Role of monoamine pathways in the control of attention: Effects of droperidol and methylphenidate in normal adult humans

Abstract

Methylphenidate (0.65 mg/kg), droperidol (15 gg/ kg) or placebo were administered to normal adult males undertaking a dichotic auditory attention task. Performance following placebo, as measured by the ability of subjects to detect nominated target words and discriminate them from phonemically distracting words, was superior when attention was focused on one ear than when divided between the ears. Following droperidol, target detection and discrimination were reduced for both divided and focused attention and in the latter case responses were also slowed. However, these effects were small compared to the striking withdrawn behaviour of the subjects, who reported an unwillingness to attend to external events. Methylphenidate reversed all of these effects when administered following droperidol. Administered alone, methylphenidate had no effect on dichotic measures of attention but had marked effects on spontaneous behaviour, when most subjects reported a substantial increase in both the field and distractibility of attention. These results are interpreted as implicating central dopaminergic pathways in the regulation of attention without precluding a role for other neurotransmitter systems including ascending noradrenaline and serotonin pathways to cerebral cortex. The disparity between these objective and subjective assessments of the effects of the drugs on attention is discussed in terms of the degree of mental effort voluntarily brought to bear by subjects in the selective allocation of their attentional capacity.The anatomy of the ascending monoamine pathways from the brainstem that innervate the cerebral cortex has been intensively studied in recent years. Regional variations in density of the cortical monoamine projections and in their topographic domains, as well as the intricate and orderly laminar distribution of their terminals, often with reciprocal variations in the predominance of particular monoamines, are characteristics that are particularly striking in primate cortex (Morrison et al. 1982a, b;Levitt et al. 1984). This orderliness, in contrast to previous characterisation of the monoamine innervation of the cortex as diffuse and nonspecific, suggests that these afferents have precise roles in Offprint requests to: C.R. Clark the regulation of cortical activity. However, little is known about the functions of the monoamine innervation of the normal human cerebral cortex despite the central role attributed to monoamines by the current theories of the biochemical disturbances in schizophrenia, mania and depression.One important function of the monoamine innervation of the cortex may be the control of attention. The vast majority of central monoaminergic neuron cell bodies are located in the reticular formation of the brain stem (Ramon- Molinar et al. 1966;Nauta et al. 1969). Of particular interest are the dopamine neurons of the midbrain's ventral tegmentum and the noradrenergic neurons of the locus coeruleus in the upper pons. Lesion and pharmacological studies in animals implicate both noradrenaline...

Cognitive improvement during Tolcapone treatment in Parkinson's disease

“…A similar role of this monoamine has been proposed in other regions of the cortex (Aston-Jones et al, 1981;Scheibel, 1984). Studies on normal adults have implicated the ascending monoamine projections which innervate the cortex in attention control (Clark et al, 1986(Clark et al, , 1989; moreover, the changes in affect-arousal state that often accompany the on-off swing in PD (Brown et al, 1984) have also been attributed to noradrenergic deficits (Marsden and Jenner, 1981).…”

Role of monoamine pathways in attention and effort: Effects of clonidine and methylphenidate in normal adult humans

“…The dichotic monitoring task used has been described in detail in an earlier report (Clark et al 1986). The task required the subject to monitor pre-recorded lists of monosyllabic words presented dichotically at the rate of two pairs per s and depress a microswitch whenever a predesignated target word was heard.…”

“…We have been investigating this role in normal humans and have Offprint requests to : C.R. Clark recently reported the effect on behavioural measures of attention of the dopamine antagonist drug droperidol, and the catecholamine agonist, methylphenidate (Clark et al 1986). In the present study, we examine the effect on auditory selective attention of methylphenidate and clonidine administered intravenously to normal volunteers.…”

Scopolamine attenuates the motor disruptions but not the attentional disturbances induced by haloperidol in a sustained attention task in the rat

“…produced by chlorpromazine in attention tasks in rats are qualitatively similar to the errors produced by other neuroleptic drugs in humans (Kornetsky and Mirsky 1966;Clark et al 1986) the examination of neurolepticinduced attention deficits in animals is of interest. In addition, it is important to note that rats trained to perform choice tasks, without a sustained attention requirement, do not show evidence of disrupted discriminative capabilities (Tombaugh et al 1980;Anisman et at.…”