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Biomedical subjects

R E See

Publications and source records attributed to R E See.

At least 55 records · Page 3Linked to original sources
PubMed1992

Comparison of chronic intermittent haloperidol and raclopride effects on striatal dopamine release and synaptic ultrastructure in rats.

The effects of chronic intermittent administration (7 months) of two neuroleptics, haloperidol (HAL) and raclopride (RAC), were compared using several different measures. Both drugs were administered weekly by subcutaneous injection at 7.0 mg/kg. Both neuroleptics consistently produced catalepsy throughout the treatment period, although HAL was generally more cataleptogenic than RAC. Assessment of dopamine (DA) release in the caudate putamen (CPu), through the use of in vivo microdialysis, showed that chronic HAL or RAC administration caused a prolonged decrease of DA release in response to a low dose of the DA D2 agonist quinpirole (0.03 mg/kg, sc). Injection of the muscarinic agonist pilocarpine (1.0 mg/kg, IP) did not have any significant within-group effects, although both neuroleptic treatment groups showed decreased DA release when compared to controls. Ultrastructural analysis of the dorsolateral CPu showed that both HAL and RAC treatment resulted in a significant increase in the number of perforated synapses, which contain a discontinuous density along the postsynaptic membrane. These results demonstrate that two different DA D2 receptor antagonists produce a similar effect on DA function and ultrastructural changes within the CPu following chronic, intermittent treatment.

Animals↗
PubMed1992

Neurotensin increases extracellular striatal dopamine levels in vivo.

This study employed intracranial microdialysis to assess the effects of neurotensin (NT) infusion on extracellular dopamine (DA) and DA metabolite concentrations in the rat striatum and nucleus accumbens, and the effects of NT on alterations in extracellular DA levels induced by cocaine and the DA D-2 receptor agonist, quinpirole. Direct NT infusion (.10, 1.0, 10.0 microM) did not significantly affect extracellular DA in the nucleus accumbens, but did produce a significant increase in the DA metabolite homovanillic acid (HVA). In contrast, direct NT infusion produced an increase in striatal DA levels, without altering DA metabolites. Neurotensin infusion (.10 microM) into the striatum significantly attenuated the peak DA increase induced by an intraperitoneal (IP) injection of a low dose (10.0 mg/kg) but not a high dose (30.0 mg/kg) of cocaine. Neurotensin infusion (.10 microM) did not affect the decrease in DA and its metabolites induced by an IP injection of a low dose of quinpirole (.03 mg/kg), but did alter the decrease in HVA induced by a high dose of quinpirole (.10 mg/kg). These results suggest that NT differentially affects in vivo DA release in the striatum and nucleus accumbens, and further strengthens the assertion that NT is an important modulator of dopaminergic function.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Striatal dopamine metabolism increases during long-term haloperidol administration in rats but shows tolerance in response to acute challenge with raclopride.

The release and metabolism of dopamine (DA) in the striatum of rats during long-term haloperidol administration (32 weeks) was assessed using in vivo microdialysis. Basal levels of homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were significantly elevated over control values, while basal DA release was not significantly increased. The specific DA D2 receptor antagonist, raclopride (0.5 mg/kg, i.p.), increased DA release and metabolism in control animals, but this effect was profoundly blocked in the haloperidol treated group. These results suggest that chronic haloperidol treatment may induce compensatory increases in basal DA activity even though response to an acute D2 antagonist shows significant tolerance.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

In vivo assessment of release and metabolism of dopamine in the ventrolateral striatum of awake rats following administration of dopamine D1 and D2 receptor agonists and antagonists.

The ability of specific dopamine (DA) receptor agonists and antagonists to modify the release and metabolism of DA in the ventrolateral striatum of awake rats was assessed using in vivo microdialysis. The specific DA D2 receptor antagonist, raclopride (0.1, 0.5 and 2.0 mg/kg, i.p.), dose-dependently increased release of DA and levels of the metabolites DOPAC and HVA, while the D2 receptor agonist, quinpirole (0.03, 0.1 and 0.3 mg/kg), decreased levels of DA, DOPAC and HVA. The DA D1 receptor antagonist, SCH23390 [(R + (+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepin-7-ol) (0.01, 0.05 and 0.25 mg/kg), produced an increase in DA, DOPAC and HVA but of a lesser magnitude than raclopride. The D1 agonist SKF38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol) (1.0, 3.0 and 10.0 mg/kg) failed to affect the release of metabolism of DA at any dose. These results support previous findings that activation of D2 receptors has greater control over in vivo DA function, than drugs specifically affecting D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Cholinergic modulation of oral activity in drug-naive and chronic haloperidol-treated rats.

The cholinergic agonists pilocarpine, physostigmine, oxotremorine, and arecoline were administered IP at various doses to rats. Oral activity was assessed in these animals with a computerized video analysis system that determined the number and form of jaw openings and closings (computer scored movelets "CSMs"). The different cholinergic drugs produced distinctive changes in the number of CSMs at various amplitudes and in the frequency distribution of CSMs as determined by fast fourier analysis. Rats treated for 28 weeks with haloperidol showed a previously described, late onset oral dyskinesia characterized by increases in small amplitude CSMs, decreases in CSM slope, increased energy at the 1-3 Hz range and decreased energy at the 5-7 Hz range. Administration of pilocarpine (1.0 mg/kg) reversed all of these effects, while the anticholinergic drug, scopolamine (0.05 mg/kg), had no effect. These results indicate that different cholinomimetics can uniquely alter oral activity in rats and that symptoms of late onset, neuroleptic-induced oral dyskinesia are modified by a cholinergic agonist.

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↗
PubMed1989

Rats administered chronic neuroleptics develop oral movements which are similar in form to those in humans with tardive dyskinesia.

Oral movements (OMs) in rats chronically administered haloperidol (HAL), fluphenazine (FLU), or no drug were recorded using a computerized video analysis system which measured the distance between two fluorescent dots painted above and below the rat's mouth. The resulting data was analyzed using fast-fourier analysis. Following an initial period of sedation (decreased energy at all frequencies), the drugged animals (and especially the FLU animals) began to show increased oral movements of 1-2 Hz, an effect which increased substantially upon drug withdrawal. This is precisely the altered energy spectrum observed in humans with tardive dyskinesia.

Animals↗
PubMed1989

Chronic neuroleptic treatment in rats produces persisting changes in GABAA and dopamine D-2, but not dopamine D-1 receptors.

The effects of continuous treatment with haloperidol (HAL) or fluphenazine (FLU) for 10 months on dopamine and GABA receptors in the rat brain was examined using in vitro autoradiography. Rats treated with HAL, but not FLU, showed an increase in D-2 receptor binding in the caudate-putamen as revealed by [3H]spiperone. Labeling of D-1 receptors by [3H]SCH23390 revealed no changes in either drug-treated group. Both drug-treated groups, however, exhibited a significant increase in [3H]muscimol binding in substantia nigra, pars reticulata (SNR). These dopaminergic-GABAergic receptor alterations may be related to previously reported changes in oral movement activity seen in these neuroleptic-treated animals.

Animals↗
PubMed1989

Delayed appearance of facial tics following chronic fluphenazine administration to guinea pigs.

Guinea pigs were administered chronic fluphenazine decanoate for 11 months and oral movements (OMs) were periodically observed using several different paradigms. Shortly after the initiation of neuroleptic treatment, increased OMs were seen in the drugged animals, but these did not persist and may have reflected a decreased fear (freezing) reaction in the tranquilized animals, being correlated with increased locomotion in open field. After 7 months of neuroleptics, twitch-like movements of the orofacial region were observed in the drugged animals; these dyskinetic movements were enhanced by administration of d-amphetamine. These twitch-like movements appear to be a better model of tardive dyskinesia in the guinea pig than the initially observed and normal-appearing OMs.

Animals↗
PubMed1989

Effects of dopamine D1 and D2 receptor antagonists on oral activity in rats.

Two experiments were performed to investigate the actions of the selective D1 blocker SCH 23390 and the selective D2 blocker sulpiride, on oral movements in rats; these were quantified by a human observer scoring vacuous chewing movements (VCMs), jaw tremor and head movements, as well as a computer analysis system which measured the amplitude and slope of each movement. In the first experiment it was found that both SCH 23390 and sulpiride decreased VCMs and head movements in a dose-dependent manner, with SCH 23390 more effectively decreasing head movements and sulpiride more effectively decreasing VCMs. In a second experiment, the effectiveness of these two drugs in blocking the actions of selective D1 (SKF 38393) and D2 (LY 171555) agonists was studied. The SKF 38393-induced increase in computer-scored movement was attenuated by both sulpiride and SCH 23390, whereas the LY 171555-induced decrease in VCMs was attenuated by sulpiride, while SCH 23390 exacerbated it. These findings, together with our earlier results, suggest a simple relationship of D1 receptors to oral movement, with increased activation resulting in increased oral movement and decreased activation resulting in decreased oral movement. The relationship of D2 receptors to oral movement shows a more complex pattern, with both stimulation and blockade decreasing oral movement. One possibility may be the existence of more than one subpopulation of D2 receptors mediating these effects.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

D1 and D2 dopamine receptor interactions with pilocarpine-induced oral activity in rats.

To investigate the relationship between dopamine (DA) and acetylcholine (ACh) systems in the control of oral movement, we studied the effects of specific D1 and D2 drugs on vacuous chewing movements induced by the muscarinic ACh agonist, pilocarpine. In previous experiments we found that when given alone, the D1 agonist SKF 38393 increased vacuous chewing and the D1 antagonist SCH 23390 decreased it, while both the D2 agonist LY 171555 (quinpirole) and the D2 antagonist sulpiride decreased vacuous chewing. In the present experiment, the effects of the D1 drugs had similar effects in rats concurrently given pilocarpine. In contrast, the effects of both of the D2 drugs were altered by pilocarpine. Surprisingly, the actions of D2 agonist and antagonist were affected in opposite ways. The effect of sulpiride in reducing oral movement activity was eliminated by pilocarpine, while the effect of LY 171555 in reducing oral movement was enhanced by pilocarpine.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Characteristics of oral movements in rats during and after chronic haloperidol and fluphenazine administration.

Rats were chronically administered either haloperidol (HAL) or fluphenazine (FLU) via depot injections for 8 months, given these same drugs in their drinking water for the next 2 months, and then withdrawn from the drugs. Throughout the experiment the animals were tested repeatedly in an enclosed tube using a computerized device which measured computer-scored movelets (CSMs) and, in the latter half of the experiment, were also scored by a human observer in the tube, as well as in an open cage, for observed oral movements (OMs). In the tube, the animals in both neuroleptic-treated groups showed initial decreases in the number of CSMs and made sluggish CSMs; these effects were generally larger in the FLU animals. After 6 months of chronic neuroleptics, the HAL-treated animals showed increased oral movements, both as reported by the human observer and in CSMs of all amplitudes, and this effect increased upon drug withdrawal. FLU-treated animals showed a more persistent depression of both OMs and CSMs of large amplitudes. However, the behavior most characteristic of both neuroleptic-treated groups was the gradual development of increases in CSMs of the smallest amplitudes measurable. A different pattern was observed in the open cage test, where both neuroleptic groups showed significant increases in vacuous OMs during drug administration which rapidly became attenuated upon drug withdrawal. These results indicate a complex syndrome of oral activity in the drugged animals which changed over time. The measure of oral activity which most clearly showed the time-course for late-onset changes in oral activity was CSMs of the smallest amplitudes.

Animals↗
PubMed1987

Neuroleptic-induced oral movements in rats: methodological issues.

In three separate experiments groups of rats were chronically administered neuroleptics in a variety of ways (chronic injections, subcutaneous implants, and decanoate injections) and examined for oral movements (OMs) in two different tests: in an open cage using a human observer, or in a plexiglas tube enclosure, where OMs were monitored both by a human observer and computerized video analysis system. These two testing methods showed different effects of neuroleptic administration. In the open cage, OMs tended to be enhanced during chronic neuroleptic exposure and to rapidly subside upon drug withdrawal. The enhanced OMs were especially present just after drug injections, when activity levels were low. In the observation tube environment, however, OMs tended to be low soon after drug treatments, and elevated upon withdrawal. Thus, the type of behavioral test used determines how neuroleptic-induced increases in oral activity should be interpreted.

Animals↗
PubMed1987

Recording oral activity in rats reveals a long-lasting subsensitivity to haloperidol as a function of duration of previous haloperidol treatment.

Rats pretreated with no drug or with one of two dose levels of continuous haloperidol for 6, 12, or 24 weeks were then given a 5 month drug free interval followed by a single injection of 1 mg/kg haloperidol. Oral movement activity was recorded 2 days before and 7 days after the acute injection of haloperidol using a computerized scoring apparatus. Whereas prior to the acute injection there were no differences between groups, postinjection scores indicated a linear response curve, with the animals which had the least time of exposure showing the greatest increases in oral movement behavior. These data indicate that duration of treatment is a more important factor than is dose level in the development of persistent changes in dopamine-mediated oral activity.

Animals↗