Paul Dudchenko

Activating the damaged basal forebrain cholinergic system: tonic stimulation versus signal amplification.

The hypothesis that the cognitive decline in senile dementia is related to the loss of cortical cholinergic afferent projections predicts that pharmacological manipulations of the remaining cholinergic neurons will have therapeutic effects. However, treatment with cholinesterase inhibitors or muscarinic agonists has been, for the most part, largely unproductive. These drugs seem to disrupt the normal patterning of cholinergic transmission and thus may block proper signal processing. An alternative pharmacological strategy which focuses on the amplification of presynaptic activity without disrupting the normal patterning of cholinergic transmission appears to be more promising. Such a strategy may make use of the normal GABAergic innervation of basal forebrain cholinergic neurons in general, and in particular of the inhibitory hyperinnervation of remaining cholinergic neurons which may develop under pathological conditions. Disinhibition of the GABAergic control of cholinergic activity is assumed to intensify presynaptic cortical cholinergic activity and to enhance cognitive processing. Although the extent to which compounds such as the benzodiazepine receptor antagonistβ-carboline ZK 93 426 act via the basal forebrain GABA-cholinergic link is not yet clear, the available data suggest that the beneficial behavioral effects of this compound established in animals and humans are based on indirect cholinomimetic mechanisms. It is proposed that an activation of residual basal forebrain cholinergic neurons can be achieved most physiologically via inhibitory modulation of afferent GABAergic transmission. This modulation may have a therapeutic value in treating behavioral syndromes associated with cortical cholinergic denervation.

Toward modeling age-related changes of attentional abilities in rats: Simple and choice reaction time tasks and vigilance

Fischer-344 rats aged 4, 12, or 18 months were trained in a simple or choice reaction time task (SRTT; CRTT). Animals were required to detect a brief (50 ms), rarely, and unpredictably occurring signal that was presented either at the central panel light (SRTT) or above one of the two levers (CRTT). Animals reported detection by pressing either lever (SRTT) or the cued lever (CRTT) within 3 s. False alarm rates were obtained from a nonsignal 3-s bin. In comparison to younger animals, 18-month-old animals showed a reduced signal detectability, and this effect did not interact with practice. These results suggest that age affected vigilance and practice did not attenuate this effect. The benzodiazepine receptor agonist chlordiazepoxide (at subsedative doses; 1, 3, and 5 mg/kg) and the beta-carboline ZK 93 426 (1, 3, and 5 mg/kg) failed to affect signal detectability. Scopolamine HBr and MBr impaired detectability and responsivity to a similar extent. However, scopolamine MBr, unlike the tertiary compound, failed to affect response accuracy in the CRTT. It is speculated that the failure of chlordiazepoxide to affect performance was related to low processing demands of both tasks. Although these behavioral models show good face validity, they do not allow determination of the major components of attentional processes (perceptual sensitivity, response criterion, processing capacity). Animal behavioral paradigms that allow determination of such components are required for the investigation of the neuronal basis of age-related changes in attentional abilities.

Behavioral microanalysis of spatial delayed alternation performance: rehearsal through overt behavior, and effects of scopolamine and chlordiazepoxide

Rats were trained in an operant spatial delayed alternation task utilizing retention intervals from 2 to 32 s. In addition to response accuracy, operations of the levers during the retention intervals were recorded and analyzed. Animals were tested following the administration of the muscarinic antagonists scopolamine hydrobromide and methylbromide, and the benzodiazepine receptor agonist chlordiazepoxide. In vehicle-treated animals, the relative number of correct responses and correct rehearsal operations (operation of the forthcoming correct lever during retention intervals) varied with the length of the retention intervals, and these measures were correlated. The response rate for rehearsal operations increased with the length of the retention intervals. It is speculated that the delay-dependent increase in response rate reflects an effect of delayed reward that was also associated with a delay-dependent increase in the tendency to alternate between levers. The effects of delay on the accuracy of rehearsal operations may have contributed to the delay-dependent correct responding. Scopolamine hydrobromide (0.01, 0.03, 0.1, 0.3 mg/kg) and methylbromide (0.1, 0.3 mg/kg) impaired correct responding, but did not seem to interfere with the relative number of correct rehearsal operations. As only the presentation of the panel light indicated trial onset, it is speculated that the cholinergic receptor blockade resulted in an increase in the probability of a repositioning response that was triggered by light onset. Chlordiazepoxide (1, 3, 5, 10 mg/kg) did not affect behavioral performance. These results suggest that in tasks that allow the development of rehearsal operations, delay-dependent response accuracy does not represent a sufficient condition for conclusions on task demands on memory. Blockade of peripheral cholinergic receptors may account for the effects of muscarinic antagonists on performance in this task.

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

The effects of benzodiazepine receptor (BZR) full agonists chlordiazepoxide and midazolam, and the partial agonistβ-carboline ZK 91 296 on the rats 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.

Interactions between the effects of basal forebrain lesions and chronic treatment with MDL 26,479 on learning and markers of cholinergic transmission

The effects of ibotenic acid-induced basal forebrain lesions and treatment with the triazole MDL 26,479 on the acquisition of an operant visual conditional discrimination task and on [3H]hemicholinium-3 and [3H]vesamicol binding were examined. Lesioned animals required more training sessions to acquire the stimulus-response rules of this task. They also showed longer response latencies throughout the experiment. The effects of the treatment with MDL 26,479 (5 mg/kg; i.p. 60 min before each training session) interacted with the effects of the lesion, producing a decrease in the number of sessions required to perform above chance-level in lesioned but not in control animals. MDL 26,479 did not seem to produce immediate performance effects but interacted with the learning process. The lesions destroyed the cell bodies in the area of the substantia innominata, basal nucleus of Meynert, and the globus pallidus. The number of frontocortical cholinergic terminals as primarily indicated by hemicholinium-3 binding was reduced in lesioned animals; however, another measure of cholinergic terminals, vesamicol binding, was unchanged. Behavioral performance of animals correlated significantly with hemicholinium binding in the frontal cortex of the right hemisphere. The fact that the lesion delayed but did not block the acquisition of the task may have been a result of compensatory mechanisms in remaining cholinergic terminals as indicated by stable vesamicol binding. These data allow assumptions about the conditions for the demonstration of beneficial behavioral effects of MDL 26,479. They also suggest that the long-term effects of basal forebrain lesions on cortical cholinergic transmission remain unsettled.

Failure of a chlordiazepoxide to reproduce the behavioral effects of muscimol administered into the basal forebrain

Bilateral infusion of the GABAA-receptor agonist muscimol into the basal forebrain was previously found to impair visual conditional discrimination performance in rats. In order to examine whether the GABAergic input into the basal forebrain is active during performance of this task, the benzodiazepine receptor agonist chlordiazepoxide (15, 25, 40 micrograms/0.5 microliters/hemisphere) was bilaterally infused. Surprisingly, chlordiazepoxide did not affect performance. The impact of this result for the understanding of basal forebrain GABAergic functions is discussed.

Cognition Enhancement Based on GABA-Cholinergic Interactions

Since the early anatomical descriptions of the basal forebrain (Brockhaus, 1942; Gorry, 1963) and the determination of acetylcholine (ACh) as a major transmitter of its cortical projections (for review see Fibiger, 1982; Butcher and Wolf, 1986), research aimed at the determination of the functions of forebrain ACh has flourished. Early theories have proposed that central cholinergic systems are involved in the processing of relatively specific components of behavioral functions (e.g., in the effects of unrewarded behavior; Carlton, 1963); however, evidence suggesting the involvement of cortical cholinergic affeents in the symptoms of dementia (Bowen et al., 1976; Whitehouse et al., 1983; Palmer et al., 1987a,b; Reinikainen et al., 1990) has resulted in an almost exclusive research focus on the cholinergic mediation of learning and memory (Bartus et al., 1982).

Modulation of Frontal Cortical Acetylcholine Release by Benzodiazepine Receptor Ligands: Age-Dependent Effects and Behavioral Correlates

The previous optimism about the efficacy of cholinomimetics for the treatment of age- and dementia-associated syndromes was based on the assumption that a neurotransmitter replacement strategy, similar to the successful treatment of the dopaminergic deficiency in Parkinson’s disease, would attenuate the behavioral consequences of loss of basal forebrain cholinergic neurons. This “cholinergic hypothesis’’ (e.g., Bartus et al., 1985) was derived mainly from correlative neuropathological evidence (Whitehouse et al., 1981; Bowen et al., 1976; Palmer et al., 1987; Procter et al., 1988), and from animal studies that used basal forebrain lesions as a neurological model or muscarinic blockade as a pharmacological model (Hagan and Morris, 1988) for the behavioral consequences of cholinergic cell loss (Smith, 1988). However, it has more recently become evident that: (1) in the absence of a specific cholinotoxin, the basal forebrain model is invalid in terms of revealing the consequences of disruption to the basal forebrain cholinergic system (Robbins et al., 1989a; Salter and Dudchenko, 1991); (2) muscarinic antagonism produces behavioral deficits that model only some of the symptoms of dementia but spare major aspects such as the failure to retrieve information from remote memory (e.g., Beatty et al., 1986); and (3) traditional cholinomimetic drugs do not appear to exhibit clinically useful effects (for review see Sarter et al., 1991a). Reviewing this literature, Fibiger (1991) concluded that the contribution of the cholinergic system to the cognitive decline in dementia is unsettled, and that “programs aimed at developing cholinergic pharmacotherapies for the cognitive deficits in AD are based more on faith than on established facts” (p. 223). Fibiger, as well as others (e.g., Whalley, 1989) predicts that successful therapies will become obvious only after we learn more about etiological processes.