The roles of the noradrenergic and serotonergic innervations of the hippocampus were investigated with respect to their involvement in the intracranial self-stimulation of this structure. In the first study, 6-hydroxydopamine-induced lesions of the dorsal tegmental noradrenergic bundle ascending to the forebrain had no effect on hippocampal self-stimulation in rats. In the second study, intragastric administration of para-chlorophenylalanine decreased hippocampal self-stimulation, suggesting the importance of a serotonin input in maintaining this behavior. Identical para-chlorophenylalanine treatments resulted in temporary depletions of brain serotonin which paralleled the changes in hippocampal self-stimulation. The maximal decreases in both the biochemical and behavioral measures occurred at 4 days' post-drug. Interpretations of this deficit in hippocampal self-stimulation in terms of gross sensory and/or motor changes were ruled out, as animals with lateral hypothalamic electrodes showed increases in self-stimulation paralleling the post-drug serotonin changes. An intrasessional analysis of the para-chlorophenylalanine-induced behavioral changes revealed that lateral hypothalamic self-stimulation was facilitated mainly during the first hr of the 2 hr test sessions, whereas the depression in hippocampal self-stimulation occurred primarily in the last hour of the sessions. The differential effects of para-chlorophenylalanine on lateral hypothalamic and hippocampal self-stimulation provide evidence against simple monoamine theories of reinforcement. / Arts, Faculty of / Psychology, Department of / Graduate

High frequency repetitive stimulation of an excitatory input in the hippocampus results in a post-tetanic potentiation (PTP) of short duration (about 3 min) that can be followed by a long-term synaptic potentiation (LTP) of the same excitatory input (Schwartzkroin and Wester, 1975; Andersen et al., 1977). It has been reported that this tetanus-induced LTP cannot be elicited in a Ca²⁺-free medium and is therefore a Ca²⁺-dependent process (Dunwiddie et al., 1978; Dunwiddie and Lynch, 1979; Wigstrӧm et al., 1979). Whether the induction of LTP is directly dependent upon Ca²⁺, or whether, Ca²⁺ is required because synaptic transmission is needed to initiate certain postsynaptic process(es) (a postsynaptic depolarization, for instance) leading to LTP, is unknown. Recent studies from this laboratory showed that both short-term potentiation (STP; with a duration resembling PTP) and LTP can be associatively induced if activation of a test input co-occured with either a tetanic stimulation of separate excitatory inputs or a sufficient depolarization of the postsynaptic neurone (Sastry et al., 1985). In this study, experiments were performed to investigate (1) whether associative STP could be induced when activation of the test input preceded or followed the onset of the conditioning train and (2) whether LTP could be induced in the absence of Ca²⁺ in the extracellular medium if sufficient depolarizations of the presynaptic terminals and postsynaptic neurones were provided. All experiments were performed using the transversely sectioned hippocampal slice preparation. Test stimuli were delivered via an electrode located in the stratum radiatum while the conditioning tetani (100 Hz, 10 pulses per train) were delivered via another electrode located in the recorded from the apical dendritic area of CA₁ neurones. After the initial control stimulation period, 5 conditioning tetani were given at a frequency of 0.2 Hz. The test stimuli either preceded (-) or followed ( + ) the onset of each conditioning train by 0 to 100 ms. When the test stimulus followed the onset of each conditioning train, there was significant STP of the test EPSP up to a conditioning-test interval of +80 ms. When the test stimulus preceded the onset of each conditioning train, there was significant STP of the test EPSP up to a conditioning-test interval of -50 ms. Conditioning tetani that were given without co-activation of the test input resulted in a subsequent depression of the test EPSP. It is suggested that either the test or the conditioning input can initiate some postsynaptic process(es) which can in turn affect the activated presynaptic terminals to increase transmitter release or alter the subsynaptic dendritic properties. For studying the possibility of the induction of LTP in the absence of Ca²⁺ in the extracellular medium, population EPSPs were recorded from apical dendritic area of CA₁ neurones in response to stratum radiatum stimulation. After the control stimulation period, slices were exposed either to Ca²⁺-containing or Ca²⁺-free (with Mn²⁺ and Mg²⁺ replacing Ca²⁺) medium, with the concentration of KC1 at 10 to 80 mM. Long-term potentiation of the population EPSPs was observed following the exposure to high K⁺ in Ca²⁺-free media. Following a brief period of potentiation initially, population EPSPs often exhibited a tendency toward depression after exposure to high K⁺ in Ca²⁺-containing media. LTP induced by high K⁺ in Ca²⁺-free medium could also be observed when a fixed number of axons were being activated, indicating that a recruitment of presynaptic fibres cannot entirely account for the potentiation. LTP of the depolarizing commands were paired with activation of the stratum radiatum while the slices were exposed to Ca²⁺ -free medium (normal concentration of KC1). These results suggest that extracellular Ca²⁺, synaptic transmission and thus subsynaptic receptor activation are not necessary for the induction of LTP as long as sufficient depolarizations of the presynaptic terminals and postsynaptic neurones are provided. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Thesis (Ph. D.)--University of California, San Diego, 2008. / Title from first page of PDF file (viewed September 3, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 128-137).

Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2008. / Vita. Bibliography: p.184-192

Thesis (Ph.D. in Pharmacology) -- University of Colorado, 2006. / Typescript. Includes bibliographical references (leaves 125-149). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

The regulation of calcium (Ca²⁺) was examined during long-term changes of neuronal excitability in the mammalian CNS. The preparations under investigation included the kindling model of epilepsy, a genetic form of epilepsy and long-term potentiation (LTP) of neuronal activity. The study also includes a discussion of the possible roles of a neuron-specific calcium-binding protein (CaBP). The findings are summarized as follows: 1) The distribution of CaBP was determined in cortical areas of the rat using a specific radioimmunoassay. The protein was found to have an unequal distribution in various cortical areas with preponderence in ventral structures. 2) Extending previous studies on the role of CaBP in kindling-induced epilepsy, its decline was correlated to the number of evoked afterdischarges (AD's) during the process of kindling. 3) Marked changes in CaBP levels were also found in the brains of the epileptic strain of mice (El). The hippocampal formation and the dorsal occipital cortex contained significantly lower CaBP than the control (CF-1) strain. The induction of seizures further decreased the levels of CaBP in the El mice. These findings are indicative of a possible genetic impairment of neuronal Ca²⁺ homeostasis in the El strain. 4) The levels of total hippocampal Ca²⁺ and Zn²⁺ were measured by atomic absorption spectrophotometry in control and commissural-kindled animals. While no change was found in the total Ca²⁺ content of the region, hippocampal Zn²⁺ of kindled preparations was found to be significantly elevated. 5) To measure Ca²⁺ -homeostasis, the kinetic analysis of ⁴⁵Ca uptake curves was undertaken in the in vitro hippocampus. This technique was found to be a valid method for assessment of Ca²⁺-regulation in the CNS under both physiological and pathophysiological conditions. The effect of various extracellular Ca²⁺ concentrations, 2,3-dinitrophenol (DNP), calcitonin, nifedipine and 3-isobutyl-1-methylxanthine (IBMX) on ⁴⁵Ca uptake curves was examined in order to identify the two exchangeable Ca²⁺ pools derived through kinetic analysis. 6) The kinetic analysis of ⁴⁵Ca uptake curves revealed that Ca²⁺-regulation of the hippocampus is impaired following amygdala- and commissural kindling. The changes reflect an enhancement of a Ca²⁺ pool that includes free cytosolic Ca²⁺ and a concomitant decrease in the amount of buffered calcium probably as a result in the decrease of hippocampal CaBP levels. 7) A novel form of long-term potentiation (LTP) of neuronal activity in the CA1 region of the hippocampus is described. Perfusion of 100 uM of IBMX in the hippocampal slice preparation induced a long lasting increase in the amplitude of the stratum radiatum evoked population spike and EPSP responses with changes in synaptic efficacy as indicated by the altered input/output relationships. Intracellular correlates of IBMX-induced LTP included lowering of synaptic threshold and enhancement of the rate of rise of the EPSP with no alterations in the passive membrane characteristics of CA1 pyramidal neurons. The fact that IBMX was able to exert its effect even in the presence of the calcium-blocker cation Co²⁺, taken together with the drug's action on hippocampal exchangeable Ca²⁺, raises the possibility that the Ca²⁺ necessary for induction of LTP may be derived from an intraneuronal storage site. These studies indicate the significance of intracellular Ca²⁺ -regulatory mechanisms in long-term changes of neuronal excitability which occur in experimental models of epilepsy and long-term potentiation. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

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