6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine

Abstract

The effects of 6-hydroxydopamine lesions of the prefrontal cortex in monkeys were investigated on two cognitive tests of prefrontal function, spatial delayed response, and attentional set shifting. The latter test provided a componential analysis of the Wisconsin Card Sort Test, a commonly used clinical test of frontal lobe function in man. Acquisition of a visual compound discrimination requiring a shift of attention from one dimension to another (extradimensional shift), for example, shapes to lines, was significantly improved. This enhancement was behaviorally specific in that there were no effects on acquisition of a discrimination that required the continued maintenance of an attentional set toward one particular dimension (intradimensional shift), nor any effects on a series of visual or spatial discrimination reversals that involved the repeated shifting of responding between two exemplars from the same dimension. In contrast, spatial delayed response performance was impaired, in agreement with previous results. Neurochemical measures showed a marked depletion of dopamine limited to the prefrontal cortex and a smaller loss of prefrontal noradrenaline. This was accompanied by a long-term adaptive change in the striatum such that extracellular dopamine in the caudate nucleus, as measured by in vivo microdialysis, was elevated in response to potassium stimulation as long as 18 months postsurgery. It is proposed that attentional set shifting is mediated by a balanced interaction between prefrontal and striatal dopamine, and that elevated dopamine contributes to the improvement in attentional set-shifting ability. This interpretation is consistent with the impairment in attentional set-shifting ability observed in patients with Parkinson's disease or with damage to the frontal lobes using the same test as used here for infrahuman primates.

Prefrontocortical Dopamine Loss in Rats Delays Long-Term Extinction of Contextual Conditioned Fear, and Reduces Social Interaction Without Affecting Short-Term Social Interaction Memory

“…Prefrontocortical serotonin levels were reduced to a much lesser extent, and noradrenergic content was not modified, an important fact because reduced noradrenergic activity after prefrontocortical dopamine loss can lead to paradoxical recovery of extracellular dopaminergic levels (Venator et al, 1999). Interestingly, dopamine and metabolite contents were enhanced in the nucleus accumbens after 6-OHDA lesion, suggesting that there is an inverse relation between mesocortical and mesolimbic dopaminergic systems, as proposed by others Pycock, 1978, 1980;Pycock et al, 1980;Glowinski et al, 1984;Grace, 1991;Roberts et al, 1994;Kolachana et al, 1995;Kurachi et al, 1995). Accumbal DA turnover was reduced after mPFC lesion, a fact that could be interpreted as reflecting a decrease in firing of DA neurons projecting to nucleus accumbens after DA lesion of the mPFC, in accordance with electrophysiological studies (Harden et al, 1998).…”

“…The mPFC also plays an important role in the dopaminergic system network, since it receives input from the mesocortical dopamine (DA) system, and sends efferents to the nucleus accumbens, dorsal striatum, and midbrain DA cell groups Pycock, 1978, 1980;Pycock et al, 1980;Glowinski et al, 1984;Grace, 1991;Roberts et al, 1994;Kolachana et al, 1995;Kurachi et al, 1995). Dopaminergic activity in the mPFC is quite important in the neuromodulation of the 'cognitive functions' of the prefrontal cortex.…”

The Neuropsychopharmacology of Phencyclidine From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia

“…Because a delay period is interposed between trials, the rat is required to briefly maintain information regarding the next choice "on-line," thus, requiring the working memory construct. This task is closely linked with the function of the frontal cortex and its dopaminergic innervation (Brozoski et al 1979;Kolb 1984;Goldman-Rakic 1987; Bubser and Schmidt 1990;Roberts et al 1994). Longterm PCP administration produces delay-dependent performance impairments on a variable-delay spatial T-maze alternation task (Jentsch et al 1997b).…”

“…It could be hypothesized that reduced cortical dopamine transmission induced by long-term PCP exposure may be associated with a hyperactivity of subcortical dopamine systems (as with acute administration), because the mesocortical and mesolimbic dopamine systems demonstrate an inverse relationship in animals; that is, hypoactivity of the cortical dopamine system propagates subcortical dopamine hyperactivity (Pycock et al 1980;Grace 1991;Deutch 1992;Roberts et al 1994). Although no changes in basal, resting dopamine utilization in the nucleus accumbens were noted after subchronic treatment with PCP (Jentsch et al 1997b,c), we have now found that the mesolimbic dopamine pathway has increased responsivity to haloperidol, d-amphetamine, or mild stress (Jentsch et al 1998c).…”

“…In contrast, we failed to find any effect of single-dose PCP exposure on subcortical dopamine utilization in the monkey (Jentsch et al 1997a). The activation in accumbens dopamine transmission in the rat has been associated with the ability of PCP to stimulate locomotor behavior (McCullough and Salamone 1992;Steinpreis and Salamone 1993; Jentsch et al 1998d) and may be associated with some psychopathology in PCP-treated humans.It could be hypothesized that reduced cortical dopamine transmission induced by long-term PCP exposure may be associated with a hyperactivity of subcortical dopamine systems (as with acute administration), because the mesocortical and mesolimbic dopamine systems demonstrate an inverse relationship in animals; that is, hypoactivity of the cortical dopamine system propagates subcortical dopamine hyperactivity (Pycock et al 1980;Grace 1991;Deutch 1992;Roberts et al 1994). Although no changes in basal, resting dopamine utilization in the nucleus accumbens were noted after subchronic treatment with PCP (Jentsch et al 1997b,c), we have now found that the mesolimbic dopamine pathway has increased responsivity to haloperidol, d-amphetamine, or mild stress (Jentsch et al 1998c).…”