Behavioral Vigilance Research Articles

Effects of benzodiazepine receptor inverse agonists and nicotine on behavioral vigilance in senescent rats.

Previous experiments demonstrated that, compared with 6-month-old rats, the performance of 20-month-old rats in a behavioral vigilance task was characterized by an impairment in their ability to detect visual signals, whereas their ability to discriminate between longer signals and nonsignal events was unaffected. The benzodiazepine receptor (BZR) agonist chlordiazepoxide potently and selectively interacted with the effects of age on the relative number of hits. However, negative modulators of GABAergic transmission (Zk 93 426, beta-CCtB, RU 33965) failed to attenuate the effects of age on behavioral vigilance. the present experiment tested the hypothesis that the performance of senescent animals (28 months) is further impaired and thus would allow the demonstration of beneficial effects of BZR inverse agonists or nicotine. However, administration of ZK 93 426 (0.39, 1.56, 6.25 mg/kg), Ru 33965 (0.1, 0.5 mg/kg), or nicotine (0.09, 0.287, 0.689 mg/kg) did not beneficially affect the performance of senescent animals; rather, detrimental effects were found. Considering the beneficial behavioral effects of these compounds in animals with experimentally induced impairments in cholinergic function, the present finding point to limitations of normal aging as a variable in animal experiments on BZR inverse agonist or nicotine-induced attenuation of cognitive impairments that result from cholinergic hypofunction.

Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: Selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density.

Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: Selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density.

Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density.

Rats were trained in a previously validated behavioral vigilance task that required them to detect visual signals of variable length and to discriminate signal from nonsignal events. Baseline performance was characterized by a signal length-dependent ability to score hits, a decline in hits over time, and a correct rejection rate of approximately 70%. After the rats reached criterion performance in this task, the immunotoxin 192 IgG-saporin or its vehicle was infused into the area of the nucleus basalis/substantia innominata of the basal forebrain. Postoperative performance in lesioned rats was characterized by a decrease in their ability to detect signals while their ability to correctly reject nonsignals remained unaffected. The effect of the lesion did not recover in the course of over 180 sessions of postlesion testing. The overall performance of the rats correlated with acetylcholinesterase (AChE)-positive fiber density in all cortical areas measured except the cingulate and pyriform cortex. These findings help to elucidate the nature of the attentional impairments resulting from the loss of cortical cholinergic inputs.

Dissociation between the attentional effects of infusions of a benzodiazepine receptor agonist and an inverse agonist into the basal forebrain.

The effects of infusions of the benzodiazepine receptor (BZR) full agonist chlordiazepoxide (CDP) or the full inverse agonist beta-CCM into the basal forebrain on behavioral vigilance were tested. Vigilance was measured by using a previously characterized task that requires the animals to discriminate between visual signals of variable length and non-signal events. Measures of performance included hits, misses, correct rejections, false alarms, side bias, and errors of omission. Following the infusion of saline (0.5 microliters/hemisphere), the relative number of hits varied with signal length. In response to shorter signals, the number of hits decreased over time, indicating a vigilance decrement. Infusions of CDP (20, 40 micrograms/hemisphere) initially decreased the relative number of hits in response to shorter signals and, later in the course of the test sessions, to longer signals as well. CDP did not affect the relative number of correct rejections. In contrast, infusions of the inverse agonist beta-CCM (1.5, 3.0 micrograms/hemisphere) did not affect the relative number of hits but decreased the relative number of correct rejections (i.e., increased the number of false alarms). These data suggest that the basal forebrain mediates the attentional effects of BZR ligands. As systemic or intrabasalis administration of BZR agonists and inverse agonists was previously demonstrated to decrease and augment, respectively, activated cortical acetylcholine (ACh) efflux, their effects on behavioral vigilance are hypothesized to be mediated via their effects on cortical ACh.

Effects of nicotinic acetylcholine receptor ligands on behavioral vigilance in rats.

The effects of nicotinic receptor ligands on performance in a task measuring sustained attention, or vigilance, were tested. This task required the animals to discriminate between signal and non-signal events. The sequence of signal (central panel light illumination for 500, 50 or 25 ms) and non-signal presentations was randomized over three blocks of 54 trials each (27 signal trials, 9 per length, and 27 non-signal trials). A left lever press following a signal was counted as a hit, and a right lever press following a non-signal event was counted as a correct rejection. Hits and correct rejections were rewarded, whereas misses and false alarms (defined as incorrect right and left lever presses, respectively) were not. Baseline performance was characterized by a signal length dependent ability of the animals to discriminate between signal and non-signal events. Administration of nicotine (0.19, 0.62, 1.9 mumol) or of two novel nicotinic receptor agonists, ABT-418 and A-82695, did not produce main effects on vigilance performance. Lobeline (1.9, 6.2, 19 mumol), a nicotinic receptor ligand with mixed agonist/antagonist activities, impaired the animals' ability to discriminate between signal and non-signal events. The antagonist mecamylamine (5, 15, 50 mumol) potently impaired performance while increasing the number of errors of omission. The lack of effect of nicotine largely corresponds with the findings from previous studies on the acute effects of nicotine in intact subjects and non-smoking humans. While the detrimental effects of lobeline may have been related to the antagonist effects of this compound, the reasons for the differences between the effects of nicotine and lobeline still remain unsettled. These data support the hypothesis that nicotine receptor mechanisms are maximally activated in intact animals performing this task, and suggest that effects of acute nicotinic agonist treatment would not produce further cognitive benefit for these animals.

Behavioral vigilance in rats: task validation and effects of age, amphetamine, and benzodiazepine receptor ligands

An operant task for the measurement of sustained attention or vigilance in rats was characterized. The task requires the animals to respond to the presentation of visual signals (presented for 25, 50, or 500 ms) by operating one lever ("hits") and to the absence of a signal by operating the opposite lever ("correct rejection"). Incorrect responses ("misses" and "false alarms", respectively) were not rewarded. Performance in this task is a function of signal length, i.e., the shorter the signals the higher the number of misses. An increase in "background noise" by flashing the chamber houselight (at 0.5 Hz) impaired the animals' ability to discriminate between signal and non-signal events. Also flashing the houselight augmented the vigilance decrement observed for shortest signals. An increase in the event-rate also resulted in a vigilance decrement. Finally, the inability of the animals to time signals was examined by testing the effects of an increase in event asynchrony. In a second experiment, the performance of differently aged rats (6- and 20 month-old male BNNia/F344 rats) was studied. Compared to young animals, 20-month-old rats showed a decrease in their ability to discriminate between shortest signals (25 ms) and non-signal events but did not differ in their ability to correctly reject non-signal trials. Administration of the benzodiazepine receptor (BZR) agonist chlordiazepoxide (CDP; 3, 5, 8 mg/kg) resulted in an impairment of the animals' ability to discriminate between signal and non-signal events and, similar to the effects of age, this effect was exclusively due to an increase in the number of misses. CDP generally produced potent effects while affecting the aged animals to a greater degree. BZR-ligands with weak or "selective" inverse agonist properties (ZK 93426; beta-CCtB) did not affect vigilance performance. The BZR partial inverse agonist RU 33965 (0.1, 0.5 mg/kg) dose-dependently impaired vigilance performance. The administration of amphetamine (0.4, 0.8 mg/kg) also impaired performance, but these impairments were possibly based on effects unrelated to attentional mechanisms. The finding that performance in this task revealed the interactions between the effects of age and BZR agonists on attentional abilities further supports the validity of measures of performance generated by this task.

Dissociation between the effects of benzodiazepine receptor agonists on behavioral vigilance and responsitivity.

The effects of benzodiazepine receptor (BZR) full agonists chlordiazepoxide and midazolam, and the partial agonist beta-carboline ZK 91,296 on the rat's performance in a simple reaction time paradigm were examined. This task required the animals to respond to a rarely and unpredictably occurring brief (50 ms) visual stimulus. Non-parametric measures of signal sensitivity and response bias derived from signal-detection theory were used as a basis for the dissociation between the effects of these drugs on attentional abilities and general responsivity. The dose-dependent effects of midazolam (0.1-3.13 mg/kg) on signal sensitivity and general responsivity occurred in parallel. In contrast, the effects of chlordiazepoxide (1.56-12.5 mg/kg) on signal sensitivity were largely independent from effects on response bias. The partial agonist ZK 91,296 (0.39-25 mg/kg) in general had little effect on performance. The effects of the highest doses of chlordiazepoxide and midazolam were reversed by the co-administration of the BZR antagonist Ro15-1788 (15 mg/kg). Additionally, extension of the stimulus presentation time to 500 ms decreased the magnitude of the effect of chlordiazepoxide on signal sensitivity. These results support the hypothesis that BZR agonist-induced disruption of attentional abilities is not necessarily confounded by effects on general responsivity or sedation, and thus may represent a discrete pharmacological property of BZR-agonists.