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3-Acetylpyridine (3-AP) administration to rats results in degeneration of the dopamine (DA) innervation of the striatum as well as degeneration of the olivocerebellar system. We now report that administration of this pyridine neurotoxin results in a decrease in striatal DA concentration which is restricted to the dorsolateral aspects of the caudatoputamen. 3-AP treatment did not alter DA levels in the ventromedial striatum, the nucleus accumbens, or the anteromedial prefrontal cortex. Both 3-AP and another pyridine neurotoxin, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), potently inhibited in vitro MAOB activity and in contrast weakly inhibited MAOA activity. However, in vitro inhibition of MAOB by the selective inhibitor deprenyl did not prevent or attenuate 3-AP-induced striatal DA depletion. These data indicate that 3-AP administration to rats not only results in degeneration of the olivocerebellar system, but also effects degeneration of the DA innervation of the dorsolateral striatum, the striatal sector thought to subserve motoric and sensorimotor function. 3-AP-induced nigrostriatal degeneration differs from that elicited by MPTP in that the former is not prevented by deprenyl pretreatment. The 3-AP-induced degeneration of both extrapyramidal and cerebellar motor systems may offer insight into the mechanisms involved in degeneration of the two motor systems in certain strains of rodents (such as the Weaver mutant mouse), and suggests that the sequelae of administration of this pyridine may serve as a useful model for olivopontocerebellar atrophy-associated parkinsonism.
Mild footshock stress results in the metabolic activation of the prefrontal cortical dopamine (DA) innervation, but does not augment DA utilization in mesolimbic areas (such as the nucleus accumbens septi, NAS) or the striatum. However, increases in either the intensity or duration of footshock stress increase DA utilization in the subcortical sites. DA afferents to the prefrontal cortex (PFC) hold corticofugal projection neurons under tonic inhibition. Previous data suggest that removal of these corticofugal glutamatergic neurons from tonic DA inhibition results in a transsynaptic alteration in the NAS, such that the DA innervation of the NAS is rendered hyperresponsive to certain perturbations. We therefore examined the effects of stress on subcortical DA systems in rats previously subjected to 6-hydroxydopamine lesions of the PFC DA innervation. Mild footshock stress resulted in an increase in concentrations of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the PFC, but not NAS or striatum, of sham-lesioned animals. Footshock resulted in a significant increase in the concentration of DOPAC in the nucleus accumbens of animals sustaining PFC lesions two weeks previously. The PFC lesion did not result in a stress-induced increase in DA release in the striatum. These results suggest that disruption of the PFC DA innervation results in an enhanced responsiveness of the mesolimbic DA innervation to stress. These data may help explain the stress-elicited exacerbation of the psychotic process in schizophrenia.
Morphological changes in ventral mesencephalic dopamine (DA) neurons of a monkey sustaining a unilateral electrolytic lesion of the ventromedial mesencephalic tegmentum four years earlier were examined. Substantia nigra (A9) DA neurons lateral to the lesion underwent hypertrophic changes. The mean area of these neurons was enlarged by approximately 30% relative to corresponding neurons in the contralateral substantia nigra. Semi-quantitative immunohistochemical measurements of the intensity of tyrosine hydroxylase-like immunoreactivity (TH-li) indicated an increase in the amount of TH-li protein per cell in the hypertrophied neurons. Hypertrophic changes were also observed in ipsilateral A11 DA neurons of the caudal hypothalamus, suggesting that the increase in size was related to transection of the axons of DA neurons as they pass through the midbrain in their projections to target sites. The lesion did not overtly change the density or pattern of the substance P innervation of the substantia nigra, indicating that the striato- and pallido-nigral projections were spared by the lesion. These data suggest that hypertrophy may be a compensatory mechanism of dopaminergic neurons in response to partial lesions of the nigrostriatal system, and thus represent a morphological counterpart to the compensatory biochemical processes effected in response to partial lesions of the striatal dopaminergic innervation.
We have developed and characterized dopamine-containing liposomes which exhibited in vitro sustained release of dopamine for over 40 days. These liposomes were stereotactically implanted into the partially denervated corpus striatum of rats subjected to unilateral lesions of the substantia nigra. In vivo release of dopamine into striatal extracellular fluid was monitored by microdialysis and behavior was assessed by quantifying apomorphine-induced asymmetric rotation. Extracellular dopamine levels in the partially denervated striatum of the dopamine liposome-treated rats were greater than the levels in the lesioned rats which received control liposomes and these levels remained elevated for 25 days. In parallel, those rats which received dopamine liposomes exhibited partial behavioral recovery, with attenuation of asymmetric rotation following systemic apomorphine administration. These results suggest that dopamine-containing liposomes can partially ameliorate the deficits associated with a rodent model of Parkinson's disease, and demonstrate the potential of this technology as a method for the controlled delivery of therapeutic agents into discrete areas of the brain.
A recent hypothesis of the pathogenesis of schizophrenia posits a developmentally-specific dysfunction of the dopaminergic innervation of the prefrontal cortex (PFC; Weinberger, 1987; Berman and Weinberger, 1990). It has been difficult to reconcile this hypothesis with the observation that all clinically effective antipsychotic drugs used for the treatment of schizophrenia block dopamine D2 receptors (see Deutch et al., 1991a). A resolution between the suggestion of functional dopamine (DA) "depletion" in the PFC and enhanced subcortical DA function was offered by studies of Carter, Pycock, and associates (Carter and Pycock, 1980; Pycock et al., 1980a, b). These investigators reported that depletion of DA in the rat PFC enhanced DA utilization in subcortical sites such as the nucleus accumbens septi (NAS) and striatum. Thus, a functional deficit in DA neurotransmission in the PFC would increase subcortical DA turnover, and the D2 receptor blockade induced by antipsychotic drugs would counteract the increase in dopaminergic tone in subcortical sites. This hypothesis has been particularly influential because it incorporates both an explanation for negative symptoms, which are thought to reflect cortical dysfunction (a derangement in DA transmission in the PFC), and the efficacy of antipsychotic drugs in the treatment of positive symptoms (arising from increases in subcortical DA tone). As attractive as this hypothesis has been, the physiological underpinnings that subserve such system interactions have remained elusive. Pycock, Carter, and colleagues (Carter and Pycock, 1980; Pycock et al., 1980a, b) reported that 6-hydroxydopamine (6-OHDA) lesions of the PFC increase DA levels and DA turnover in the striatum; certain aspects of their findings have been confirmed (Martin-Iversen et al., 1986; Leccese and Lyness, 1987; Haroutounian et al., 1988). However, other groups have been unable to confirm either the biochemical or behavioral findings of Pycock and associates (Joyce et al., 1983; Oades et al., 1986; Deutch et al., 1990). Moreover, Pycock and colleagues did not observe consistent effects of PFC DA deafferentation on various indices of subcortical DA function (Carter and Pycock, 1980; Pycock et al., 1980a, b). In light of the importance that such DA system interactions may have in the pathogenesis of schizophrenia, we have reinvestigated the effects of cortical DA lesions on subcortical DA function.
The effects of prefrontal cortical dopamine depletion on subcortical dopamine function in the rat were examined. 6-Hydroxydopamine lesions of the dopaminergic innervation of the prefrontal cortex did not alter concentrations of dopamine or its metabolite 3,4-dihydroxyphenylacetic acid in either the striatum or nucleus accumbens. Similarly, the activity of the catecholamine biosynthetic enzyme tyrosine hydroxylase in the striatal complex was not changed in animals with prefrontal cortical lesions. Animals sustaining neurotoxic lesions of the prefrontal cortex were challenged with haloperidol in order to activate submaximally tyrosine hydroxylase activity. The magnitude of the haloperidol-induced increase in enzyme activity in the nucleus accumbens was significantly greater in lesioned subjects than in control animals. These data suggest that lesions of the prefrontal cortical dopamine innervation do not result in significant alterations in basal dopaminergic function in the striatal complex. However, lesions of the dopaminergic innervation of the prefrontal cortex significantly increase the responsiveness of mesolimbic dopamine afferents to pharmacological challenge.
The degree of parallel processing in frontal cortex-basal ganglia circuits is a central and debated issue in research on the basal ganglia. To approach this issue directly, we analyzed and compared the corticostriatal projections of two principal oculomotor areas of the frontal lobes, the frontal eye field (FEF) and the supplementary eye field (SEF). We first identified cortical regions within or adjacent to each eye field by microstimulation in macaque monkeys and then injected each site with either 35S-methionine or WGA-HRP conjugate. We analyzed the corticostriatal projections and also the interconnections of the pairs of cortical areas. We observed major convergence of the projections of the FEF and the SEF within the striatum, principally in the caudate nucleus. In cross sections through the striatum, both projections were broken into a series of discontinuous input zones that seemed to be part of complex three-dimensional labyrinths. Where the FEF and SEF projection fields were both present, they overlapped patch for patch. Thus, both inputs were dispersed within the striatum but converged with one another. Striatal afferents from cortex adjacent to the FEF and the SEF did not show convergence with SEF and FEF inputs, but did, in part, converge with one another. For all pairs of cortical areas tested, the degree of overlap in the corticostriatal projections appeared to be directly correlated with the degree of cortical interconnectivity of the areas injected. All of the corticostriatal fiber projections observed primarily avoided immunohistochemically identified striosomes. We conclude that there is convergence of oculomotor information from two distinct regions of the frontal cortex to the striatal matrix, which is known to project into pallidonigral circuits including the striatonigrocollicular pathway of the saccadic eye movement system. Furthermore, functionally distinct premotor areas near the oculomotor fields often systematically projected to striatal zones adjacent to oculomotor field projections, suggesting an anatomical basis for potential interaction of these inputs within the striatum. We propose that parallel processing is not the exclusive principle of organization of forebrain circuits associated with the basal ganglia. Rather, patterns of both convergence and divergence are present and are likely to depend on multiple functional and developmental constraints.