little effect on extracellular population excitatory postsynaptic potentials (pEPSPs) sampled during low-frequency stimulation, whereas it had marked effects on the duration, magnitude, and probability of induction of LTP at these synapses. 3. The beta-adrenoceptor agonist isoproterenol mimicked all of the effects of NE, whereas the beta-adrenoceptor antagonists propranolol and timolol reversibly blocked the induction of LTP, suggesting the effects of NE are mediated by a beta-adrenoceptor and that beta-adrenoceptor activation may be an important constituent for the expression of LTP at these synapses. 4. Frequency-dependent effects of NE and isoproterenol on mossy fiber pEPSPs were also observed in the presence of the gamma-aminobutyric acid (GABA) antagonist, picrotoxin, suggesting that NE can enhance LTP by a mechanism that does not depend on intact inhibition. However, propranolol did not block LTP in these disinhibited slices and did not affect LTP magnitude. 5. The adenylate cyclase activator forskolin augmented pEPSPs sampled during low-frequency stimulation in disinhibited slices and significantly enhanced LTP. Forskolin, however, did not produce LTP in the absence of tetanic stimulation. This supports the hypothesis that NE and isoproterenol augment features of LTP by stimulating adenosine 3',5'-cyclic monophosphate (cAMP) production and that cAMP plays a modulatory role in the induction of LTP. 6. The postsynaptic injection of the cAMP analogue 8-bromoadenosine 3',5'-cyclic monophosphate (8-bromo-cAMP) significantly increased the probability of induction of LTP measured intracellularly under voltage-clamp conditions with intact inhibition. An analysis of the inhibitory synaptic slope conductance during these experiments indicated that changes in this measure could neither account for the increase in mossy fiber synaptic slope conductance in those cells that displayed it nor account for the group differences in this variable. 7. The amplitude and duration of the postsynaptic depolarization during tetanic stimulation in the cells that displayed LTP in the 8-bromo-cAMP-injected group were significantly greater than in the cells that did not display LTP in the adenosine 5'-monophosphate-injected group.(ABSTRACT TRUNCATED AT 400 WORDS)     

Release of proteins during long-term potentiation in the hippocampus of the anaesthetized rat

Using a push-pull device, the release of endogenous proteins in the extracellular space was investigated in the CA1 region of the hippocampus of anaesthetized rats. With low-frequency stimulation of the Schaffer collaterals, there was a relatively stable release of 5 proteins (64, 54, 48, 45 and 16 kDa). A train of high-frequency stimulation produced a long-lasting enhancement of the negative field EPSP and a delayed (90-120 min) enhancement of the release of these proteins. An additional 19 kDa protein was present only 90 min after the train. These observations raise the possibility that release of proteins might be involved in the maintenance of LTP.     

4-Aminopyridine-mediated increase in long-term potentiation in CA1 of the rat hippocampus

The effect of 4-aminopyridine (4-AP) on long-term potentiation (LTP) was studied in the hippocampal slice preparation of the rat. Field excitatory postsynaptic potentials (EPSPs) were recorded and evoked in the stratum radiatum of the CA1. Both the low frequency EPSP and LTP of the EPSP were significantly increased by treatment with 4-AP. These effects were inhibited by increasing the magnesium concentration from 1 to 4 mM. Pretreatment with 20 microM DL-2-amino-5-phosphonovalerate antagonized only the increase in LTP produced by 4-AP. It is suggested that 4-AP enhances Ca influx either pre- or postsynaptically and thereby increases LTP.     

Loss of long-term potentiation in the hippocampus after experimental subarachnoid hemorrhage in rats

Survivors of aneurysmal subarachnoid hemorrhage (SAH) often suffer from cognitive impairment such as memory loss. However, the underlying mechanisms of these impairments are not known. Long-term potentiation (LTP) of synapses in the hippocampus is generally regarded as a molecular substrate of memory. The purpose of this study was to examine the effect of SAH on LTP in the hippocampal Schaffer collateral (CA3–CA1) pathway in a rat model of SAH. We found SAH caused significant vasospasm of the middle cerebral artery (MCA) compared to saline injected or sham controls (P<0.001). Basic neurotransmission quantified as excitatory post synaptic and spike response from animals with SAH were significantly decreased as compared to naive controls (P<0.05). However, sham operated and saline injected controls showed similar amplitude as naive controls. This suggests that reduction in basic neurotransmission is due to blood in the subarachnoid space. Similarly, analysis of LTP demonstrated that naive, sham and saline controls have a 92±16%, 69±27% and 71±14% increase over the baseline in the average spike amplitude following high frequency stimulation (HFS), respectively. This indicates the presence of LTP (P<0.05). In contrast, the spike amplitude in animals of SAH returned to baseline level within 60 min post HFS indicating the absence of LTP. We conclude that SAH caused vasospasm of the MCA that was associated with disrupted basic neurotransmission and plasticity at CA3–CA1 synapses. These changes might be accountable for the memory loss in humans with SAH.     

Temporal contiguity requirements for long-term associative potentiation/depression in the hippocampus

A previous study utilizing the powerful ipsilateral and weak crossed projection from the entorhinal cortex to the dentate gyrus in the rat revealed that long-term potentiation is an associative process in these systems. If the weak crossed projection alone receives potentiating stimulation consisting of 8 high-frequency trains 17.5 ms in duration, it does not exhibit long-term potentiation. However, long-term potentiation can be induced in the crossed projection if it is activated concurrently with the converging ipsilateral system. The present study is designed to determine the degree of synchrony required for the associative interactions by varying the timing and order of the potentiating trains delivered to the two converging systems.The associative induction of long-term potentiation does not require perfectly synchronous activation of the converging systems. The order of the trains is crucial, however. Long-term potentiation of the crossed projection can be induced if activity in the ipsilateral system is concurrent with or follows activity in the crossed projection. Indeed, there can be as much as 20ms between the 17.5ms trains in the two systems, and long-term potentiation of the crossed projection is still induced. Activation of the ipsilateral system that precedes activation of the crossed system depresses the responses evoked by the crossed system. If potentiating stimulation of the ipsilateral system follows activation of the crossed projection by too long an interval (200 ms, for example), then the crossed projection is depressed rather than potentiated.These results are discussed with regard to the nature of the associative process permissive for the induction of long-term potentiation and lead us to the conclusion that perfect temporal contiguity is not a requirement of this prototypical elemental memory unit.     

Thyrotropin-releasing hormone inhibits long-term potentiation in synaptic systems of rat hippocampus

The effects of thyrotropin-releasing hormone (TRH) on long-term potentiation of field responses in mossy fibers—CA3 and Shaffer collaterals—CA1 synaptic systems were studied on rat hippocampal slices. Incubation with micromolar concentrations of TRH inhibited the development of long-term potentiation in both synaptic systems. It is suggested that this phenomenon underlies the antiamnesic effect of TRH. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No. 12, pp. 690–693, December, 1999     

Persistent enhancement of transmitter release accompanying long-term potentiation in the guinea pig hippocampus

In order to examine temporal changes in enhancement of transmitter release during long-term potentiation (LTP), we examined amplitude fluctuation of excitatory postsynaptic potentials (EPSPs) for longer periods than 2 h after tetanic stimulation (up to 4 h in the longest observation). The relative magnitude of excitatory postsynaptic potentiation (EPSP) fluctuation (coefficient of variation, CV) reduced throughout the observation periods in association with an increase in EPSP amplitude after tetanic stimulation. The reciprocals of squared CVs (= mean²/variance) were almost in proportion to the magnitude of LTP, and the ratio of 1/CV² and the LTP magnitude did not change significantly for up to 4 h. These findings suggest that a prolonged enhancement of transmitter release from presynaptic terminals underlies LTP, and the relative contribution of this presynaptic enhancement does not change significantly for 2 h (maybe up to 4 h, or longer) after tetanic stimulation.     

Cholinergic stimulation enhances long-term potentiation in the CA1 region of rat hippocampus

The effect of the cholinergic agonist carbachol on a putative substrate for memory (long-term potentiation; LTP) was investigated in slices of rat hippocampus (CA1 region). Carbachol (5 microM) increased LTP when the presynaptic depression of the EPSP was controlled. The results indicate that carbachol enhances the effectiveness of the tetanus, probably through postsynaptic mechanisms. This effect may have implications for the role of acetylcholine in memory and the use of cholinergics in memory disorders.     

Exposure of mouse to high gravitation forces induces long-term potentiation in the hippocampus

The central nervous system is highly plastic and has been shown to undergo both transient and chronic adaptive changes in response to environmental influences. The purpose of this study was to investigate the effect of hypergravic field on long-term potentiation (LTP) in the mouse hippocampus. Exposure of mice to 4G fields for 48 h had no effect on input-output coupling during extracellular stimulation of Schaffer collaterals and paired pulse facilitation, suggesting that the hypergravic exposure had no detrimental effect on basal neurotransmission in the hippocampus. However, the exposure to 4G fields for 48 h significantly induced LTP compared with the control mouse hippocampus. In contrast, no significant changes of late-phase LTP (L-LTP) were found in the hippocampi of mice exposed to the hypergravic field. Exposure of mice to 4G fields for 48 h enhanced AMPA receptor phosphorylation but not cyclic AMP-responsive element binding protein (CREB) phosphorylation. These results suggest that exposure to hyperdynamic fields influences the synaptic plasticity in the hippocampus.     

Modulation of long-term potentiation induction in the hippocampus by N-methyl-D-aspartate-mediated presynaptic inhibition.

We investigated mechanisms involved in the modulation of long-term potentiation by low concentrations of N-methyl-D-aspartate in the CA1 region of rat hippocampal slices. When applied for 5 min prior to and during tetanic stimulation, 1 microM N-methyl-D-aspartate inhibited long-term potentiation induction. Studies examining paired-pulse facilitation of non-N-methyl-D-aspartate receptor-mediated synaptic responses suggest that the effects of N-methyl-D-aspartate result in part from a presynaptic mechanism. This conclusion is supported by the observation that 1 microM N-methyl-D-aspartate failed to diminish N-methyl-D-aspartate receptor-mediated synaptic currents and that agents that enhance glutamate release, including high extracellular concentrations of calcium and an adenosine A1 receptor antagonist, overcome the long-term potentiation inhibition. Furthermore, the calcineurin inhibitors, FK-506 and cyclosporin A, as well as the phosphatase 1 and 2A inhibitor, okadaic acid, blocked the effects of N-methyl-D-aspartate on long-term potentiation suggesting a role for phosphatase activation in modulating the induction of long-term potentiation. These results show that the inhibition of long-term potentiation by untimely N-methyl-D-aspartate receptor activation is reversed by treatments that enhance glutamate release and suggest that adenosine release and diminished calcium influx during tetanic stimulation coupled with phosphatase activation contribute to the modulation of synaptic plasticity.     

Long-term potentiation in the hippocampus

Long-term potentiation of field and single neuronal responses recorded in various hippocampal fields is described on the basis of author's and literary data. Most of intrahippocampal and extrinsic connections in both in vivo and in vitro hippocampal preparations show this phenomenon after one or several conditioning trains of comparatively short duration (20 s or less) at various frequencies (from 10 to 400 Hz). Properties of hippocampal potentiation are described. The properties include long term persistence (hours and days) of the potentiated response, its low frequency depression, self-restoration after the depression, specificity of the potentiation for the tetanized pathway, necessity of activation of a sufficient number of neuronal elements (‘cooperativity’) to produce the potentiation, possible involvement of ‘reinforcing’ brain structures during conditioning tetanization. These properties are distinct from those of ‘usual’ short-term post-tetanic potentiation and lead to the suggestion that the neuronal mechanisms underlying long-term potentiation are similar to those underlying memory and behavioralconditioned reflex. Neurophysiological mechanisms of long-term potentiation are discussed. The main mechanism consists in an increase in efficacy of excitatory synapses as shown by various methods including intracellular recording and quantal analysis. The latter favours presynaptic localization of the changes of synaptic efficacy showing increase in the number of transmitter quanta released per presynaptic impulse. However, changes in the number of subsynaptic receptors or localized changes in dendritic postsynaptic membrane are not excluded. Biochemical studies indicate the increase in transmitter release and calcium-dependent phosphorylation of pyruvate dehydrogenase after tetanization. Instances of persistent response facilitations at other levels of the vertebrate central nervous system (especially at neocortical level) are considered and compared with hippocampal long-term potentiation.

It is suggested that modifiable excitatory synapses necessary for learning have been identified in studies of long-term potentiation. These synapses are presumably modified as a result of close sequential activation of the following three structures: excitatory presynaptic fibers, the postsynaptic neuron and a ‘reinforcing’ brain system.     

Glycine facilitates induction of long-term potentiation of evoked potential in rat hippocampus

Effects of glycine were investigated in Schaffer/commissural-CA1 pyramidal cell synapses of the rat hippocampal slices. Perfusion of glycine (0.05 mM) did not change baseline population spikes evoked by test stimulation but significantly enhanced short-term potentiation induced by a single shorter tetanus (100 Hz, 11 impulses); the effects resulted in production of long-term potentiation (LTP). LTP produced by a longer tetanus (100 Hz, 100 impulses, 2 trains) was not significantly influenced. Higher concentration (0.5 mM) of glycine increased the baseline spike amplitude. All these effects of glycine were not observed in the presence of 10(-5) M 2-amino-5-phosphonovalerate, an N-methyl-D-aspartate (NMDA) antagonist. These results demonstrate that glycine can facilitate induction of LTP probably by activating NMDA receptor.     

Anticonvulsants do not suppress long-term potentiation (LTP) in the rat hippocampus

Long-term potentiation (LTP) of population spikes in the CA1 area of rat hippocampus was induced by tetanic stimulation of stratum radiatum in slices kept submerged in a perfusion chamber. Addition of the two antiepileptic drugs phenytoin or the diazepine midazolam to the medium did not significantly alter this phenomenon within 22 min after the tetanus. The early enhancement (post-tetanic potentiation, PTP) was reduced only by phenytoin. Therefore an interaction of these drugs with N-methyl-D-aspartate (NMDA) receptors and LTP induction is unlikely.     

Benzodiazepines block long-term potentiation in slices of hippocampus and piriform cortex.

The effects of two benzodiazepines, diazepam and triazolam, on long-term potentiation were tested in slices of hippocampus and piriform cortex. The drugs had little influence on baseline synaptic responses but both were very effective in blocking LTP elicited by theta pattern stimulation. The effects were fully reversible upon washout. Diazepam reduced the increase in burst responses that occurs during theta stimulation and thus appears to interfere with the initial triggering events for long-term potentiation. This may reflect the enhancing action of the drug on GABA-mediated inhibitory potentials. Triazolam did not detectably change the burst responses elicited by theta pattern stimulation. Experiments with slices of piriform cortex indicated that triazolam also failed to disrupt the development of long-term potentiation but instead caused the potentiation to decay back to baseline in 15-30 min. Triazolam thus seems to act on the mechanisms that stabilize long-term potentiation. These results provide a possible explanation for the amnestic effects of benzodiazepines in humans and animals and support the hypothesis that long-term potentiation contributes to memory encoding.     

Mechanisms underlying the inhibition of long-term potentiation by preconditioning stimulation in the hippocampus in vitro

We have investigated the mechanisms underlying a form of metaplasticity, namely the inhibition by preconditioning stimulation of high frequency stimulation (HFS)-induced long-term potentiation (LTP) in the medial perforant path of the dentate gyrus. Preconditioning stimulation (weak 50 Hz) was found to inhibit subsequent LTP induction if applied 10-20 min, but not 2 or 45 min, prior to the HFS. Preconditioning stimulation in the form of low frequency stimulation did not block LTP induction. The inhibition of LTP was not caused by a reduction in N-methyl-D-aspartate receptor (NMDAR) transmission, as the preconditioning stimulation did not reduce isolated NMDAR-mediated EPSPs. The involvement of group I and group II metabotropic glutamate receptor (mGluR) activation in the inhibition of LTP was demonstrated by experiments in which the inhibition of LTP by the preconditioning stimulation was prevented by the presence of antagonists of group I or group II mGluR during the preconditioning stimulation. Moreover, group I and group II mGluR agonists directly inhibited subsequent LTP induction. The involvement of NMDAR in the preconditioning stimulation was shown by the ability of an NMDAR antagonist to prevent the inhibition of LTP by the preconditioning stimulation. The preconditioning inhibition of LTP induction was shown by the use of kinase inhibitors to involve activation of PKC and p38 MAP kinase, but not p42 MAP kinase or tyrosine kinase. We conclude that the preconditioning inhibition of LTP induction is a complex process which involves activation of NMDAR, group I and group II mGluR, and intracellular cascades activating PKC and p38 MAP kinase.