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Biomedical subjects

G Ellison

Publications and source records attributed to G Ellison.

At least 37 records · Page 2Linked to original sources
PubMed1995

The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias.

Phencyclidine (PCP) and ketamine can induce a model psychosis in drug addicts and exacerbate the symptoms of chronic schizophrenics. The model psychoses these drugs induce mimic a variety of schizophrenic symptoms, including flattened affect, dissociative thought disorder, depersonalization and catatonic states. These symptoms can persist for prolonged periods and chronic PCP and ketamine addicts have persisting memory deficits. Dizocilpine (MK-801) is a simpler drug than PCP or ketamine in its actions, but it shares with both the property of blocking in a non-competitive manner the N-methyl-D-aspartate (NMDA) ion-channel. Behavioral observations and drug-discrimination studies in animals indicate that PCP and dizocilpine are similar in their effects and they both have a neurotoxic effect on neurons in posterior cingulate cortex. Recent studies have indicated that both of these drugs, when given continuously for several days, further induce neuronal degeneration in other limbic structures. These include brain regions of rats related to olfaction, associated limbic structures such as piriform cortex and posterior regions of entorhinal cortex and in it's projections, through the perforant pathway, to dentate gyrus and other cells in ventral hippocampus. These degenerative consequences may be excitatory neurotoxic effects, for these compounds also induce an elevation in glucose metabolism maximal in just those structures where degeneration is observed and the degeneration involves entire cells, with all of their processes. It has been suggested these non-competitive NMDA antagonists induce an increase in firing rate in a limbic circuit which includes the perforant pathway. At least some competitive NMDA antagonists induce the same pattern of degeneration and altered glucose utilization. There is anatomical and functional evidence that alterations in these same limbic structures are present in the dementia syndrome manifested by some schizophrenics and most Alzheimer's patients. This suggests that these non-competitive NMDA antagonists may provide a more complete model of psychoses and memory disturbances than previously recognized, in that they can mimic both persisting symptomatology and neuroanatomical abnormalities. While the neurochemical underpinnings of this effect remain elusive, it appears to be both age and sex dependent. Further studies of the mechanisms by which NMDA antagonists induce increased glucose utilization and neurotoxicity in these limbic structures may clarify these alterations in this simplified Papez-like circuit.

Animals↗
PubMed1994

Competitive and non-competitive NMDA antagonists induce similar limbic degeneration.

Neural degeneration was observed in a similar set of limbic structures following the continuous administration of several NMDA antagonists (phencyclidine, dizocilpine, and LY235959). The earliest signs involved terminals and processes, followed by cell bodies. In retrosplenial cortex the predominant staining showed a distribution very similar to that observed for cholinergic innervations. Considerable degeneration was also observed in entorhinal cortex and its principal output, dentate gyrus of hippocampus, and in olfactory regions such as olfactory tubercle and tenia tecta, and in piriform cortex. These results, when considered together with those from studies of glucose metabolism following NMDA antagonists, suggest that a hypermetabolic circuit was involved, and indicate that both competitive and non-competitive NMDA antagonists can induce these effects.

Animals↗
PubMed1994

Continuous cocaine induces persisting alterations in dopamine overflow in caudate following perfusion with a D1 agonist.

The present study examined whether exposure to 5 days of continuous cocaine in rats would produce any persisting alterations of the decrease in striatal dopamine (DA) overflow produced by local infusion of a D1 receptor agonist. Using a microdialysis probe in striatum, changes in DA, DA metabolites, and GABA were assessed 14 to 21 days following a 5-day continuous cocaine treatment. There were no differences in baseline levels of DA and it's metabolites. SKF 38393 (10(-6) infusion into the striatum decreased striatal DA levels in the controls and this effect was attenuated in cocaine-pretreated rats. This result, together with other observations, supports the hypothesis of a persistently altered D1-mediated negative feedback produced by previous exposure to continuous cocaine.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Stimulant-induced psychosis, the dopamine theory of schizophrenia, and the habenula.

While one of the original underpinnings of the dopamine theory of schizophrenia was the paranoid psychosis which often develops during the binges or speed runs of chronic amphetamine addicts (and, more recently, in cocaine addicts), neurochemical studies of such drug abusers or from animals given continuous stimulants in an effort to model stimulant psychoses have not played a major role in the further evolution of this theory. One clear persisting alteration produced by continuous amphetamine is a neurotoxicity to dopaminergic innervations in caudate. Yet continuous cocaine administration apparently does not induce a similar neurotoxicity and this makes this effect a poor candidate for an underpinning of stimulant psychoses. However, it has recently been found that both continuous amphetamine and cocaine induce a strong pattern of degeneration which is highly confined to the lateral habenula and its principal output pathway, fasciculus retroflexus. This finding has led to a reconsideration of the role of these structures in psychoses. The habenula, as the chief relay nucleus of the descending dorsal diencephalic system (consisting of stria medullaris, habenula and fasciculus retroflexus), is an important link between limbic and striatal forebrain and lower diencephalic and mesencephalic centers. Studies of glucose utilization have consistently shown the habenula to be highly sensitive to dopamine agonists and antagonists. Lesions of habenula produce a wide variety of behavioral alterations. The dorsal diencephalic system has major and predominantly inhibitory connections onto dopamine-containing cells and it mediates part of the negative feedback from dopamine receptors onto dopamine cell bodies. It represents one of the major inputs in brain to the raphe nuclei and has anatomical and functional connections to modulate important functions such as sensory gating through thalamus, pain gating through central gray and raphe and motor stereotypies and reward mechanisms through substantia nigra and the ventral tegmental area. It is argued that alterations in these pathways are ideal candidates for producing the behaviors which occur during psychosis and that future considerations of the circuitry underlying psychoses need to include this highly important but relatively neglected system.

Animals↗
PubMed1993

Dissimilar patterns of degeneration in brain following four different addictive stimulants.

Patterns of neural degeneration were compared following continuous administration of four drugs of addiction, each of which induces model psychoses in chronic addicts. D-amphetamine (D-Amph), cocaine (Coc), or phencyclidine (PCP) were administered continuously over a 5-day period. Both D-Amph and Coc induced pronounced degeneration in fasciculus retroflexus, but only D-Amph further induced substantial degeneration in striatum. Continuous PCP produced entirely different degeneration largely confined to the posterior entorhinal cortex, ventral dentate gyrus, and cingulate cortex. Methamphetamine (Meth) administered in the very high dose but less prolonged drug regimen often employed in studies of dopamine toxicity induced pronounced degeneration in striatum, but widespread degeneration in many other regions as well. These results indicate that drugs of abuse with psychotomimetic properties induce distinctively different patterns of neural degeneration, a finding with implications for theories of addiction and psychosis. They predict two different anatomical loci for alterations in psychosis: fasciculus retroflexus and ventral parahippocampus and hippocampus.

Animals↗
PubMed1992

Continuous amphetamine and cocaine have similar neurotoxic effects in lateral habenular nucleus and fasciculus retroflexus.

Both amphetamine and cocaine lead to an intake pattern in chronic addicts in which the drug is taken repeatedly over prolonged periods. While continuously administered amphetamines, designed to mimic this intake pattern, have a neurotoxic effect on caudate dopamine terminals, several studies have failed to find similar effects following continuous cocaine. In this study, these findings in striatum were replicated in rats using silver staining for degenerating neurons. But it was further found that either amphetamine or cocaine given continuously over a 3- to 5-day period induce a highly specific pattern of axonal degeneration extending from the lateral habenular nucleus along the fasciculus retroflexus towards the ventral tegmentum. This finding supports a rich literature on the involvement of these same pathways in the actions of dopamine agonists, reward mechanisms, and the integration of limbic, extrapyramidal, and midbrain centers.

Amphetamine↗
PubMed1991

Hyperthyroidism associated with a thyroid adenoma in a dog.

Hyperthyroidism associated with thyroid adenoma was diagnosed in a dog. Typical clinical signs of hyperthyroidism were resolved with surgical excision of the adenoma. Hyperthyroidism in dogs usually is associated with thyroid carcinoma, which has a poor prognosis. This case emphasizes the importance of obtaining a histologic diagnosis of thyroid tumors in hyperthyroid dogs before giving a prognosis.

Adenoma↗
PubMed1991

Continuous cocaine administration produces persisting changes in brain neurochemistry and behavior.

Rats were administered either continuous cocaine, daily injections of cocaine, continuous amphetamine, or no drug for 5 days and then given a 30 day drug-free recovery period. When subsequently tested in open field, the daily cocaine injection animals were the most hyperactive whereas the cocaine pellet animals were the most fearful. In vitro autoradiography was then utilized to examine persisting changes in receptor binding for D2 ([3H]spiperone), D1 ([3H]SCH23390), benzodiazepine ([3H]flunitrazepam), 5-HT1 ([3H]5-HT), 5-HT2 ([3H]ketanserin), and muscarinic acetylcholine (ACh) receptors ([3H]QNB; quinuclidinyl benzilate). In the amphetamine pellet animals, there were large increases in [3H]spiperone binding in several dopamine (DA)-rich regions; these were accompanied by conversely decreased [3H]SCH23390 binding. Cocaine pellet animals showed a completely different pattern, with appreciable increases in [3H]flunitrazepam binding in DA-rich areas, cortex, and amygdala but decreased [3H]QNB binding in DA-rich areas, hippocampus, and amygdala. While cocaine injection animals showed elevated [3H]spiperone binding in caudate and substantia nigra, they had generally smaller changes in most brain regions than the other drug groups. These findings replicate and extend previous reports that continuous drug administration induces long-lasting alterations in brain chemistry, but indicate that continuous cocaine has enduring effects on different neurochemical systems from continuous amphetamine.

Amphetamine↗
PubMed1991

A silicone pellet for continuous cocaine: comparison with continuous amphetamine.

An inexpensive silicone pellet is described for the continuous administration of cocaine for up to 5 days. Rats implanted with this pellet show minimal skin irritation and go through distinct behavioral stages, with an initial period of hyperactivity followed by motor stereotypies. Then, at 3-4 days after implantation, a variety of hallucinogen-like ("late-stage") behaviors appear, including limb flicks, sudden startle responses, and repetitive mid-air grasping movements. Compared to continuous d-amphetamine, continuous cocaine induces decreased motor stereotypies but heightened "late-stage" behaviors.

Animals↗
PubMed1990

Comparison of chronic administration of haloperidol and the atypical neuroleptics, clozapine and raclopride, in an animal model of tardive dyskinesia.

Rats were administered haloperidol, clozapine, raclopride, or no drug for either 28 days or 8 months and then withdrawn from drug treatment for 3 weeks. Oral movements were repeatedly recorded, both by a human observer and by a computerized video analysis system which determined mouth openings and closings, or computer-scored movelets (CSMs). Four weeks of neuroleptic administration produced no changes in CSMs in any drug-treated group. Long-term administration induced distinctively different patterns of oral activity in the three drug groups, both in number of CSMs and the form of these movements. The oral movements which developed in the haloperidol-treated rats fit a previously described syndrome of late-onset oral dyskinesias which increased upon drug withdrawal. The clozapine- and raclopride-treated rats did not show the increased oral movements seen in the haloperidol animals, but each exhibited uniquely different CSM characteristics compared to controls. The results from this rodent model imply that haloperidol, but not clozapine or raclopride, produces late-onset oral dyskinesias in rats that fit the pattern expected for tardive dyskinesia.

Animals↗
PubMed1990

Autoradiographic analysis of regional alterations in brain receptors following chronic administration and withdrawal of typical and atypical neuroleptics in rats.

Rats were administered haloperidol, clozapine, raclopride, or no drug for 28 days or 8 months. Following a 3 week withdrawal period, in vitro autoradiography was utilized to examine receptor binding for dopamine D2 ([3H]spiperone and [3H]raclopride), dopamine D 1 ([3H]SCH23390), GABA(A) ([3H]muscimol), benzodiazepine ([3H]RO15-1788), and muscarinic ACh receptors ([3H]QNB). [3H]spiperone was elevated in striatal subregions only in haloperidol-treated rats, with the largest increases seen in the 8 month duration animals. Striatal [3H]raclopride binding was increased after both short- and long-term treatment in both haloperidol and raclopride, but not clozapine-treated animals. Clozapine-treated rats showed significant increases in [3H]SCH23390 in the nucleus accumbens after 28-day administration; otherwise no changes were seen for this ligand in any other groups. Increases in [3H]muscimol binding in the substantia nigra reticulata were seen in haloperidol-treated rats after 8 month treatment. Binding of [3H]QNB and [3H]RO151788 were not significantly different from control for any of the drug-treated groups. These data suggest that persisting alterations in receptor binding are primarily seen in dopamine D2 and GABA receptors after withdrawal from chronic administration of haloperidol but not the atypical neuroleptics, clozapine and raclopride.

Animals↗
PubMed1990

Intermittent and continuous haloperidol regimens produce different types of oral dyskinesias in rats.

Rats were administered equivalent doses of haloperidol for either 28 days or 8 months using one of two different drug regimens: intermittent (i.e., weekly injections) or continuously (via drinking water and osmotic mini-pumps). Oral movements were determined by human observers and by a computerized video analysis system, which determined number and amplitude of jaw openings and closings (computer-scored movelets "CSMs") as well as the slope (amplitude/duration) and frequency spectrum (fourier transform) of oral activity. The two drug groups developed distinctively different changes over time. Continuous administration resulted in late-onset oral activity changes at 1-3 Hz and withdrawal increases in CSMs, a pattern expected of tardive dyskinesia. Intermittent treatment produced a primed dystonia-like pattern: large amplitude CSMs which had steep onset slopes and a peak energy at 4-7 Hz. These results demonstrate the importance of drug regimen in determining the type of neuroleptic-induced dyskinesias which develop with prolonged neuroleptic treatment in rodents.

Animals↗
PubMed1990

Chronic administration of typical, but not atypical neuroleptics induce persisting alterations in rest-activity cycles in rats.

The behavior of rats administered chronic neuroleptics was observed using an extremely sensitive, computerized device which detected any cage movements, thereby continuously monitoring even very small levels of activity. In the first experiment, it was found that normal rats have a strong rest-activity rhythm with a cycle length of 60-70 min, whereas rats which have been chronically administered either haloperidol (HAL) or fluphenazine (FLU) decanoate for 20 months show a distinct lengthening of this cycle and that this effect persists long after cessation of drug injections. In a second experiment, it was further observed that these lengthened rest-activity cycles also occur when HAL is administered chronically either via osmotic minipumps or in the drinking water, but not following the chronic administration of two atypical neuroleptics (clozapine and raclopride). These findings suggest a useful new technique for the study of side-effects of neuroleptics in rats.

Animals↗
PubMed1990

Chronic nicotine induces a specific appetite for sucrose in rats.

Thirty female albino rats were implanted with subcutaneous pellets releasing nicotine or amphetamine in order to study the effects of chronic pharmacological treatment on food intake and body weight. The pellets were removed after tolerance (a decrease in anorectic properties of the drugs) had developed. Nicotine administration produced a specific appetite for sucrose both during and following treatment (p less than 0.05).

Amphetamine↗
PubMed1990

Chronic nicotine and withdrawal effects on radial-arm maze performance in rats.

Rats were tested for choice accuracy in an eight-arm radial maze during and after chronic administration of nicotine via subcutaneously implanted glass and Silastic capsules. Nicotine administration significantly improved choice accuracy relative to controls. The effect gradually became apparent over the first 2 weeks of exposure and persisted through the third week. Surprisingly, the significant facilitation of the nicotine-treated rats relative to controls continued for 2 weeks after the end of nicotine administration. No effects of nicotine were seen on choice latency or the strategy to make adjacent arm entries.

Animals↗