Pharmacological evaluation of idazoxan-induced noradrenergic modulation of excitatory and inhibitory processes in the dentate gyrus of the anaesthetized rat

Knight, John Christopher (2002) Pharmacological evaluation of idazoxan-induced noradrenergic modulation of excitatory and inhibitory processes in the dentate gyrus of the anaesthetized rat. Masters thesis, Memorial University of Newfoundland.

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Abstract

Exogenous norepinephrine (NE) potentiates the evoked potential (EP) recorded from the dentate gyrus (DG) of the hippocampus in vivo (Neuman and Harley, 1983; Winson and Dahl, 1985) and in vitro (Lacaille and Harley, 1985; Stanton and Sarvey, 1985b). Endogenous NE released by activation of the locus coeruleus (LC) system by glutamatergic (Harley and Milway, 1986; Harley and Evans, 1988) or electrical stimulation (Dahl and Winson, 1985, Assaf et al., 1979; Washburn and Moises, 1989) of the LC or its input, the nucleus paragigantocellularis (Babstock and Harley, 1992) has similar effects. Evidence suggests that the initiation of these potentiations are mediated by ?-adrenergic activation and that local ?-receptors in the DG play an important role in this phenomenon (Lacaille and Harley, 1985; Stanton and Sarvey, 1985b; Babstock and Harley, 1992; Washburn and Moises, 1989; Harley and Milway, 1986). NE has also been shown to excite and inhibit interneurons recorded in the DG (Rose and Pang, 1989; Clarke 1995). -- Yet another method of releasing endogenous LC-NE and subsequent potentiation of the DG EP is via systemic application of the ?2-antagonist idazoxan (IDA) (Cedarbaum and Aghajanian, 1978; Richter-Levin, 1991; Sara and Bergis, 1991). IDA has also been shown to result in an increase in paired-pulse inhibition in the DG (Sara and Bergis, 1991). -- The present study utilized the paired-pulse paradigm and double pipette technique to examine the role of ?-receptor activation in IDA-induced NE modulation of excitation and inhibition in the local circuitry of the DG. Saline and timolol-filled micropipettes were placed in the DG of urethane-anaesthetized rats. The perforant path was stimulated with paired pulses spaced at short intervals and rats were given systemic injection of IDA after baseline recroding. Evidence was demonstrated for five distinct effects of NE in the local circuitry of the DG. These were: 1) enhancement of tonic activity of somatic inhibitory interneurons at baseline via low threshold p-receptor activation; 2) increased cell firing to a constant input supported by a high-threshold direct p-receptor action on granule cell membranes; 3) a decrease in EPSP size probably due to increased feed-forward dendritic inhibition; 4) inhibition of somatic feedback disinhibition circuits (rather than an increase in inhibition per se); and 5) enhancement of firing of feedback dendritic inhibitory interneurons possibly via ?1 -receptor activation. Effects observed in the DG with IDA in the present study were compared to those observed during learning and exploration of a new environment in other studies.

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