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D F Emerich

Publications and source records attributed to D F Emerich.

At least 73 records · Page 4Linked to original sources
PubMed1993

Nicotine potentiation of haloperidol-induced catalepsy: striatal mechanisms.

Nicotine potentiated the catalepsy produced by haloperidol. The excitotoxin quinolinic acid (QA) selectively destroys striatal neurons when injected directly into the striatum. Bilateral QA lesions of the rat striatum (150 nmol) significantly reduced the catalepsy produced by haloperidol as well as the ability of nicotine to potentiate haloperidol-induced catalepsy. A second experiment examined whether the ability of nicotine to potentiate haloperidol-induced catalepsy was associated with a potentiation of dopamine turnover following haloperidol. Nicotine alone produced a mild increase in dopamine turnover relative to saline treated controls while haloperidol produced a marked increase in dopamine turnover relative to saline- and nicotine-treated controls. However, the combined administration of haloperidol and nicotine did not further elevate dopamine turnover over that observed following haloperidol alone. The results indicated that: 1) nicotine could not potentiate haloperidol-induced catalepsy without an intact striatum and 2) the behavioral effect of nicotine and haloperidol cotreatment was not due to any change in dopamine turnover.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Intraseptal injection of GABA and benzodiazepine receptor ligands alters high-affinity choline transport in the hippocampus.

Injection of GABA and benzodiazepine (BDZ) agonists and antagonists into the medial septum produced bidirectional alterations in hippocampal high-affinity choline transport (HAChT). Male Sprague-Dawley rats were injected in the medial septum with either drug vehicle, a BDZ agonist, antagonist, or inverse agonist, or with a GABA-A or GABA-B agonist or antagonist and sacrificed 1 h later for assessment of HAChT in hippocampal synaptosomes. The GABA-A agonist muscimol, the GABA-B agonist baclofen, and the BDZ agonist chlordiazepoxide (CDP) produced dose-related decreases in HAChT 1 h following injection into the septum. The muscimol-induced decrease in HAChT was prevented by prior intraseptal injection of the GABA-A antagonist, bicuculline. Intraseptal injection of GABA-A (bicuculline) or GABA-B (2-hydroxysaclofen) antagonists did not alter HAChT, whereas the BDZ antagonist flumazenil (RO15,1788) and the BDZ inverse agonist methyl-beta-carboline-3-carboxylate (beta-CCM) increased this measure up to 30% in a dose-dependent manner. These results demonstrate that cholinergic neurons in the medial septum can be modulated in a bidirectional way through the pharmacological manipulation of GABA-A, GABA-B, and BDZ receptors. The potential functional and therapeutic consequences of these interactions are discussed.

Acetylcholinesterase↗
PubMed1993

Locomotion of aged rats: relationship to neurochemical but not morphological changes in nigrostriatal dopaminergic neurons.

Spontaneous locomotion and motor coordination was evaluated in young (5-6 month old) and aged (24-25 month old) rats. Animals were tested for spontaneous locomotor activity in Digiscan Animal Activity Monitors during the nocturnal cycle. Aged animals exhibited a significant hypoactivity compared to their young counterparts. Evaluation of the time course of activity revealed that the young animals had a cyclical pattern of activity during the 12-hour testing period with clear peaks at 2-4 hours after the initiation of testing and at 8- to 10-hour intervals thereafter. In contrast, the aged animals exhibited a blunted initial activity peak. During the remainder of the test period the aged animals activity was stable with no further peaks in activity. Compared to the young animals the aged animals also (a) remained suspended from a horizontal wire for less time, (b) were unable to descend a wooden pole covered with wire mesh in a coordinated manner, (c) fell more rapidly from a rotating rod and (d) were unable to maintain their balance on a series of wooden beams with either a square or rounded top of varying widths. Histological analysis demonstrated that there was no reduction in the number, area, or length of tyrosine hydroxylase-immunoreactive neurons within the A8, A9, or A10 region of the aged animals. Neurochemical analysis revealed that while DA and HVA levels were not decreased in the aged rats, DOPAC levels, as well as the ratios of DA/DOPAC and DA/HVA, were decreased. These results indicate that neurochemical but not morphological changes within the nigrostriatal dopaminergic system underlie the deficits in motor behavior observed in aged rats.

Aging↗
PubMed1992

Transplantation of fetal cholinergic neurons into the hippocampus attenuates the cognitive and neurochemical deficits induced by AF64A.

The present experiments examined whether transplanted fetal cholinergic neurons would attenuate the behavioral and neurochemical deficits induced by the cholinotoxin AF64A (ethylcholine aziridinium ion). Bilateral injections of AF64A (3 nmol) into the lateral ventricles produced significant learning and memory impairments together with decreases in hippocampal high-affinity choline uptake (HAChU). AF64A-treated rats were impaired on both a standard radial arm maze (RAM) task and a working memory version in which a one-hour delay was imposed between the fourth and fifth arm choices. Transplantation of embryonic day E-17 septal/diagonal band tissue into the hippocampus (HPC) promoted recovery of performance on the standard version of the RAM task. However, this recovery was not observed when the animals were tested on the more difficult delay version of the task. Neurochemical analysis indicated that AF64A produced a significant (31%) decrease in hippocampal HAChU that was attenuated (14%) by transplantation of fetal cholinergic neurons. Histological analysis revealed that the transplants survived and innervated the HPC. There was no apparent relationship between fiber ingrowth into the HPC and behavioral recovery. These data indicate that transplant-induced behavioral recovery may be related to and limited by the cognitive demands of the testing situation. Generalized increases in cholinergic activity, transplant-mediated release of trophic factors, or a combination of both may underlie the behavioral recovery observed in the present studies.

Analysis of Variance↗
PubMed1992

A novel approach to neural transplantation in Parkinson's disease: use of polymer-encapsulated cell therapy.

Transplantation of dopaminergic neurons derived from fetal or adrenal tissue into the striatum is a potentially useful treatment for Parkinson's disease (PD). Although initially promising, recent clinical studies using adrenal autografts have demonstrated limited efficacy. The use of human fetal cells, despite promising preliminary results, is complicated by tissue availability and ethical concerns. An attractive alternative is based on encapsulating dopamine-producing cells into polymer capsules prior to transplantation. Polymer capsules can be fabricated to surround the cells with a semi-permeable and immunoprotective barrier. The semi-permeable membrane allows nutrients to enter the capsule, so the encapsulated cells will survive and function, and dopamine and other low molecular weight constituents to diffuse out into the host tissue. Thus, the technique allows use of unmatched human tissue (allografts), or even animal tissue (xenografts) without immunosuppression of the recipient. Cell-loaded polymer capsules can also be retrieved if necessary or desired. The demonstration that striatal implants of encapsulated dopamine-producing cells promote behavioral recovery in rodent and primate models of PD further suggests that cellular encapsulation may be a useful strategy for ameliorating the behavioral consequences of PD.

Adrenal Medulla↗
PubMed1992

Behavioral effects of neural transplantation.

Considerable evidence suggests that transplantation of fetal neural tissue ameliorates the behavioral deficits observed in a variety of animal models of CNS disorders. However, it is also becoming increasingly clear that neural transplants do not necessarily produce behavioral recovery, and in some cases have either no beneficial effects, magnify existing behavioral abnormalities, or even produce a unique constellation of deficits. Regardless, studies demonstrating the successful use of neural transplants in reducing or eliminating behavioral deficits in these animal models has led directly to their clinical application in human neurodegenerative disorders such as Parkinson's disease. This review examines the beneficial and deleterious behavioral consequences of neural transplants in different animal models of human diseases, and discusses the possible mechanisms by which neural transplants might produce behavior recovery.

Animals↗
PubMed1991

Female rats are more sensitive to the locomotor alterations following quinolinic acid-induced striatal lesions: effects of striatal transplants.

The effects of sex differences and hormonal factors on the locomotor alterations following intrastriatal injections of quinolinic acid (QA) and the ability of fetal striatal transplants to reverse those effects were examined. Male, female, or ovariectomized female rats received bilateral injections of 150 nmol QA or vehicle into the striatum. Using a multidimensional analysis of spontaneous nocturnal locomotor behavior, a significant increase in locomotion was observed in female but not male or ovariectomized female rats. The increases in activity observed in the lesioned females were attenuated at 6 and 10 weeks following transplantation of rat fetal (E17) striatal tissue into the lesioned striata. Transplanted striatal tissue had no effect on locomotion in male or ovariectomized female rats. Cytochrome oxidase histochemistry revealed that QA produced a marked loss of metabolic activity in regions exhibiting cell loss. Within these areas there was a marked loss of striatal neurons including those reactive for NADPH diaphorase. Despite the sex-related differences in QA-induced locomotion, there were no apparent differences in the extent of striatal pathology or survival of the grafts in any of the groups receiving QA. These experiments demonstrate a sex-dependent dissociation between the behavioral and neurobiological consequences of QA and suggest that sex and hormonal variables play an important role in the locomotor changes following excitotoxic-induced striatal damage.

Animals↗
PubMed1991

Ganglioside AGF2 prevents the cognitive impairments and cholinergic cell loss following intraventricular colchicine.

Ganglioside AGF2 prevented the cognitive and locomotor alterations induced by intraventricular colchicine. Adult male rats were initially trained to perform a standard radial arm maze (RAM) task. Following training, they were injected intraperitoneally with 10 mg/kg AGF2 (COL/AGF2), cerebrospinal fluid (CSF/AGF2) or the saline vehicle (COL/SAL, CSF/SAL) for 3 days prior to and for 14 days following the bilateral injection of colchicine (7 micrograms/0.5 microliters) or artificial CSF into the lateral ventricles. Colchicine (COL/SAL) impaired performance of the standard RAM task as well as a working memory version of the task in which various delays were imposed between the fourth and fifth arm choices. Colchicine also produced a transient hyperactivity which subsided within 10 weeks following surgery. In contrast, AGF2 (COL/AGF2) prevented the impairments in RAM performance and the alterations in locomotor behavior. Colchicine also produced significant decreases in hippocampal ChAT activity and high affinity choline uptake that were prevented by prior treatment with AGF2. Finally, colchicine produced a 35% decrease in the number of acetylcholinesterase-positive (cholinergic) neurons in the medial septum and vertical limb of the diagonal band (MS/VLDB) which was also prevented by AGF2. Thus, the behavioral and neurochemical protection afforded by AGF2 was paralleled by a prevention of the loss of hippocampal cholinergic parameters and cholinergic neurons in the MS/VLDB.

Animals↗
PubMed1991

Nicotine potentiates haloperidol-induced catalepsy and locomotor hypoactivity.

Nicotine was found to potentiate the catalepsy and reduced locomotion following the administration of haloperidol. The ability of various doses of nicotine (0.1, 0.2, or 0.3 mg/kg) to potentiate the catalepsy produced by haloperidol (0.1, 0.2 or 0.4 mg/kg) was investigated. Nicotine potentiated the cataleptic effects of both the 0.2 and 0.4 mg/kg doses of haloperidol, but had no effect following the lowest (0.1 mg/kg) dose of haloperidol. The nicotine potentiation of catalepsy produced by the highest dose of haloperidol was independent of the dose of nicotine used. Nicotine alone did not produce catalepsy. A second experiment evaluated the ability of nicotine to potentiate the decreases in spontaneous locomotor activity produced by haloperidol. Animals received nicotine (0.1 mg/kg) alone or in conjunction with haloperidol (0.1 or 0.4 mg/kg) and were tested in Digiscan Animal Monitors. Haloperidol produced a dose-related decrease in locomotion. Nicotine significantly potentiated the hypoactivity produced by both doses of haloperidol. These results indicated that: 1) nicotine produces a significant potentiation of both the catalepsy and locomotor decreases following haloperidol and 2) the Digiscam Animal Activity Monitors may provide a more sensitive assessment of the interaction between nicotine and haloperidol than the catalepsy bat test. These data suggest that adjunct treatment with nicotine may prove useful for treating neuroleptic responsive disorders such as Tourette Syndrome, schizophrenia and Huntington's disease.

Animals↗
PubMed1991

Nicotine potentiates the behavioral effects of haloperidol.

Nicotine potentiates the catalepsy produced by haloperidol. Furthermore, nicotine as an adjunct to haloperidol produces a remarkable improvement in motor tics in Tourette's syndrome (TS) patients. The present experiments (1) compared the ability of nicotine to potentiate the catalepsy produced by haloperidol or the selective D1 dopamine receptor antagonist SCH 23390 and (2) examined the effects of various doses of nicotine (0.1, 0.2, or 0.3 mg/kg) on haloperidol-induced (0.1, 0.2, or 0.4 mg/kg) catalepsy and locomotor hypoactivity. In the first experiment, nicotine produced a five-fold increase in catalepsy following haloperidol but had no effect on the catalepsy produced by SCH 23390. In the second experiment, nicotine potentiated the cataleptic effects of both the 0.2 and 0.4 but not the 0.1 mg/kg dose of haloperidol. Haloperidol (0.1 and 0.4 mg/kg) also produced a dose-related decrease in locomotion that was significantly potentiated by nicotine (0.1 mg/kg). Nicotine alone did not produce catalepsy or any significant changes in locomotion. These results indicated that nicotine's potentiation of haloperidol-induced catalepsy is likely related to striatal D2 receptor mechanisms. Nicotine potentiated the locomotor effects of doses of haloperidol that were previously found to be subcataleptic, indicating that catalepsy testing may actually underestimate the behavioral interaction between haloperidol and nicotine. Nicotine may prove useful for treating neuroleptic responsive disorders such as TS, schizophrenia, and Huntington's disease.

Animals↗
PubMed1990

Ganglioside AGF2 promotes task-specific recovery and attenuates the cholinergic hypofunction induced by AF64A.

Ganglioside AGF2 attenuated both the cognitive impairments and the cholinergic hypofunction induced by ethylcholine aziridinium ion (AF64A). Adult male rats were initially trained to perform a standard radial arm maze (RAM) task. Following training, they were injected intraperitoneally with 10 mg/kg AGF2 (AF/AGF2, CSF/AGF2) or the saline vehicle (AF/SAL, CSF/SAL) for 3 days prior to and for 14 days following bilateral injection of AF64A (3 nmol/side) or artificial CSF into the lateral ventricles. AF64A (AF/SAL) impaired performance of the standard RAM task and a working memory version of the task in which various delays were imposed between the fourth and fifth arm choices. In contrast, animals that received AGF2 and AF64A (AF/AGF2) were initially impaired on the standard RAM task but rapidly recovered and were performing as well as the control groups (CSF/SAL, CSF/AGF2) by the end of training. The AF/AGF2 group, however, exhibited persistent deficits on the working memory version of the RAM task. These data demonstrate that AGF2 promotes behavioral recovery in a task-dependent manner in this model system. Neurochemical analysis revealed that AF64A produced a significant 37% decrease in hippocampal ChAT activity that was significantly attenuated, but not prevented, by prior treatment with AGF2. Thus the behavioral recovery afforded by AGF2 might be related to increased cholinergic activity in the hippocampus that is sufficient for the performance of tasks which either lack or have a minimal working memory component. An analysis of the temporal profile of AGF2-induced neurochemical recovery revealed that ChAT activity was enhanced at 20, but not 2 or 11, weeks following AF64A. Since AGF2 did not attenuate the cholinergic cell loss (35%) induced by AF64A in the medial septum these data indicate that AGF2 might have (1) enhanced sprouting of cholinergic terminals following the initial insult, (2) directly increased ChAT activity in surviving neurons, or (3) induced behavioral and neurochemical recovery through a combination of these or other mechanisms.

Acetylcholinesterase↗
PubMed1990

Cholinergic cell loss and cognitive impairments following intraventricular or intradentate injection of colchicine.

Bilateral injections of colchicine (3.5 or 7.0 micrograms/0.5 microliters/site) into either the dentate gyrus or the lateral cerebroventricles (i.c.v.) of Sprague-Dawley rats produced specific behavioral, histopathological and neurochemical alterations. Colchicine, administered via either route, produced impairments in the performance of a radial-arm maze task which did not subside during 8 weeks of testing. Intradentate colchicine decreased (1) the thickness of both blades of the dentate granule cell layer, (2) the size of the overlying molecular layer, (3) hippocampal volume, and (4) the number of cholinergic neurons in the medial septum/vertical limb of the diagonal band (MS/VLDB). I.c.v. administration of colchicine did not alter any index of hippocampal morphology but did significantly decrease the number of cholinergic neurons in the MS/VLDB. An analysis of the time course of cholinotoxicity revealed that both intradentate and i.c.v. colchicine decreased choline acetyltransferase (ChAT) activity and high affinity choline uptake (HAChU) in the hippocampus at 1 and 3, but not 9, weeks following surgery. Furthermore, i.c.v. colchicine decreased ChAT activity in the septum at both 3 and 9 weeks following surgery. Neither route of administration altered ChAT or HAChU in the frontal cortex, olfactory bulb or striatum. The decreases in presynaptic cholinergic parameters were paralleled by a reduction in acetylcholinesterase staining in the hippocampus which appeared to recover within 9 weeks. These data suggest that intradentate colchicine produces either (i) transsynaptic degeneration of cholinergic neurons due to a loss of their target sites (granule cells in the dentate gyrus), (ii) a direct cholinotoxic effect, or (iii) a combination of these mechanisms. The i.c.v. injection of colchicine appears to exert a direct toxic effect on cholinergic neurons and/or nerve terminals that results in the death of these neurons. Colchicine may be a useful tool for investigating the behavioral and neurobiological properties of the septohippocampal cholinergic pathway and its response to injury.

Animals↗
PubMed1990

Hyperactivity following intradentate injection of colchicine: a role for dopamine systems in the nucleus accumbens.

The role of dopamine systems in the nucleus accumbens (NA) in mediating the hyperactivity following colchicine-induced granule cell damage was investigated. In the first experiment adult Sprague-Dawley rats were bilaterally injected with 6-hydroxydopamine (6-OHDA; 8 micrograms/2 microliters) or 0.5% ascorbate into the NA. Eight days later, rats received intradentate COLCH or CSF and were tested for locomotor activity 2, 4, 6, 8, and 10 days later. Intradentate COLCH produced a significant hyperactivity which was prevented by prior injection of 6-OHDA into the NA. Neurochemical analysis revealed that 6-OHDA decreased dopamine (80%) but not norepinephrine in the NA without altering either catecholamine in the striatum. In the second experiment animals were injected with COLCH or CSF in the dentate gyrus and immediately implanted with bilateral cannulae in the NA. Animals received intraaccumbens injections of CSF or d-amphetamine (20 micrograms/l microliters) and were tested for locomotor activity. Amphetamine produced a significant increase in locomotor activity in both CSF- and COLCH-treated animals. However, COLCH produced an exaggerated response to the motor stimulating effects of amphetamine. These results suggest that the destruction of dentate granule cells following colchicine results in a "functional" hyperactivity of the mesolimbic dopamine input to the NA which might disinhibit locomotor activity.

Animals↗
PubMed1990

Sex differences in regulatory changes following quinolinic acid-induced striatal lesions.

The effects of sex differences and hormonal factors on the weight loss following intrastriatal injections of quinolinic acid (QA) were examined. Male, female or ovariectomized female rats were weighed each day for 30 days following bilateral injections of 150 nmol of QA or vehicle into the striatum. Although all rats injected with QA exhibited an equivalent initial loss of body weight, female lesioned rats rapidly regained weight and did not differ from controls after the first postsurgical day. On the other hand, male lesioned and female ovariectomized lesioned rats exhibited a significant but transient loss of body weight. By 19 days postsurgery all rats had recovered and exhibited comparable body weights. Histological analysis did not reveal any sex-related differences in the extent of striatal pathology following QA. These results suggest that sex and hormonal variables such as estrogen levels play an important role in the regulatory changes following excitotoxic-induced striatal damage.

Animals↗