The cytoskeleton of the vertebrate smooth muscle cell

Four experiments were conducted to determine the effects of dopamine (DA) antagonists and DA depletions on progressive-ratio responding for food reinforcement. On this schedule, ratio requirement increased by one response after each reinforcer was obtained, and rats were tested in 30-min sessions. Response rates and highest ratio completed were reduced in a dose-related manner by systemic injections of the D1 antagonist SCH 23390, and also by the D2 antagonists haloperidol and raclopride. Drug-treated rats also showed reductions in time to complete the last ratio, demonstrating that they had stopped responding before the end of the session. DA depletions produced by injections of 6-OHDA directly into the nucleus accumbens substantially decreased both the number of responses and the highest ratio completed. The deficits in response number and highest ratio completed induced by DA depletions persisted through the first 3 weeks of postsurgical testing, with some recovery by the fourth week. However, the deficits resulting from dopamine depletions were largely a manifestation of a decrease in response rate; although time to complete the last ratio was significantly reduced by dopamine depletions in the first few days of testing, rats recovered on this measure by the fifth day after surgery. Although previous work has shown that performance on several schedules (e.g., continuous, low value ratios, variable interval) is relatively unaffected by accumbens DA depletions, the present data demonstrate that such depletions do produce a substantial and persistent impairment of progressive ratio response output. Rats with accumbens DA depletions appear to have deficits in maintaining the high work output necessary for responding at large ratio values. The relative sparing of responding on some simple schedules, together with the present progressive ratio results, suggest that rats with accumbens DA depletions remain directed toward the acquisition and consumption of food, but they show deficits in work output for food.     

Evolution of immunoglobulin kappa chain variable region genes in vertebrates

In order to characterize the development of orolingual motor effects of chronic haloperidol treatment in rats, this typical neuroleptic was administered for 102 days while daily measurements of tongue movement dynamics (peak force, lick rhythm, number of licks) during water licking were recorded. After chronic haloperidol dosing (vehicle, 0.06. 0.12, 0.24 mg/kg for four separate groups) for 32 days and continuing every second or third day of the chronic dosing period, the effects of cholinergic (scopolamine: 0.05-0.20 mg/kg; trihexyphenidyl: 0.15-1.0 mg/kg) or serotonergic (ritanserin: 0.5-4.0 mg/kg; quipazine: 0.5-4.0 mg/kg) probe drugs were examined for their capacity to antagonize the alterations in licking behavior induced by haloperidol. Haloperidol dose-dependently reduced peak force and number of licks, effects which were apparent within 2 or 3 days of the start of treatment. Significant effects of haloperidol on lick rhythm first emerged on day 13 and gradually increased in magnitude through the remaining treatment period. Scopolamine, trihexyphenidyl, and quipazine reduced haloperidol's effects on at least one measure of licking behavior. During a 7-day haloperidol withdrawal period, the four dosage groups were similar on all measures of tongue dynamics. Overall, the results exhibited features suggesting the co-occurrence of Parkinson-like and tardive dyskinesia-like effects.     

Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost/benefit task

This experiment was conducted to study the role of nucleus accumbens dopamine in the performance of a novel T-maze cost/benefit procedure. Rats were trained on a T-maze task for food reinforcement. Under one of the test conditions, one arm of the maze contained a high reinforcement density (4 x 45 mg Bioserve pellets) and the other arm contained a low reinforcement density (2 x 45 mg pellets). A large vertical barrier (44 cm) was placed in the arm that contained the high density of food reinforcement. In the second test condition, a separate group of rats was trained in the same T-maze, in which there were 4 food pellets in the arm that was obstructed by the barrier, yet there were no food pellets in the unobstructed arm. After training rats received intra-accumbens of injections 6-hydroxydopamine or ascorbate vehicle. Nucleus accumbens dopamine depletions substantially decreased the number of selections of the obstructed arm with the high reinforcement density when the unobstructed arm also contained 2 food pellets. Dopamine-depleted rats in this condition showed increased selection of the no-barrier arm as well as decreased entry into the arm that contained the barrier. These effects persisted throughout the 3 weeks of post-surgical testing. Nevertheless, when the unobstructed arm contained no food pellets, and the only way to obtain food was to climb the barrier, rats with nucleus accumbens dopamine depletions showed only a modest effect on selections of the obstructed arm, which recovered by the second week of testing. Dopamine-depleted rats that were tested with food in the unobstructed arm showed significantly fewer barrier crossings than dopamine-depleted rats that were tested with no food in the unobstructed arm. Thus, the present findings are not consistent with the notion that nucleus accumbens dopamine depletion rendered the animals unable to climb the barrier, or set an absolute ceiling on the number of barrier crossings the animals could perform. Instead, the present results indicate that nucleus accumbens dopamine depletions affected the relative allocation of barrier climbing responses if alternative food sources were available.     

Colourimetric point mutation assay: for detection of precore mutants of hepatitis B

Rats with unilateral dopamine (DA) depletions (hemiParkinson analogue rats) produced by intracerebral 6-hydroxydopamine injection are impaired in using the contralateral (bad) limbs for postural adjustments. This article examines whether the bad limbs are impaired in applying the forces required to initiate postural adjustments that anticipate and accompany voluntary movements. The rats were trained to reach for food using their good paw while standing on small platforms, each of which measured force changes produced by an individual limb. In one condition the force platforms were aligned to support the limb placement of normal rats and in the second they were aligned to permit the DA-depleted rats to use a compensatory reaching stance. It was found that the bad limbs of the DA-depleted rats produced normal supporting reactions but did not initiate adjustments in posture. Postural adjustments were initiated with the good limbs and preceded rather than accompanied the reaching movements. When constrained to use the posture of normal rats, the DA-deplete rats could not reach successfully, but when allowed to adjust their stance to increase reliance on the good limbs, reaching performance improved. Measures of ground reaction forces confirm that DA-depleted rats can support posture but cannot initiate postural adjustments with their impaired limbs.     

Low doses of haloperidol interfere with rat tongue extensions during licking: A quantitative analysis.

Orolingual dyskinetic effects of haloperidol were studied in rats trained to lick drops of water from a force-sensing disk. Haloperidol dose-dependently decreased force of tongue protrusion, decreased lick duration, increased interlick interval, and decreased number of licks. Fourier methods showed that haloperidol, in doses as low as 0.06 mg/kg, slowed the lick oscillations from an average of 5.250 Hz to 5.096 Hz (p?=?.014). Lick force was modulated by water drop delivery, but this effect was not influenced by haloperidol, which suggests no interference of the drug with sensory regulation of licking. The drug-induced deficits in tongue force may be manifestations of either postural alterations (pseudoparkinsonism) or orobuccolingual dyskinesias or both. Orolingual motor impairments may account for some of the neuroleptic-engendered behavioral decrements that have previously been explained in terms of reward, motivational deficits, or both. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Methamphetamines pretreatment and the vulnerability of the striatum to methamphetamine neurotoxicity

Pretreatment with intermittent low-dose administrations of stimulants increases mesostriatal dopamine transmission upon administration of a challenge dose. This occurs without evidence of a long-term dopamine or serotonin depletion. The purpose was to examine whether pretreatment with low doses of methamphetamine enhances dopamine and/or glutamate efflux and the subsequent depletion of dopamine and serotonin produced by neurotoxic challenge doses of methamphetamine. Microdialysis was used to measure simultaneously extracellular concentrations of dopamine and glutamate in the striatum and prefrontal cortex of awake rats. Basal extracellular concentrations of dopamine and glutamate were unaltered following pretreatment with methamphetamine. The increase in methamphetamine-induced striatal dopamine efflux was not significantly different between methamphetamine and saline pretreated groups. In contrast, after high challenge doses of methamphetamine, dopamine efflux in prefrontal cortex was enhanced to a greater extent in methamphetamine pretreated rats as compared to saline pretreated controls. Acute methamphetamine did not enhance glutamate efflux in prefrontal cortex after pretreatment with saline or methamphetamine. The increase in striatal glutamate efflux was blunted in rats pretreated with methamphetamine. When measured 4 days later, dopamine and serotonin content in striatum was depleted in all rats acutely challenged with methamphetamine. However, these depletions were attenuated in rats pretreated with methamphetamine. An acute methamphetamine challenge did not affect dopamine tissue content in the prefrontal cortex of any rats. Serotonin content in cortex was depleted in all groups following the methamphetamine challenge administration, but these depletions were diminished in methamphetamine-pretreated rats. These results are the first evidence that an intermittent pretreatment regimen with low doses of methamphetamine, followed by a 1 week withdrawal, reduces the vulnerability of striatal dopamine and serotonin terminals and cortical serotonin terminals to methamphetamine neurotoxicity. These findings provide evidence for the mechanism leading to methamphetamine neurotoxicity.     

Tolerance to amphetamine hypophagia: A miscrostructural analysis of licking behavior in the rat.

The development of tolerance to amphetamine-induced hypophagia was assessed by recording changes in lick parameters in rats given chronic administration of the drug (2 mg/kg) and access to sweetened milk. Although licking and milk intake gradually recovered, the volume of milk ingested per lick remained suppressed. Amphetamine had no effect on the interlick interval or the force per lick. In contrast, the drug caused a sustained increase in the number of lick bursts (defined by pause criteria of 0.5-2.0 s) and a decrease in the number of licks per burst (but only at pause criteria of 0.5 and 1.0 s). These results suggest that tolerant rats frequently interrupt licking, resulting in less efficient capture of milk. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Skilled motor deficits in rats induced by ventrolateral striatal dopamine depletions: behavioral and pharmacological characterization

Rats were tested in an instrumental lever pressing procedure, in which a computer program recorded detailed parameters of responding such as response initiation and duration. Initially, rats with ventrolateral striatal dopamine depletions and control rats were tested on days 3-5 after surgery. Dopamine depletions produced by local injections of 6-hydroxydopamine substantially reduced the number of lever presses emitted. Dopamine depleted animals showed significant increases in average response initiation times, average length of fast initiation times, average length of pauses and total pause time. The distribution of initiation times was altered so that DA depleted rats showed significant reductions in the relative number of very high rate responses and also showed increases in the relative number of pauses. On day 7 after surgery, dopamine-depleted rats received one of three drug treatments: injections of ascorbate vehicle, injections of 20.0 mg/kg L-DOPA, and injections of 40.0 mg/kg L-DOPA. Injections of 40.0 mg/kg L-DOPA led to some improvement in several parameters of instrumental responding. Compared to the previous baseline day, the group that received 40.0 mg/kg L-DOPA showed a significant increase in number of responses on the drug treatment day, and also showed significant decreases in average response initiation time and total pause time. The group that received 40.0 mg/kg L-DOPA also showed significant increases in number of responses (expressed as a percent of the previous day) when compared to the control group that received injections of ascorbate vehicle. These results indicate that L-DOPA can partially reverse the skilled motor deficits produced by ventrolateral striatal dopamine depletions, and suggest that this test may be useful for the assessment of antiparkinsonian drugs.     

Dissociation of licking and volume intake controls in rats ingesting glucose and maltodextrin.

The volume of fluid that rats acquire with each lick was systematically varied across short-term tests with 12.5% glucose (Experiment 1) or 12.5% maltodextrin (Experiment 2). For glucose, rats increased the number of licks emitted as lick volume was reduced such that meal size remained remarkably stable across all (8, 4, and 2 μl) but the smallest (1 μl) lick volume conditions tested. Rats similarly compensated for lick volume reduction (8 to 4 μl) with maltodextrin by approximately doubling the number of licks emitted. Meal duration and a number of lick-microstructural parameters (initial ingestion rate, mean burst duration, terminal lick and ingestion rates and burst duration) were not correlated with the intake outcome insofar as they varied significantly across conditions over which intake remained stable. Thus, in response to lick volume manipulation, rats demonstrated an impressive degree of behavioral flexibility in what may be regarded as a defense of meal size. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of deprenyl on methamphetamine-induced dopamine depletions

The effects of deprenyl on methamphetamine-induced dopamine depletions were studied in mice. Four SC injections of 12.5 mg/kg of methamphetamine at two-hour intervals caused substantial (72-82%) and long-lasting depletions of striatal dopamine. Pretreatment with either 25 or 40 mg/kg of deprenyl did not significantly alter the magnitude of this depletion. These results indicate that, unlike what is observed following MPTP, there is no protection afforded dopaminergic cells by deprenyl pretreatment in the methamphetamine model of parkinsonism.     

Electronic communication and the rapid dissemination of public health information

Pretreatment with ginseng total saponin (GTS) reduced the magnitude of the methamphetamine-induced dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillinic acid (HVA) depletions. It is suggested that GTS can, in part, prevent the methamphetamine-induced striatal dopaminergic depletions.     

Substrates of energy metabolism attenuate methamphetamine-induced neurotoxicity in striatum

High doses of methamphetamine (METH) produce a long-term depletion in striatal tissue dopamine content. The mechanism mediating this toxicity has been associated with increased concentrations of dopamine and glutamate and altered energy metabolism. In vivo microdialysis was used to assess and alter the metabolic environment of the brain during high doses of METH. METH significantly increased extracellular concentrations of lactate in striatum and prefrontal cortex. This increase was significantly greater in striatum and coincided with the greater vulnerability of this brain region to the toxic effects of METH. To examine the effect of supplementing energy metabolism on METH-induced dopamine content depletions, the striatum was perfused directly with decylubiquinone or nicotinamide to enhance the energetic capacity of the tissue during or after a neurotoxic dosing regimen of METH. When decylubiquinone or nicotinamide was perfused into striatum during the administration of METH, there was no significant effect on METH-induced striatal dopamine efflux, glutamate efflux, or the long-term dopamine depletions measured 7 days later. However, a delayed perfusion with decylubiquinone or nicotinamide for 6 h beginning immediately after the last METH injection attenuated the METH-induced striatal dopamine depletions measured 1 week later. These results support the hypothesis that the compromised metabolic state produced by METH administration predisposes dopamine terminals to the neurotoxic effects of glutamate, dopamine, and/or free radicals.     

Assay of bropirimine in rat plasma by means of robotic solid-phase extraction and high-performance liquid chromatography

Vacuous jaw movements induced by the muscarinic agonist pilocarpine and striatal dopamine depletions were examined using a slow motion videotape system. With this procedure, rats were videotaped in a Plexiglas tube so that the profile of the head region could be seen. Vacuous jaw movements were analyzed by examining the tape at 1/6 normal speed. An observer recorded each jaw movement using a computer, and the computer program re-calculated the temporal characteristics of jaw movement responses back to normal speed. The interresponse time was recorded for each jaw movement, and each jaw movement interresponse time was assigned to a 50 ms wide time bin. Thus, the distribution of interresponse times could be used to analyze the temporal characteristics of jaw movement responses. In the first experiment, rats were administered saline vehicle, 1.0 mg/kg and 2.0 mg/kg pilocarpine. The rats were videotaped 10-15 min after injection, and the data were analyzed as described above. Pilocarpine induced very high levels of vacuous jaw movements, and the vast majority of all movements occurred in "bursts" with interresponse times of 1.0 s or less. Analysis of the interresponse time distributions showed that most of the jaw movements were within the 150-350 ms range. The modal jaw movement interresponse time was in the 150-200 ms range, which corresponds to a local frequency of 5-6.66 Hz. In the second experiment, the neurotoxic agent 6-hydroxydopamine was injected directly into the ventrolateral striatum in order to produce a local dopamine depletion. The dopamine-depleted rats were observed for jaw movements 7 days after surgery. The overall level of jaw movement activity resulting from dopamine-depletion was much lower than that produced by pilocarpine. There was a significant inverse correlation between ventrolateral striatal dopamine levels and total number of vacuous jaw movements. Videotape analysis indicated that the temporal characteristics of jaw movements induced by dopamine depletions were similar to those shown with pilocarpine. These experiments indicate that vacuous jaw movements induced by pilocarpine and striatal dopamine depletion occur in a frequency range similar to that shown in parkinsonian tremor.     

Effects of ventral striatal 6-OHDA lesions or amphetamine sensitization on ethanol consumption in the rat

Female rats with continuous access to water and 6% ethanol were given bilateral ventral striatal 6-OHDA infusions, which induced pronounced striatal depletions of dopamine. The postoperative ethanol consumption of these rats was not significantly affected in comparison to vehicle-infused controls. In a second experiment, female rats received escalating doses of d-amphetamine over a 5-week period (from 1 to 9 mg/kg/injection). Control females were given saline injections. Following a 3-month drug-free interval, the females were given access to ethanol, the concentration of which was gradually increased from 2% to 12% with weekly intervals. Amphetamine-sensitized rats consumed significantly more alcohol than the saline-treated controls. Taken together, these results suggest that striatal dopaminergic mechanisms, while not necessary for basal ethanol drinking, can facilitate alcohol drinking.     

Dopamine in the lateral caudate-putamen of the rat is essential for somatosensory orientation.

Two studies examined the possible localization of somatosensory orientation in the caudate putamen (CP) of the rat. In Exp I 6-hydroxydopamine (6-OHDA [6 μg]) was injected into either the anterodorsal (AD), anteroventral (AV), posterodorsal (PD), or posteroventral (PV) CP of 19 Long-Evans and 39 Sprague-Dawley rats. Only Ss with PV-CP 6-OHDA injections showed impaired orientation scores. However, these PV injections often caused widespread CP dopamine (DA) depletions, and no specific CP region appeared to be particularly associated with somatosensory orientation. In Exp II, with 32 male Sprague-Dawley rats, multiple injections of 6-OHDA were directed toward the medial or lateral CP to assess their relative contributions directly. DA depletions confined to the lateral (but not medial) CP resulted in orientation deficits; these deficits were greater than would be predicted from the volume of CP/DA loss. The magnitude of the DA fluorescence loss in the lateral CP was more highly correlated with the orientation impairment than was the medial CP fluorescence loss. Thus, the lateral CP contributes to sensorimotor functions to a greater extent than does the medial CP, but the volume of CP/DA depletion also appears to be important. (31 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Depletion of dopamine in the nucleus accumbens prevents the generation of locomotion by metabotropic glutamate receptor activation

The contribution of dopamine (DA) to the locomotion elicited by activation of nucleus accumbens (NAcc) metabotropic glutamate receptors (mGluRs) was investigated in the rat. Different groups of rats were pretreated with bilateral microinjections of either 6-hydroxydopamine (6-OHDA) or its vehicle into the NAcc and, on separate tests starting 10 days later, were tested for locomotion following microinjections (into the same site) of saline, the mGluR agonist, 1-aminocyclopentane-trans-1,3-dicarboxylic acid [(1S, 3R)-ACPD, 0.5 nmol/side] and amphetamine (AMPH, 6.8 nmol/side). DA levels at the microinjection sites were significantly depleted in 6-OHDA-treated rats (42-99% depletions compared to control values obtained in vehicle-treated rats). In contrast to the increased locomotion observed in non-lesioned animals, rats pretreated with 6-OHDA showed no increase in locomotor activity in response to (1S, 3R)-ACPD or AMPH when these were microinjected into the NAcc. The two groups of rats were indistinguishable when tested following NAcc saline. These findings suggest that, as with AMPH, enhanced locomotion produced by NAcc mGluR activation is dependent on intact DA neurotransmission in this site.     

Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats

In the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease, controversy exists concerning the use of apomorphine- or D-amphetamine-induced rotations as reliable indicators of nigrostriatal dopamine depletion. Our objective was to evaluate which, if either, drug-induced behavior is more predictive of the extent of nigrostriatal dopamine depletion. Fischer 344 and Sprague-Dawley rats were unilaterally injected with 9 micrograms/4 microliters/4 min 6-hydroxydopamine into the medial forebrain bundle. The animals were behaviorally tested with apomorphine (0.05 mg/kg, s.c.) and D-amphetamine (5.0 mg/kg, s.c.). Following testing, the brains were removed and the right and left striata, substantia nigra and ventral tegmental area were dissected free and quickly frozen at -70 degrees C for analysis of catecholamine content by high performance liquid chromatography coupled with electrochemical detection. Our results indicate that an animal which has greater than a 90% depletion of dopamine in the striatum might not rotate substantially on apomorphine, without a concomitant depletion of > 50% of the DA content in the corresponding substantia nigra. No correlations were seen involving depletions of the ventral tegmental area and the extent of the lesions to the striatum. Submaximally lesioned (75-90% depleted) rats were found to rotate on D-amphetamine but not on apomorphine. In addition, control rats that did not receive lesions were often seen to rotate extensively on D-amphetamine. We therefore conclude that maximal lesions of the striatum and substantia nigra are required to generate rotations demonstrable with low dose apomorphine but not with D-amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral taste responses of developmentally NaCl-restricted rats to various concentrations of NaCl.

The behavioral taste responses of developmentally NaCl-restricted rats were examined with a brief-exposure taste test. Neurophysiological and morphological alterations have been reported in rats whose dietary sodium is restricted during pre- and postnatal development, there exists little data discerning their behavioral response to tastants. Control and developmentally NaCl-restricted rats were maintained on a low-NaCl diet and trained to lick from individually presented sipper tubes. Each subject received 4 days of testing on various NaCl concentrations. Results indicate that developmentally NaCl-restricted rats have dramatically increased lick rates to NaCl solutions. These responses are likely due to some combination of factors including (a) numbers and type of active chorda tympani fibers, (b) compensatory responses to NaCl-solutions from other nerves of the oral cavity, and (c) increased sensitivity of central taste systems to NaCl. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Activation-induced restoration of sensorimotor functions in rats with dopamine-depleting brain lesions.

Bilateral electrolytic lesions of the lateral hypothalamus or intraventricular 6-hydroxydopamine injections produced substantial depletions of striatal dopamine in 14 male albino rats. All Ss with brain damage showed marked sensorimotor impairments compared to 21 controls; however, they began to move and respond appropriately to environmental stimuli when placed in a sink of water, in a shallow ice bath, or among a colony of cats or rats. A reversal of the sensorimotor dysfunctions was still apparent shortly after Ss were removed from each activating situation; however, the therapeutic effects dissipated rapidly, and by 4 hrs after an exposure Ss responded as poorly as they had prior to activation. Findings are strikingly similar to the "paradoxical kinesia" seen in parkinsonism, a clinical disorder attributed to degeneration of central dopamine-containing neurons. Collectively, they suggest the importance of activation in maintaining responsiveness to sensory stimuli in rats following dopamine-depleting brain lesions. (36 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Mesocortical Dopamine Projection to Anterior Cingulate Cortex Plays No Role in Guiding Effort-Related Decisions.

Both mesolimbic dopamine (DA) and the anterior cingulate cortex (ACC) have been implicated in enabling animals to expend effort to obtain greater reward. To investigate the role of the DA pathway to ACC in working for reward, the authors tested rats on a cost-benefit T-maze paradigm in which they could either climb a barrier to obtain large reward in 1 arm (high reward [HR]) or select the low-effort alternative containing less reward (low reward [LR]). Surprisingly, ACC DA depletions had no effect on choice performance. Manipulations of barrier and reward sizes demonstrated that lesioned rats were as sensitive to the costs and benefits of the alternatives as controls. These results imply that the DA projection to ACC is not involved in guiding effort-related decisions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)