Potentiation effects in the dentate gyrus of pentylenetetrazol-kindled rats.

The study examines changes in the function of perforant pathway dentate granule cell synapses after pentylenetetrazol (PTZ) kindling. Field potentials evoked in the dentate area by test stimuli to the perforant pathway were recorded in freely moving rats at different times after injection of PTZ. In fully kindled animals, but not in sham-kindled controls, subconvulsive test doses of PTZ induced long-lasting potentiation of the population spike. Also, potentiation was not induced in naive controls injected with equieffective doses of the convulsant. The slope function of the field EPSP was depressed 90-120 min after PTZ administration, in both kindled and control animals, indicating that this was an effect of acute-injected PTZ. Later on, only in kindled animals that showed seizure stages 4 or 5 did it increase in parallel with the population spike potentiation. Finally, when compared to controls the kindled animals showed a greater pop spike potentiation induced by moderate tetanization of the perforant pathway. The model offers the possibility of differentiating between acute effects of the convulsant drug and kindling-related changes in neuronal plasticity.

PTZ-kindling after colchicine lesion in the dentate gyrus of the rat hippocampus.

Pentylenetetrazol (PTZ)-kindling represents a model of a primarily generalized epilepsy. We investigated the role of the dentate gyrus of the hippocampus in this model of epilepsy by destruction of this structure by colchicine, injected in the dorsal and ventral hippocampus of rats. After a period of 7 days PTZ-kindling was started. The kindling development was slightly accelerated in colchicine treated animals compared to control rats. After kindling completion the learning performance of the rats was tested in a shuttle-box experiment. The learning deficit found in fully kindled rats was not influenced by colchicine pretreatment. However, colchicine itself impaired the learning performance of rats in the shuttle-box.

Pharmacological effects on two inbred substrains of AB mice.

Mice of the two substrains AB/Gat and AB/Hal from the Jena AB inbred strain differ in behavior from each other by their aggressiveness occurring especially in the latter group after maturity. In order to ascertain the neurobiological background of aggressiveness, we injected mice of both substrains with either haloperidol, diazepam, or hexobarbital and measured their response on motor activity. In a second experiment, the reaction to a seizure evoking agent (pentylenetetrazol) was determined. Mice of both substrains were found to differ significantly in their reaction to haloperidol or diazepam injection. In contrast to that no changes in motor activity could be detected following hexobarbital administration. Animals of the aggressive AB/Hal substrain reacted more pronounced to pentylenetetrazol than those of the AB/Gat group. In conclusion, the varying aggressiveness of both AB mice substrains may be due to differences in dopaminergic and GABAergic neurotransmission.

Long-term potentiation and postconditioning potentiation--the same mechanism?

Stimulation of the perforant pathway with different stimulus pattern was used in freely moving rats to elicit classical posttetanic long-term potentiation (LTP), paired-pulse potentiation and postconditioning potentiation which appeared after using the perforant pathway stimulation as a conditioned stimulus in a shuttle-box learning paradigm. The changes in amplitude and latency of the population spike were compared. While in all experimental groups an amplitude potentiation of the population spike occurred, the changes in its latency were different. Only after inducing posttetanic LTP the latency decreased together with the amplitude increase. Postconditioning potentiation in good learners, however, was accompanied by a latency increase. In poor learners, on the other hand, a latency decrease immediately after the training session was the only change. Paired-pulse potentiation which occurred with an interstimulus interval of 50 ms, was also accompanied by a latency increase. The results indicate that the mechanism of learning-related potentiation cannot only be long-term potentiation. Even if assuming an involvement of LTP in the synaptic changes occurring after learning, it seems to be modified or overlapped by another alteration. Considering the similarity to observations after paired-pulse potentiation, a recruiting phenomenon can be assumed to contribute to these differences.

Avoidance and brightness discrimination conditioning in genetically different lines of rats.

Rats from an albino stock were selected for high (HAS) and low (LAS) avoidance scores measured in a shuttle-box. Learning performance of male rats was compared in three different tests: the shuttle-box, the pole jumping-box, and the Y-chamber. It was shown that rats of the HAS line more rapidly acquired conditioned avoidance in the shuttle-box experiment and the pole-jumping experiment than LAS, whereas we could not detect any significant differences in brightness discrimination. In the open field test rats of the HAS line were more active in comparison to LAS's, measured in terms of higher ambulation scores. In conclusion, it is verified that the shuttle-box performance as well as pole-jumping performance is highly determined by the emotional status of the animals and, moreover, that avoidance learning is based on mechanisms other than brightness discrimination learning.

Low frequency perforant path stimulation as a conditioned stimulus demonstrates correlations between long-term synaptic potentiation and learning.

Stimulation of the perforant path with impulse trains of 15 cps and 670 msec duration was used as a conditioned stimulus in a two-way shuttle box avoidance on rats. Field potentials in the dentate area evoked by test stimuli were measured after the training sessions until the 7th day. Foot-shock and unconditioned escape elicited only a transient slight depression of the population spike amplitude (P) and increased also slightly the slope function (SF) of the population EPSP of the evoked test potentials. The control stimulation of the perforant path without pairing with foot-shock as in conditioning did only slightly increase SF of test potentials, but produced a strong transient inhibition followed by a long lasting moderate depression of P. After conditioning, all animals exhibited the same initial inhibition of P as shown in control stimulation of the perforant path. However during the following 4 hours, good learners with a relearning index greater than 30% developed a significant potentiation of P lasting until the second training session 24 hours later, which resulted in a further enhancement. SF of the evoked test potentials increased in good learners with a similar time course after conditioning but without initial depression. After 7 days P showed still enhanced but non-significant values. Poor learners with a relearning index less than 10% did not develop a potentiation of P after conditioning and initial inhibition, but a long-term depression. Also SF of test potentials decreased in poor learners during 4 hours after conditioning and returned almost to baseline until the following day. After 7 days, P and SF did not differ from baseline. The analysis of the observed synaptic changes by E-S curves demonstrated the post-tetanic LTP seems to differ in some ways from post-conditioning LTP in good learners. The latter exhibits a clear tendency of a right shift contrary to the left shift commonly occurring after tetanization. Furthermore poor learners do not only fail to produce long-term potentiation, but fail to show a change in the opposite direction with a left shift of the E-S curves. The observed correlation of LTP in the conditioning pathway with the learning ability suggests an involvement of LTP at least in the acquisition and early retention of this learned behavior. The results do however not finally clarify the role of LTP in long-term retention.

Derivatives of beta-casomorphins with high analgesic potency.

Beta-casomorphin (5) Tyr-Pro-Phe-Pro-Gly, a partial sequence of bovine beta-casein with moderate opioid properties and mu-receptor affinity, was modified by substituting for the natural L-amino acids their D-analogs, and D-pipecolic acid, as well as by amidation of the C-terminal. Substitution of D-Pro or D-pipecolic acid for L-Pro4 considerably increased the analgesic action and the potency on guinea-pig ileum of beta-casomorphin (5) as well as of casomorphin [4] amide. The resulting D-Pro4 analogs Deprolorphin and Deproceptin which showed high analgesic potency after both intracerebroventricular and intravenous administrations. Also, the substitution of D-Phe for L-Phe3 enhanced, even though to a lesser degree, the antinociceptive action. Both naltrexone and naloxone completely blocked the effects in vivo and in vitro. The substitution of D-Pro for L-Pro2 abolished the opioid-like actions, while substituting D-pipecolic acid for L-Pro2 resulted in an increased analgesic effect of remarkably long duration. The correlation of analgesic action with the effects on isolated organs separates the L-Pro4-substituted derivatives and D-Phe3-CM(5) from the other modified casomorphins and morphine, indicating that the analgesic potency of the former was about ten times that of the latter group in the case of identical GPI-potency. This may involve different subpopulations of opiate mu-receptors.