We have recently reported on the differential alterations of various cholinergic markers in cortical and subcortical regions in Alzheimer's disease (AD). The main purpose of the present study was to determine if cholinergic deficits observed in patients with AD are unique to this disorder or can be generalized to others such as idiopathic Parkinson's disease (PD) and PD with Alzheimer-type dementia (PD/AD). Muscarinic M1, M2, and nicotinic receptor binding parameters (Kd and Bmax) were determined in various cortical and subcortical areas using selective radioligands ([3H]-pirenzepine, [3H]AF-DX 116, and N[3H]methylcarbamylcholine). Choline acetyltransferase activity was also determined as a marker of the integrity of cholinergic innervation. Alterations of cholinergic markers are comparable in cortical areas in AD, PD, and PD/AD brains. In frontal and temporal cortices, as well as in the hippocampus, choline acetyltransferase activity and binding capacities of M2 and nicotinic binding sites are similarly decreased in these three disorders compared with age-matched control values. M1 receptor binding parameters are not significantly modified in cortical areas in patients with these disorders. In contrast, important differences between AD and PD brain tissues are found in subcortical areas such as the striatum and the thalamus. The density of M1 sites is significantly increased in striatal areas only in patients with AD, whereas densities of nicotinic sites are decreased in thalamus and striatum in PD and PD/AD, but not AD, brain tissues. The binding capacity of M2 sites is apparently unchanged in subcortical areas in all three disorders, although tendencies toward reductions are observed in the striatum of PD and PD/AD patients. Thus, although comparable alterations of various cholinergic markers are observed in cortical areas in the three neurological disorders investigated in the present study, important differences are seen in subcortical areas. This may be relevant to the respective etiological and clinical profiles of AD and PD.

Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer's and Parkinson's diseases.

Interactions between the classical monoamine neurotransmitter dopamine (DA) and the peptide neurotransmitter neurotensin (NT) in the central nervous system (CNS) have now been investigated for over two decades. Interest in this topic has been sustained, primarily because of the potential clinical relevance of these interactions to schizophrenia and drug abuse. In the past five years, important new discoveries in the NT field have markedly expanded our previous database. Additional NT receptors have been cloned, and novel and refined techniques have contributed to a more detailed description of the anatomy of the CNS NT system. Additionally, lipophilic NT receptor antagonists, active in the CNS after peripheral administration, have rendered more facile the investigation of the physiologic importance of endogenous NT at electrophysiologic, neurochemical, and behavioral levels. In the present review, the discussion of NT/DA interactions will progress from a discussion of the anatomical interactions between these two systems, to electrophysiologic and neurochemical interactions, and finally to behavioral implications-always with focus toward the potential clinical relevance of the data. The discussion of interactions between NT and DA systems will be limited to those occurring within the CNS. Moreover, because the DA projections from the midbrain to the striatum account for the bulk of the DA innervation in the CNS, we will focus on NT/DA interactions within these brain regions. Last, because of the extensive literature on NT/DA interactions available in the rat, our discussion will be based primarily on studies using this species.

Neurotensin and Dopamine Interactions

The sources and histochemical characteristics of dopaminergic projections to motor and premotor areas of cortex were investigated in owl monkeys in which information from related studies was used to subdivide cortex into motor fields. Brainstem projections to frontal cortex were identified by injections of different fluorescent dyes in the primary motor cortex (M1) and the supplementary motor area (SMA), first identified by microstimulation. Injections were also placed in dorsal premotor cortex and lateral prefrontal cortex. The distribution of retrogradely labeled neurons was related to the location of tyrosine hydroxylase immunolabeled neurons on the same or alternate brain sections to identify the dopamine (DA) neurons. All DA cortically projecting neurons were located in the A8-A10 complex, largely in its dorsal components, including the parabrachial pigmented n. of the ventral tegmental area (VTA), pars gamma of the substantia nigra compacta, and the dorsal part of the retrorubral area (A8). Fewer cells were in the midline groups of VTA (n. linearis rostralis and caudalis) and in the n. paranigralis. DA neurons projecting to M1, SMA, and prefrontal cortex were largely intermixed, and some of these neurons were double or triple labeled by the fluorescent dyes, indicating collateralization to two or three fields; DA cells projecting to M1 were more numerous than to the other locations. The dorsal components of the A8-A10 complex from which arose the DA mesocortical projection were also characterized by the presence of calbindin-immunoreactive neurons and by a dense neurotensin and noradrenergic terminal innervation. Compared to rodents or felines, the DA neurons projecting to the lateral frontal lobe of primates appear to be shifted dorsally and laterally in the nigral complex. The topographic overlap, partial collateralization, and common histochemical characteristics of the DA mesocortical neurons projecting to different fields of the lateral frontal lobe suggest that some degree of functional unity exists within this projection.

Topography and collateralization of the dopaminergic projections to motor and lateral prefrontal cortex in owl monkeys

Neurotensin and neuroendocrine regulation.

Neurotensin (NT) is a tridecapeptide that is found in the central nervous system (CNS) and the gastrointestinal tract. NT behaves as a neurotransmitter in the brain and as a hormone in the gut. Additionally, NT acts as a neuromodulator to several neurotransmitter systems including dopaminergic, sertonergic, GABAergic, glutamatergic, and cholinergic systems. Due to its association with such a wide variety of neurotransmitters, NT has been implicated in the pathophysiology of several CNS disorders such as schizophrenia, drug abuse, Parkinson's disease (PD), pain, central control of blood pressure, eating disorders, as well as, cancer and inflammation. The present review will focus on the role that NT and its analogs play in schizophrenia, endocrine function, pain, psychostimulant abuse, and PD.

/pdf/diverse-roles-of-neurotensin-agonists-in-the-central-nervous-384gcy97aj.pdf

Diverse roles of neurotensin agonists in the central nervous system.

Several lines of anatomical, biochemical, and pharmacological evidence have suggested that specific high affinity neurotensin binding sites are associated with dopamine-containing neurons in the rat ventral tegmentum. In the present study we confirmed and quantified the extent of this association by combining monoiodinated neurotensin radioautography and tyrosine hydroxylase immunohistochemistry on adjacent 5-10 microns-thick midbrain sections. We found that 95-100% tyrosine hydroxylase-immunoreactive neurons detected in all subdivisions of the substantia nigra (pars compacta, pars lateralis, and pars reticulata) exhibited intense 125I-neurotensin labeling in adjacent light microscopic radioautographs. Tyrosine hydroxylase-positive dendrites radiating downward from compacta neurons were also heavily labeled throughout the pars reticulata. In the paranigral subdivision of the ventral tegmental area, silver grains were evenly distributed over neuropil and perikarya and therefore could not be readily attributed to any given tyrosine hydroxylase-positive element. In contrast, within the parabrachial pigmentous subdivision of the ventral tegmental area, 80-90% of the tyrosine hydroxylase-immunoreactive somata and proximal processes were clearly in register with 125I-neurotensin labeled cells. Finally, all tightly packed TH-positive neurons in the interfascicular nucleus showed intense 125I-neurotensin labeling. The vast majority of the neurotensin binding sites observed in the ventral midbrain tegmentum were of the high affinity, physiologically active receptor type since levocabastine, a selective blocker of the low affinity neurotensin binding component, had minimal effect on the binding density in any of the midbrain regions examined. The present results demonstrate an extensive overlap between specific, high affinity neurotensin binding sites and dopamine perikarya and dendrites in the rat ventral tegmentum, and thereby provide a direct anatomical substrate for observed neurotensin-dopamine interactions in the mesocorticolimbic and nigrostriatal projection systems.

Correspondence between high affinity 125I-neurotensin binding sites and dopaminergic neurons in the rat substantia nigra and ventral tegmental area: A combined radioautographic and immunohistochemical light microscopic study

The distribution of 125I-neurotensin binding sites was compared with that of acetylcholinesterase reactivity in the human basal forebrain by using combined light microscopic radioautography/histochemistry. High 125I-neurotensin binding densities were observed in the bed nucleus of the stria terminalis, islands of Calleja, claustrum, olfactory tubercle, and central nucleus of the amygdala; lower levels were seen in the caudate, putamen, medial septum, diagonal band nucleus, and nucleus basalis of Meynert. Adjacent sections processed for cholinesterase histochemistry demonstrated a regional overlap between the distribution of labeled neurotensin binding sites and that of intense acetylcholinesterase staining in all of the above regions, except in the bed nucleus of the stria terminalis, claustrum, and central amygdaloid nucleus, where dense 125I-neurotensin labeling was detected over areas containing only weak to moderate cholinesterase staining. At higher magnification, 125I-neurotensin-labeled binding sites in the islands of Calleja, supraoptic nucleus of the hypothalamus, medial septum, diagonal band nucleus, and nucleus basalis of Meynert were selectively associated with neuronal perikarya found to be cholinesterase-positive in adjacent sections. Moderate 125I-neurotensin binding was also apparent over the cholinesterase-reactive neuropil of these latter three regions. These data suggest that neurotensin (NT) may directly influence the activity of magnocellular cholinergic neurons in the human basal forebrain, and may be involved in the physiopathology of dementing disorders such as Alzheimer's disease, in which these neurons have been shown to be affected.

Distribution of 125I-neurotensin binding sites in human forebrain: comparison with the localization of acetylcholinesterase.

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Correspondence between high affinity 125I-neurotensin binding sites and dopaminergic neurons in the rat substantia nigra and ventral tegmental area: A combined radioautographic and immunohistochemical light microscopic study

Distribution of 125I-neurotensin binding sites in human forebrain: comparison with the localization of acetylcholinesterase.