The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats.

Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this impairment was largely reversed at 24-h. Animals in the high-dose NTP (20mg/kg/day) group were impaired at both short- and long-term intervals. Activity levels, used as an index of location memory during the ORT, demonstrated that rats receiving DMI were again impaired at retaining memory for location. DMI dose-dependently disrupts LTP in the dentate gyrus of anesthetized rats and also disrupts memory for tests of spatial memory when administered for long periods.

Selective tuning of hippocampal oscillations by phasic locus coeruleus activation in awake male rats.

Theta and gamma oscillations are thought to provide signal sets that promote neural coding of cognitive processes. Over 40 yrs ago, Jeffrey Gray reported event-related changes in a narrow band of hippocampal theta (7.5-8.5 Hz) which appeared to involve norepinephrine (NE) release from, the noradrenergic nucleus, the locus coeruleus (LC). These event-related alterations in EEG were elicited by novelty, attentional changes, the use of preparatory signals, and signal-mismatch events. Gray et al. have since provided indirect evidence that supports the role of NE in the modulation of 7.5- to 8.5-Hz oscillations in the hippocampus, but studies investigating the effects of direct LC activation in awake rats have been lacking. In the present study, dentate gyrus EEG was examined during glutamatergic activation of the LC in awake male rats in relation to plasticity effects on simultaneously recorded perforant path-evoked field potentials. Glutamate-injected animals were divided into three groups based on histological and plasticity outcomes; perforant path stimulated controls were also included. The three injected groups were: (1) rats with positive LC placements, demonstrating NE-LTP of the dentate gyrus evoked potential, (2) rats with positive LC placements, without NE-LTP, and (3) Non-LC injected controls. Activation of the LC in awake rats demonstrating NE-LTP increased the relative power of 7- to 9-Hz theta, a result masked in broader 4- to 12-Hz analysis. Comparatively, urethane-anesthetized rats showed an increase in 5-7 Hz, but not 7- to 9-Hz theta with LC activation. Discriminative analysis in the approximate theta band predicted by Gray (7.4-8.5 Hz) revealed that awake rats demonstrating NE-LTP had increased relative power in this narrow frequency compared to rats receiving perforant path only (noninjected) and Non-LC injected rats. Transiently reduced gamma (20-40 Hz) relative power was most commonly observed in rats with verified LC placements failing to express NE-LTP. Given current theories of LC function, these results suggest oscillatory tuning within the theta and gamma range may facilitate shifts in cognitive set.