Cholinergic denervation-like changes in rat hippocampus following developmental lead exposure

We investigated the effects of developmental lead exposure from embryonic day 16 (E16) through postnatal day 28 (PN28), on cholinergic and catecholaminergic markers in the septohippocampal pathway in rats through fourth month of age. Lead exposure resulted in a persistent 30–40% reduction of [³H]hemicholinium-3 ([³H]HC-3) binding in the hippocampus through PN120, and 20–30% reduction of septal and hippocampul choline acetyltransferase (ChAT) activity which persisted through PN84 but returned to control levels in both septum and hippocampus at PN112. The muscarinic ligand [³H]quinuclidinyl benzylate ([³H]QNB) binding was reduced in the septum at PN28 but did not differ significantly from controls at PN56–PN112. Neither short- nor long-term effects of Pb exposure on [³H]QNB binding were seen in the hippocampus. Similar to the effects of fimbria-fornix transection, Pb exposure resulted in a long-term 50–90% increase of tyrosine hydroxylase(TH) activity in the hippocampus, although neither treatment affected TH activity in the septum. The lead-induced increase in hippocampul TH was significantly attenuated by superior cervical ganglionectomy. It is concluded that the effects of perinatal lead exposure resemble in several respects those seen following surgical disruption of the septohippocampal pathway in adult animals. The denervation-like effects in the hippocampus may be an important factor in long-term learning and cognitive impairments following developmental exposure to low-levels of lead.     

一种脑胆碱乙酰基转移酶活性测定法

对测定胆碱乙酰基转移酶的Ｆｏｎｎｕｍ法稍加改进，并严格控制操作条件。应用改进的方法测定了大鼠脑胆碱乙酰基转移酶活性，结果更准确。     

Deficits in development of central cholinergic pathways caused by fetal nicotine exposure: Differential effects on choline acetyltransferase activity and [H]hemicholinium-3 binding

Nicotine has been hypothesized to induce neurobehavioral teratology by mimicking prematurely the natural developmental signals ordinarily communicated by the ontogeny of cholinergic synaptic transmission. In the current study, the effects of fetal nicotine exposure (2 mg/kg/day or 6 mg/kg/day) on development of central cholinergic pathways were examined in striatum and hippocampus of animals exposed from gestational days 4 through 20, using maternal infusions with osmotic minipumps. Brain region weights and choline acetyltransferase activity, an enzymatic marker for development of cholinergic nerve terminals, were within normal limits in the nicotine-exposed animals. However, development of [³H]hemicholinium-3 binding which labels the presynaptic high affinity cholinergic transporter, was deficient in both striatum and hippocampus. Abnormalities occurred during two distinct phases; in the early neonatal period, when [³H]hemicholinium-3 binding sites are transiently overexpressed, and during or after the period of rapid synaptogenesis, when binding in controls is rising consequent to the increase in nerve impulse activity. These data thus indicate that fetal nicotine exposure, even at doses that do not cause overt signs of maternal/fetal/neonatal toxicity or growth impairment, influences both specific gene expression of cholinergic nerve terminal markers, as well as indices of neuronal function. Comparison of regional selectivity at the two dose levels indicated greater sensitivity of the striatum, a region with a prenatal peak of neuronal mitosis, as compared to hippocampus, where mitosis peaks postnatally; the regional differences are consistent with vulnerability to nicotine during a critical phase of cell development.     

Neurotensin immunoreactivity in post-mortem brain is increased in Down's syndrome but not in Alzheimer-type dementia

Neurotensin immunoreactivity and choline acetyltransferase (ChAT) activity were measured in post-mortem brain from 10 cases of Down's syndrome (7 aged 53-63 years, one aged 27 years, one aged 16 months and one aged 10 months), 6 cases of Alzheimer-type dementia (ATD) and 19 control subjects (13 aged 40-88 years and 6 aged 9-18 months). Neurotensin concentrations in anterior and basal hypothalamus, amygdala, septal area, caudate nucleus and temporal cortex were unaltered in ATD. The concentrations of neurotensin were significantly increased in the caudate nucleus, temporal cortex and frontal cortex in the cases of Down's syndrome aged 53-63 years with the neuropathological features of ATD, and were also increased in the cerebral cortex of the 27-year-old, which did not have the neuropathological features of ATD, and in two infant Down's cases. ChAT activity was reduced in the ATD and the 53-63-year-old cases of Down's syndrome, but not in the 27-year or 10-month-old Down's cases. The increased neurotensin concentrations appear to be a feature of Down's syndrome not related to the presence of plaques and neurofibrillary tangles or to a deficit in ChAT activity.     

Production of spinal cord growth inhibitor by nonneuronal cells

Separation of chick embryo spinal cord cells into cell cultures of glial-enriched and neuronal-enriched elements by the method of selective adhesiveness indicated a greater production of growth inhibitor by the glial-enriched cultures. Glial-enriched cultures produced 177.2% more inhibitor per microgram cell protein than did unseparated spinal cord cell cultures, whereas neuronal-enriched cultures produced less. The glial-enriched cultures contained 28% of the choline acetyltransferase of neuronal-enriched cultures, few or no discernible neurons, and no cells binding dopamine or containing catecholamines by cytofluorescence. The predominant cell of the glial-enriched cultures was large, phase-light with ruffled borders, with parallel streak-like processes, and fibrillar cytoplasm. Cultures produced by serial passage of unseparated spinal cord cells also were found to be depleted in neurons and dopamine-binding cells, as well as in choline acetyltransferase activity, to 19% of control values. These serially passaged cultures, however, retained the ability to produce inhibitor as well as did primary cultures. Serially passaged cultures of spinal cord cells were composed of cells similar to those predominant in glial-enriched cultures. Nerve growth factor had no effect on inhibitor production. We suggest that the growth inhibitor of spinal cord cultures was not produced by neuronal cells but may be of glial origin.     

Selective activation of the mesocortico-frontal dopaminergic neurons induced by lesion of the habenula in the rat

Sulpiride and other benzamide (BM)-displacing activity on [³H]-spiroperidol ([³H]SPIR) binding by rat striatal dopaminergic receptors was found to be uniquely sodium-dependent, while classical neuroleptic (NL) activity was not influenced by NaCl.These results suggest the existence of at least two populations of striatal dopaminergic receptors, sodium-dependent and sodium-independent, through which BM and NL respectively interact.     

Behavioral and biochemical aspects of neuroleptic-induced dopaminergic supersensitivity: Studies with chronic clozapine and haloperidol

Rats were chronically injected with saline, clozapine, or haloperidol and tested for alterations in dopamine (DA)-mediated behavior, DA receptor binding, and both acetylcholine (ACH) concentration and cholien acetylase activity. Behaviorally, chronic haloperidol significantly enhanced apomorphine-induced chewing and sniffing stereotypies, associated with DA nigrostriatal activation, while clozapine selectively enhanced apomorphine locomotor activity and cage-floor crossing, behavior associated with DA mesolimbic activation. Biochemically, chronic haloperidol significantly enhanced ³H-spiroperidol binding in striatum and in mesolimbic loci (nucleus accumbens/olfactory tuberele) while chronic clozapine failed to produce such enhancement. Acute haloperidol induced an initial decrease in striatal ACH concentration followed by a return of ACH to normal levels within 1 week. There was no change in choline acetylase activity during the same time interval. These findings suggest that haloperidol may inhibit DA mechanisms in both the nigrostriatal and mesolimbic systems, but that the effect of clozapine on DA mechanisms may be specific to mesolimbic rather than striatal structures. At the same time, the lack of effect of clozapine on ³H-spiroperidol binding may indicate that behaviorally important changes in DA sensitivity can develop independent of changes in post-synaptic DA receptors. The pattern of cholinergic changes with chronic haloperidol suggests that the increase in striatal DA receptor number seen with chronic treatment re-establishes DA inhibition of cholinergic firing within the striatum.     

Changes in tyrosine hydroxylase, glutamic acid decar☐ylase and choline acetyltransferase after local microinoculation of scrapie agent into the nigrostriatal system of the golden hamster

A microinjection of a homogenate of scrapie agent-infected brain (strain 263 K) into the nigrostriatal system in the golden hamster is followed by the progressive development of the disease which terminates by the death of animals around the 4th month postinoculation. These intracerebral inoculations induce more rapid changes in neuronal activity which can be revealed by the assessment of the specific synthesizing enzymes of neurotransmitter systems. The microinoculation of a homogenate of an infected brain unilaterally into the substantia nigra (SN) provokes a decrease in tyrosine hydroxylase (TH), the synthesizing enzyme for dopamine in the dopaminergic neurones, in the striatum ipsilateral to the injected SN. This biochemical response, specifically induced by the active pathogen, is detectable as soon as the 5th day postinoculation and is detectable towards the 80th day. A return of TH levels to control values is detected after this period. At the end of the incubation period and towards the death of the animals, TH is not different from control TH measured from intact animals. The decrease in TH is concomitant with an increase in striatal glutamic acid decar☐ylase (GAD), the synthesizing enzyme for γ-aminobutyric acid (GABA), measured 20 days postinoculation with no change in choline acetyltransferase (ChAT), the synthesizing enzyme for acetylcholine. Studies of the biochemical responses associated locally to the scrapie agent inoculation have been performed at the striatal level. The intrastriatal administration of the infective agent induces 20 days postinoculation an increase in GAD with no change in TH and ChAT. Ninety days postinoculation, a decrease in GAD was detected associated with an increase in TH with no change in ChAT. The decrease in striatal TH 5 days after inoculation of the scrapie agent in the ipsilateral SN represents in the hamster an early marker of the slow progressive pathologic process which can only be revealed about 80 days postinoculation. The influence of the pathogen in the nigrostriatal system could be specific for certain categories of neurones. The cholinergic neurones are apparently not affected. The dopaminergic neurones seem not to be permanently damaged, as seen by the return of TH to control values during the development of the disease. The GABAergic neurones could represent a preferential target for the pathogen as shown by the early GAD activation and tardive decrease activity.     

Regional heterogeneity of choline acetyltransferase activity in primate neocortex

Choline acetyltransferase activity in precentral and temporal regions of primate neocortex is 2.5-fold higher than in occipital cortex. These results suggest large differences in the density of innervation in different regions of primate neocortex by the nucleus basalis of Meynert.