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M Sarter

Publications and source records attributed to M Sarter.

At least 55 records · Page 3Linked to original sources
PubMed1999

Cholinergic inputs to the rat medial prefrontal cortex mediate potentiation of the cardiovascular defensive response by the anxiogenic benzodiazephine receptor partial inverse agonist FG 7142.

Consistent with its putative anxiogenic actions, administration of the benzodiazepine receptor partial inverse agonist FG 7142 has been shown to potentiate defensive-like cardiovascular reactivity to an acoustic stimulus in the rat, an effect that appears to be mediated by the basal forebrain cholinergic system. The present studies tested the hypothesis that the basal forebrain cholinergic projections to the medial prefrontal cortex, an area that has been implicated in both anxiety and autonomic control, may be a relevant pathway underlying this response potentiation. Infusions of the muscarinic receptor agonist carbachol into the medial prefrontal cortex, but not into the lateral prefrontal cortex or the basolateral amygdala, mimicked the effects of systemically administered FG 7142 on the cardioacceleratory response. Infusions of the muscarinic antagonist atropine blocked this effect, as well as the response-potentiating actions of FG 7142. The effects of FG 7142 were also blocked by lesions of the cholinergic inputs to the medial prefrontal cortex produced by local infusions of the immunotoxin 192 immunoglobulin G-saporin into this area. These findings indicate that cholinergic activation of the medial prefrontal cortex is sufficient to enhance the cardioacceleratory defensive response, and that cholinergic inputs to the medial prefrontal cortex are necessary for the response-potentiating effects of FG 7142. These results are consistent with a recent neurobiological model of anxiety and autonomic control that attributes the enhanced processing of anxiety-related stimuli and contexts to increases in activity in cortical cholinergic inputs.

Animals↗
PubMed1999

Intra-accumbens infusions of antisense oligodeoxynucleotides to one isoform of glutamic acid decarboxylase mRNA, GAD65, but not to GAD67 mRNA, impairs sustained attention performance in the rat.

The effects of bilateral infusions of antisense oligodeoxynucleotides (ODNs) for the two isoforms of glutamic acid decarboxylase (GAD65; GAD67) into the nucleus accumbens on the performance of intact rats in a task designed to assess sustained attention were tested. The task required the animals to discriminate between signal and non-signal events. Signals and non-signals were presented randomly and unpredictably. The task generated all four response types of a sustained attention task, i.e., hits, misses, correct rejections, false alarms. Infusions of the scrambled sequence ODNs did not affect performance. Likewise, infusions of the GAD67 ODNs failed to produce any effect. However, infusions of the GAD65 ODNs into the nucleus accumbens resulted in a robust and reliable decrease in the relative number of hits. Similarly, the combined infusion of GAD65+67 ODNs impaired the hit rate but did not affect the animals' ability to reject non-signals. Following each treatment series, performance rapidly returned to baseline, further indicating the specificity and reversibility of the effects of the infusions of the ODNs. While these data suggest that translation arrest of specifically the GAD65 isoform of the enzyme in the nucleus accumbens impairs attentional performance, the neuronal mechanisms mediating these effects remain unsettled.

Animals↗
PubMed1999

Effects of ovariectomy, 192 IgG-saporin-induced cortical cholinergic deafferentation, and administration of estradiol on sustained attention performance in rats.

Female ovariectomized (OVX) and sham-OVX rats were trained in a task designed to assess sustained attention. After achieving asymptotic performance, OVX rats did not exhibit the impairment in performance over blocks of trials (i.e., the vigilance decrement) observed in sham-OVX rats. Furthermore, OVX rats' performance over blocks of trials was unaffected by the normally detrimental effects of a visual distractor. 192 IgG-saporin-induced lesions of basal forebrain cholinergic neurons resulted in similar impairments in the performance of OVX and sham-OVX rats. The acute, but not chronic, administration of 17beta-estradiol attenuated the lesion-induced decrease in the relative number of hits to longest signals exclusively in rats with intact ovaries. These findings indicate that the variables contributing to the potential therapeutic effects of estradiol remain poorly understood.

Animals↗
PubMed1999

In vivo neurochemical correlates of cognitive processes: methodological and conceptual challenges.

The advent of the use of in vivo microdialysis and voltammetry techniques in behaving animals has ushered in a great deal of research on the neurochemistry of cognition. While studies exploring the relationship between neurotransmitter release and cognitive processing are quite feasible, a number of methodological and conceptual issues pose challenges to the interpretation of experimental results. These challenges include: 1) a demonstration that the behavioral task highlights the particular cognitive construct under study; 2) a determination of the role of non-cognitive variables (i.e. transfer effects, sensory stimulation, motivational variables, and motor activity) in affecting transmitter release, and 3) a recognition of the value of a distributed systems approach to studying the neurochemistry of cognition. This review summarizes the data on the validity of microdialysis and voltammetry as correlates of neurotransmitter release and then illustrates the impact that the above challenges can have on the conclusions drawn from various studies.

Acetylcholine↗
PubMed1998

Cortical acetylcholine, reality distortion, schizophrenia, and Lewy Body Dementia: too much or too little cortical acetylcholine?

Aberrations in cortical cholinergic transmission have been hypothesized to mediate the development and manifestation of psychotic cognition. Based primarily on hypotheses about mesolimbic dopaminergic hyperactivity in schizophrenia, the actions of antipsychotic drugs, the trans-synaptic regulation of the excitability of basal forebrain corticopetal cholinergic neurons, and the role of cortical cholinergic inputs in attentional functions, we hypothesized that persistent disinhibition of cortical cholinergic inputs mediates the fundamental cognitive dysfunctions which form the basis for the development of positive symptoms in schizophrenia. In contrast to this hypothesis, Perry and Perry (1995), based on evidence from hallucinating patients with Lewy Body Dementia (LBD), concluded that the extensive loss of cortical acetylcholine allows irrelevant information to enter "conscious awareness" and thus hallucinations to emerge. The discussion of these contrasting hypotheses highlights the need for more dynamic and precise theories describing the cognitive variables and neuronal processes which contribute to the development and manifestation of psychotic cognition. While the hypothesis that a disinhibited cholinergic system mediates the evolution of psychotic symptoms corresponds more convincingly with current theories about the cognitive functions of cortical cholinergic inputs, both hypotheses stress the critical role of cortical acetylcholine in the highest levels of cognitive functioning.

Acetylcholine↗
PubMed1998

Effects of repeated administration of amphetamine on behavioral vigilance: evidence for "sensitized" attentional impairments.

The effects of repeated intermittent administration of amphetamine (1, 2, 3 mg/kg, i.p.) on the performance of rats in a task designed to assess sustained attention were tested. A substantial increase in the number of false alarms (i.e., "claims" for hits in nonsignal trials) was observed following subsequent administrations of amphetamine. This effect could not be accounted for by drug-induced side or position biases, switching behavior or stereotypy. The effects of repeated amphetamine may model some of the cognitive processes which mediate the attribution of incentive salience to stimuli associated with repeated psychostimulant administration and the development of psychostimulant-induced psychotic symptoms.

Amphetamine↗
PubMed1998

Age-related changes in rodent cortical acetylcholine and cognition: main effects of age versus age as an intervening variable.

Evidence from aged and demented humans has stimulated research on the effects of age on the integrity of cortical cholinergic afferents in rodents. However, a comprehensive review of the available data does not consistently support the hypothesis that normal aging in rodents robustly affects the function of basal forebrain cholinergic projections to the cortex. These data indicate the limited significance of age as an independent experimental variable in research on age-related changes in cortical acetylcholine and associated behavioral or cognitive functions. Alternatively, recent studies demonstrated that normal aging in rodents potently interacts with the consequences of experimental manipulations of this system. Thus, aging acts as an intervening variable in experiments designed to elucidate age-related changes in the vulnerability and restorative capacity of this neuronal system after injury and degenerative processes. Investigations of the interactions between the effects of age and the capacity of the cholinergic systems to respond to detrimental processes reveal robust consequences of aging on cortical acetylcholine and the cognitive functions mediated by this neuronal system.

Acetylcholine↗
PubMed1998

Cardiovascular and somatic startle and defense: concordant and discordant actions of benzodiazepine receptor agonists and inverse agonists.

Benzodiazepine receptor (BZR) agonists and inverse agonists yield generally opposing effects on GABAergic transmission, and the functional consequences of these ligands are often bidirectional. BZR agonists exert anxiolytic effects, whereas the BZR partial inverse agonist FG 7142 has been reported to have anxiogenic actions in a variety of paradigms. In keeping with this literature, we found that the cardioacceleratory defensive response is enhanced by FG 7142, and attenuated by the BZR agonist chlordiazepoxide. In contrast, both compounds attenuated basal and fear-potentiated somatic startle responses. This did not appear to reflect a global reduction of startle reactivity, however, as the cardiac startle response was not significantly altered. These findings support the view that multiple substrates underlie distinct aspects or features of fear and anxiety. The results are consistent with the suggestion that FG 7142 may selectively enhance those aspects of anxiety that depend on cortical-cognitive processing.

Aggression↗
PubMed1998

Anxiety and cardiovascular reactivity: the basal forebrain cholinergic link.

The relations between anxiety states and autonomic functions are considered from the vantage of a model of the neural systems underlying anxiety and autonomic control. An important component of this model is the involvement of the basal forebrain cortical cholinergic system that is seen to play a crucial role in the cognitive aspects of anxiety, and the links between anxiety and autonomic regulation. An additional aspect of the model is the detailing of the routes by which autonomic reactivity and associated visceral afference can modulate more rostral components of the system. The proposed model offers a more comprehensive framework for research on the neurobiology of anxiety and autonomic control.

Animals↗
PubMed1998

Effects of local cholinesterase inhibition on acetylcholine release assessed simultaneously in prefrontal and frontoparietal cortex.

To investigate whether acetylcholine is released in a similar fashion in different regions of the cortex, in vivo microdialysis was used to measure acetylcholine efflux simultaneously in the medial prefrontal and the frontoparietal cortex, under both basal conditions and following tactile stimulation. Additionally, the effects of including two different concentrations (0.05 microM and 0.5 microM) of a cholinesterase inhibitor (neostigmine) in the perfusion fluid were assessed. Basal levels of acetylcholine (i.e. during non-stimulated sessions) were similar in medial prefrontal and frontoparietal areas. Tactile stimulation reliably increased acetylcholine efflux in a similar fashion (up to 140% increase above baseline) in both cortical areas studied. Predictably, the higher concentration of neostigmine (0.5 microM) increased basal acetylcholine efflux by about 150% from levels observed with the lower neostigmine concentration (0.05 microM), but the concentration of local neostigmine had no effect on either the magnitude or the duration of the increased acetylcholine efflux following tactile stimulation. These results suggest that the pattern of acetylcholine release may be comparable in different areas of the cortex, supporting the idea that cholinergic projections from the basal forebrain to the cortex represent a globally regulated system. Furthermore, while the inclusion of neostigmine in perfusion fluid must be taken into account when interpreting acetylcholine efflux data, it appears that concentrations of up to 0.5 microM do not interfere fundamentally with the lability of cortical acetylcholine efflux in response to behavioural stimulation.

Acetylcholine↗
PubMed1998

Sustained attention performance in rats with intracortical infusions of 192 IgG-saporin-induced cortical cholinergic deafferentation: effects of physostigmine and FG 7142.

Rats with extensive lesions of cortical cholinergic afferents as a result of infusions of 192 IgG-saporin into the basal forebrain show persistent impairments in sustained attention performance (J. McGaughy, T. Kaiser, & M. Sarter, 1996). However, the administration of neither the cholinesterase inhibitor physostigmine nor the benzodiazepine receptor partial inverse agonist FG 7142 attenuated the lesion-induced impairments in performance. The present study demonstrated that less extensive cortical cholinergic deafferentation, produced by intracortical infusions of a relatively small concentration of 192 IgG-saporin, resulted in a significant impairment in sustained attention. However, the administration of neither physostigmine (0.01-0.1 mg/kg) nor FG 7142 (0.1-1.0 mg/kg) benefited the performance of the animals. Because neither compound selectively augments performance-associated increases in acetylcholine release from residual neurons, beneficial effects on cortical cholinergic deafferentation-based impairments in attention may remain limited.

Afferent Pathways↗
PubMed1997

Dopamine role.

Explore the source record for details and available documents.

Acetylcholine↗
PubMed1997

Cognitive functions of cortical acetylcholine: toward a unifying hypothesis.

Previous efforts aimed at attributing discrete behavioral functions to cortical cholinergic afferents have not resulted in a generally accepted hypothesis about the behavioral functions mediated by this system. Moreover, attempts to develop such a unifying hypothesis have been presumed to be unproductive considering the widespread innervation of the cortex by basal forebrain cholinergic neurons. In contrast to previous descriptions of the role of cortical acetylcholine (ACh) in specific behavioral phenomena (e.g., mediation of the behavioral effects of reward loss) or mnemonic entities (e.g., working or reference memory), cortical ACh is hypothesized to modulate the general efficacy of the cortical processing of sensory or associational information. Specifically, cortical cholinergic inputs mediate the subjects' abilities to detect and select stimuli and associations for extended processing and to allocate the appropriate processing resources to these functions. In addition to evidence from electrophysiological and behavioral studies on the role of cortical ACh in sensory information processing and attention, this hypothesis is consistent with proposed functions of the limbic and paralimbic networks in regulating the activity of the basal forebrain cholinergic neurons. Finally, while the proposed hypothesis implies that changes in activity in cortical ACh simultaneously occur throughout the cortex, the selectivity and precision of the functions of cholinergic function is due to its coordinated interactions with the activity of converging sensory or associational inputs. Finally, the dynamic, escalating consequences of alterations in the activity of cortical ACh (hypo- and hyperactivity) on cognitive functions are evaluated.

Acetylcholine↗
PubMed1997

Modulation of cognitive processes by transsynaptic activation of the basal forebrain.

Each of the neurotransmitter-specific afferents to the basal forebrain (BF) carry different types of information which converge to regulate the activity of cholinergic projections to telencephalic areas. Brainstem monoaminergic and cholinergic inputs are critical for context-dependent arousal. GABAergic afferents are gated by a variety of ascending and descending systems, and in addition provide an intrinsic control of BF output excitability. Corticofugal glutamatergic inputs represent reciprocal connections from sites to which BF afferents project, and carry information about the current level of cortical processing intensity and capacity. Peptidergic inputs arise from hypothalamic sources and locally modulate BF output as a function of motivational and homeostatic processes. The significance of these afferent systems can be studied by examining the behavioral consequences of infusion into the BF of drugs that act on the specific receptor systems. Although traditional analyses suggest that the BF has many behavioral functions that can be subdivided regionally, an analysis of studies employing transsynaptic approaches lead to the conceptualization of the BF as having a uniform function, that of maximizing cortical processing efficiency. The BF is conditionally active during specific episodes of acquisition and processing of behaviorally significant, externally-derived information, and drives cortical targets into a state of readiness by reducing interference and amplifying the processing of relevant stimuli and associations, thus allowing for more efficient processing. This paper describes the transsynaptic approach to studying BF function, reviews the neurobiological and behavioral consequences of altering neurotransmitter-specific inputs to the BF, and explores the functional significance of the BF.

Animals↗
PubMed1997

Trans-synaptic stimulation of cortical acetylcholine and enhancement of attentional functions: a rational approach for the development of cognition enhancers.

Activation and restoration of cholinergic function remain major foci in the development of pharmacological approaches toward the treatment of cognitive dysfunctions associated with aging and dementia. Our research has been guided by the hypothesis that (re)activation of cortical cholinergic inputs is achieved as a result of trans-synaptic disinhibition of basal forebrain cholinergic neurons. This approach depends on the ability of benzodiazepine receptor (BZR) inverse agonists to reduce the potency of GABA to block neuronal excitation. BZR inverse agonists were found to augment cortical ACh efflux through interaction with cognition-associated activation of this system. Cortical cholinergic inputs have been implicated in the processing of behaviorally significant stimuli, i.e., attentional functions. Using a recently developed and validated task for the measurement of sustained attention, or vigilance, administration of BZR inverse agonists were found to selectively increase the number of false alarms in intact animals. However, in animals with a 50-70%, but not > 90%, loss of the cortical cholinergic inputs, treatment with BZR inverse agonists alleviated the lesion-induced impairment in sustained attention and enhanced activated cortical ACh efflux. A rational development of cognitive enhancers will benefit from experiments in which cognitive and neuropharmacological variables are assessed simultaneously, thus allowing the analysis of interactions between cognition-associated neuronal activity and the neuronal and cognitive effects of putative cognition enhancers.

Acetylcholine↗
PubMed1997

Operant performance and cortical acetylcholine release: role of response rate, reward density, and non-contingent stimuli.

The relationship between acetylcholine (ACh) efflux in medial prefrontal cortex (mPFC) and performance in a visual discrimination task and a variable interval (VI) schedule of reinforcement was studied in rats. Animals were pretrained in one of the two tasks and then unilaterally implanted with microdialysis guide cannula into the mPFC. Animals were then dialyzed, during 12 min collection intervals, in the operant chambers prior to task onset and during and after task performance. Each animal was dialyzed for a total of four sessions: two standard task sessions, one session in which a houselight was flashed at 0.5 Hz during the third 12 min block, and an extinction session (always the last session) in which reinforcement was withheld during the final three blocks. Response accuracy in the discrimination task was very high (> 95% correct) and stable across the four blocks with a progressive increase in omissions. The flashing houselight did not affect performance whereas the loss of reinforcement led to an increase in omissions. VI performance was associated with a high number of lever presses and a high reward rate that declined over the four blocks. Again, the flashing houselight did not affect VI performance whereas lever pressing declined markedly during the extinction session. ACh efflux did not change, relative to baseline, during performance in either task, or with the presentation of the flashing houselight or the loss of reinforcement. These data contrast with the changes in cortical ACh efflux observed in situations characterized by the presentation of novel stimuli or changing demands on attentional processing and, therefore, assist in the specification of hypotheses on the cognitive functions of cortical ACh.

Acetylcholine↗
PubMed1997

Cortical acetylcholine and processing capacity: effects of cortical cholinergic deafferentation on crossmodal divided attention in rats.

The effects of 192 IgG-saporin-induced lesions of the corticopetal cholinergic neurons of the basal forebrain on divided attention were assessed in rats. Divided attention was measured using an operant version of the crossmodal divided attention paradigm. This task utilized the propositional response rules of visual and auditory conditional discriminations. Presentation of only visual or only auditory stimuli constituted performance under the condition of modality certainty. Conversely, the presentation of a randomized sequence of all possible stimuli represented the condition of modality uncertainty and was hypothesized to tax processing capacity. A single session was composed of two unimodal blocks of trials (20 trials each), followed by a bimodal block of 60 trials. Animals were extensively trained in this task and baseline performance was characterized by high response accuracy (> 80%) in both conditions. Compared to unimodal trials, the response latencies in the bimodal block of trials were 160 ms longer. The lesion of the cholinergic system increased the response latencies exclusively under the condition of modality uncertainty. The extent of the lesion-induced decrease in cortical cholinergic fiber density correlated highly with the differences between uni- and bimodal response latencies. These results demonstrate a lesion-induced decrease in processing capacity and a preservation of response accuracy at the cost of response latency, i.e., a speed-accuracy tradeoff. Cortical acetylcholine is suggested to mediate the regulation and allocation of processing resources.

Acetylcholine↗