Subacute Administration Research Articles

In-vitro and in-vivo action of cannabinoids.

The discovery of endocannabinoids such as anandamide and the wide spread localization of cannabinoid receptors in the brain and peripheral tissues, suggests that the cannabinoid system represents a previously unrecognized ubiquitous net work in the nervous system, whose physiology and function is unfolding. In this study, we tested the hypothesis that some of the actions of anandamide are independent of a cannabinoid receptor mechanism. This was accomplished by the use of cannabinoid agonist and antagonist interaction in an in-vitro and in-vivo test systems. In-vitro, we used Xenopus laevis oocytes expression system and two-voltage clamp technique in combination with differential display polymerase chain reaction to determine whether the differential display of genes following treatment with anandamide may be linked to AMPA glutamate receptor. The differential expression of genes in vivo after the sub-acute administration of anandamide could not be directly linked with the AMPA glutamate receptor. In the voltage clamp studies we investigated the effects of anandamide on recombinant AMPA GluR3 subunit currents generated by kainic acid in oocytes expressing the AMPA glutamate receptor. In the in-vitro studies, we present evidence that anandamide inhibited the kainate activated currents in oocytes expressing AMPA glutamate receptor involves cAMP transduction via a cannabinoid receptor independent mechanism. In the in-vivo studies, SR141716A, the CB1 antagonist, induced anxiolysis, that was dependent on the mouse strain used in the anxiety model and blocked the anxiogenic effects of anandamide or methanandamide whereas SR141716A had no effect on the anandamide inhibition of kainate activated currents in-vitro.

Different patterns of kidney toxicity after subacute administration of Na-nitrilotriacetic acid and Fe-nitrilotriacetic acid to Wistar rats.

Na-nitrilotriacetic acid (Na3NTA) and Fe-nitrilotriacetic acid (FeNTA) have both been described to cause tumors in the urinary tract of rodents. However, these effects were observed using different modes of administration at extremely different dose levels and explained by different mechanisms. Whereas FeNTA causes an iron overload of cells and is genotoxic in various assays, Na3NTA is predominantly bound to zinc in vivo and thereby causes cytotoxic effects in the urinary tract. In contrast to FeNTA, Na3NTA requires high dose levels to produce tumors. The aim of this study was to compare the effects of Na3NTA and FeNTA on cellular proliferation, histopathology, lipid peroxidation, and 8-OH-2'-deoxyguanosine levels in the kidneys as well as on the urinary excretion of Ca, Fe, and Zn. For evaluation of DNA synthesis both compounds were administered for 1 or 4 weeks to 14-week-old male Wistar rats at a tumor causing dose, Na3NTA via the diet at 150 ppm and 20,000 ppm (approximately 9 and approximately 1000 mg/kg/day) and FeNTA i.p. at 25 mg/kg/day. An osmotic minipump, containing 20 mg/ml BrdU, was implanted subcutaneously 7 days before necropsy. Na3NTA showed nearly no effect on DNA replication after 1 week but a strong reaction after 4 weeks. The increase was 10- to 18-fold in different renal compartments. The enhancement of proliferation in the proximal tubules was nearly twice that in the distal tubules. In contrast, FeNTA caused DNA replication during the first week, and this was restricted to the proximal tubules. After 4 weeks there was an 18-fold increase in the outer stripe and no effect in the inner stripe of the outer medulla. The data presented give evidence to the assumption that both substances increase cell proliferation as a compensatory mechanism, causing different pattern of tubular proliferation in terms of time course and affected cell types. Both Na3NTA at 20,000 ppm and FeNTA led to increased lipid peroxidation, whereas increased levels of 8-OH-2'-deoxyguanosine were observed only after treatment with FeNTA. Urinary excretion of Zn was increased 30-fold after administration of 20,000 ppm Na3NTA but only 2-fold after administration of FeNTA. Urinary excretion of Ca and Fe remained unchanged after treatment with either Na3NTA and FeNTA. These results show that the Na3NTA-related proliferative effects are not mediated by an internal formation of FeNTA.

Fentanyl decreases beta-CIT binding to the dopamine transporter.

Evidence from animal studies suggest that centrally acting opiates increase synaptic dopamine (DA) concentration. However, the interaction between mu-opioid receptors and the DA system is unclear. We report here an effect of fentanyl on striatal [123I]beta-CIT binding to the DA transporter in a patient and in rats. A female patient underwent [123I]beta-CIT single-photon emission tomography (SPET) study after intrathecal injection of fentanyl for her back pain. After a 2-week drug-free period, the SPET study was repeated. In the experimental study, male Wistar rats were treated with fentanyl either acutely (50 micrograms/kg, i.p.) before imaging study or subacutely for 4 days (10 micrograms/kg, twice a day, i.p.). Brain planar imaging was performed at 3.5 hours after an intravenous injection of [123I]beta-CIT with gamma camera with a pinhole collimator. In a female patient, [123I]beta-CIT binding in the basal ganglia was decreased by 37% during fentanyl as compared to the binding after 2-week drug-free period. Similarly in rats, acute fentanyl treatment decreased [123I]beta-CIT binding to the striatum by 30% as compared to that of with the control rats. After subacute administration of fentanyl, no significant difference was observed compared to the control group. According to the present data, fentanyl decreases [123I]beta-CIT binding in the basal ganglia both in human and rats, suggesting that opiates possibly directly affect DA reuptake.

The effect of subacute administration of a neem pesticide on rat metabolic enzymes

Acute toxicity of a neem pesticide (Vepacide‐Tech) was studied in male Wistar rats by oral (single) intubation for 7 days. Vepacide was found to be moderately toxic to rat based on LD50 value. Subacute toxicity of Vepacide‐Tech was also studied in male rats by oral (multiple) intubation of low (80 mg Kg‐1 day‐1), medium (160 mg Kg‐1 day‐1) and high dose (320 mg Kg‐1 day‐1) for 90 days. High dose caused a significant decrease in Cytochrome P‐450 (Cyt.P‐450) concentration at 45 and 90 days and the medium dose caused same effect at 90th day in liver and lung. Kidney showed similar effect at 90 days by the three doses. Cytochrome b5 (Cyt. b5) concentration was significantly decreased in liver, lung and kidney at 45 and 90 days at medium and high doses. Brain Cyt.b5 concentration was decreased on 90th day at high dose. Cytochrome P‐450 reductase (Cyt.P‐450 reductase) concentration was decreased significantly in liver and brain at 45 and 90 days, respectively at medium and high doses. The withdrawal study (28 days) has shown significant recovery. These results demonstrate that low levels exposure of Vepacide may have significant effect on the xenobiotic detoxification mechanism of different tissues of rat.

Lithium does not attenuate the effects of d-amphetamine in healthy volunteers

It has previously been suggested that an acute dose of 20 mg d-amphetamine can be a good model of mania. In the present study we attempted to validate this model by determining if subacute administration of lithium (for 7 days) would attenuate the effects of 20 mg d-amphetamine in human volunteers. Sixteen healthy volunteers were enrolled in this double-blind, placebo-controlled study. Subjects received either oral lithium at night for 7 nights (1200 mg) ( n=10) or matching placebo ( n=6). On day 8, subjects were assessed at baseline and then once each hour for 3 h following an oral dose of d-amphetamine (20 mg). Subjective states were measured with visual analog scales, and pulse, systolic and diastolic blood pressure were also repeatedly assessed. The results showed that d-amphetamine alone produced a number of subjective and cardiovascular changes, as expected. However, lithium did not attenuate any of these subjective or cardiovascular changes, as would be predicted if d-amphetamine were a valid model of mania. It is suggested that whilst d-amphetamine may produce effects similar to mania, its mechanism of action is different from that which occurs in mania, and therefore the usefulness of the amphetamine model of mania is called into question.

The Pharmacology of Physostigmine

The Pharmacology of Physostigmine

In Vivo Ibogaine Blockade and In Vitro PKC Action of Cocainea.

Ibogaine may have antiaddiction potential against alcohol, psychostimulant and opiate abuse, but its mechanism of action is unclear. Ibogaine, however, has been demonstrated in numerous studies to have effects in multiple central nervous system (CNS) neurotransmitters systems. We are using in vitro and in vivo systems to study the effects of cocaine and whether these effects can be blocked by ibogaine. For the In Vivo studies, we first determined the acute and subacute effects of ibogaine (1-5.0 mg/kg) in mice using the plus-maze test. Acutely increasing doses of ibogaine produced a reduced aversion to the open arms. The subacute administration provoked a variable response which was characterized by fluctuations in aversive and antiaversive behavior of the animals to the open arms of the plus-maze during the 14-day treatment period. A separate group of mice received 1.0 mg/kg cocaine for 14 days, and upon abrupt cessation from cocaine treatment, ibogaine 2.5 mg/kg was administered to a subgroup of these mice. Ibogaine reversed the withdrawal aversions produced by the abrupt cessation from cocaine administration. For the in vitro studies, the expression and activity of protein kinase C (PKC) isoforms and Ca2+ levels were examined following the incubation of PC 12 cells with cocaine. This is because PKC plays a key role in a number of cellular and neuronal functions. We report that cocaine disrupts signal transduction in PC 12 cells by altering the expression and activity of PKC isoforms and Ca2+ levels. The data obtained suggest (1) that the PC 12 cells may be useful in studying the neurobiology of abused drugs, like cocaine in vitro, (2) that if anxiety is a factor in drug dependency, then the antiaddictive property of ibogaine In Vivo may be associated with modifying the CNS neurotransmission that may be involved in anxiety. It remains to be determined whether the signaling involving PKC is important in the antiaddictive properties of ibogaine.

Observations on the review ’retroviral aetiopathogenesis of ovine pulmonary carcinoma: A critical appraisal’

For dairy cattle, the first several weeks of lactation represent the highest-risk period in their lives after their own neonatal period. Although more than 50% of cows during this period are estimated to suffer from at least one subclinical disorder, the complicated admixture of normal adaptations to lactation, infectious challenges, and metabolic disorders has made it difficult to determine which physiological processes are adaptive and which are pathological during this time. Subacute inflammation, a condition that has been well documented in obesity, has been a subject of great interest among dairy cattle physiologists in the past decade. Many studies have now clearly shown that essentially all cows experience some degree of systemic inflammation in the several days after parturition. The magnitude and likely persistence of the inflammatory state varies widely among cows, and several studies have linked the degree of postpartum inflammation to increased disease risk and decreased whole-lactation milk production. In addition to these associations, enhancing postpartum inflammation with repeated subacute administration of cytokines has impaired productivity and markers of health, whereas targeted use of nonsteroidal anti-inflammatory drugs during this window of time has enhanced whole-lactation productivity in several studies. Despite these findings, many questions remain about postpartum inflammation, including which organs are key initiators of this state and what signaling molecules are responsible for systemic and tissue-specific inflammatory states. Continued in vivo work should help clarify the degree to which mild postpartum inflammation is adaptive and whether the targeted use of anti-inflammatory drugs or nutrients can improve the health and productivity of dairy cows.

Different Patterns of Kidney Toxicity after Subacute Administration of Na-Nitrilotriacetic Acid and Fe-Nitrilotriacetic Acid to Wistar Rats

Na-nitrilotriacetic acid (Na3NTA) and Fe-nitrikrtriacetic acid (FeNTA) have both been described to cause tumors in the urinary tract of rodents. However, these effects were observed using different modes of administration at extremely different dose levels and explained by different mechanisms. Whereas FeNTA causes an iron overload of cells and is genotoxic in various assays, Na3NTA is predominantly bound to zinc in vivo and thereby causes cytotoxic effects in the urinary tract In contrast to FeNTA, Na3NTA requires high dose levels to produce tumors. The aim of this study was to compare the effects of Na3NTA and FeNTA on cellular proliferation, histopathology, lipid peroxidation, and 8-OH-2′-deoxyguanosine levels in the kidneys as well as on the urinary excretion of Ca, Fe, and Zn. For evaluation of DNA synthesis both compounds were administered for 1 or 4 weeks to 14-week-old male Wistar rats at a tumor causing dose, Na3NTA via the diet at 150 ppm and 20,000 ppm (˜9 and ∼1000 mg/kg/day) and FeNTA ip at 25 mg/kg/day. An osmotic minipump, containing 20 mg/ml BrdU, was implanted sub-cutaneously 7 days before necropsy. Na3NTA showed nearly no effect on DNA replication after 1 week but a strong reaction after 4 weeks. The increase was 10- to 18-fold in different renal compartments. The enhancement of proliferation in the proximal tubules was nearly twice that in the distal tubules. In contrast, FeNTA caused DNA replication during the first week, and this was restricted to the proximal tubules. After 4 weeks there was an 18-fold increase in the outer stripe and no effect in the inner stripe of the outer medulla. The data presented give evidence to the assumption that both substances increase cell proliferation as a compensatory mechanism, causing different pattern of tubular proliferation in terms of time course and affected cell types. Both Na3NTA at 20,000 ppm and FeNTA led to increased lipid peroxidation, whereas increased levels of 8-OH-2′-deoxyguanosine were observed only after treatment with FeNTA. Urinary excretion of Zn was increased 30-fold after administration of 20,000 ppm Na3NTA but only 2-fold after administration of FeNTA. Urinary excretion of Ca and Fe remained unchanged after treatment with either Na3NTA and FeNTA. These results show that the Na3NTA-related proliferative effects are not mediated by an internal formation of FeNTA.

Effect of intraperitoneal administration of zinc on C57/6J mouse liver--a light microscopic study.

Intraperitoneal administration of zinc chloride in vivo at 14 micrograms/g body weight (equivalent to 1/2 LD50) over a 3 week period induced an increase in liver weight. The mean weight of the livers in zinc-treated C57/6J mice was 50% higher than that of control animals. Image analysis revealed a concomitant and significant increase in the cross-sectional area and perimeter of the hepatocytes in the zinc-treated group. The mean cross-sectional area of hepatocytes in the zinc-treated mice was 337.2 +/- 4.3 microns2 as compared to 224.6 +/- 2.9 microns2 in the control group (p < 0.05, Mann-Whitney test). The mean perimeter of hepatocytes in zinc-treated mice was 72.4 +/- 0.5 micron as compared to 58.9 +/- 0.4 micron in control animals (p < 0.05). It would appear that subacute administration of zinc may result in increase in liver mass due to hypertrophy of the hepatocytes.

P-178 - Antihypertensive effect of subacute administration of Dcosahexa-enoic acid in stroke-prone spontaneously hypertensive rats

P-178 - Antihypertensive effect of subacute administration of Dcosahexa-enoic acid in stroke-prone spontaneously hypertensive rats

3,4-Benzpyrene affects the sexual behaviour of rats across the generations

Chlorinated paraffins are a group of chemicals derived from n-paraffins containing between 10 and 30 carbon atoms which are chlorinated to between 40 and 70% (w/w). Representative grades were tested for acute oral toxicity and skin irritancy in rats, eye irritancy in rabbits, and potential mutagenic effects in two in vitro tests. The effects of one grade (14–17 carbon atoms, 52% chlorinated) which is manufactured in high-tonnage quantities, was evaluated in a 90-day feeding study in rats and dogs, and its tissue retention and elimination was determined in the rat. Chlorinated paraffins are of low acute oral toxicity. Slight, reversible skin and eye irritations were produced by shorter carbon chain derivatives only and no type showed any evidence of mutagenic potential. Subacute administration of 500, 2500, and 5000 ppm reduced diet palatability to rats. Increases in SGPT or SAP levels, liver weight, and smooth endoplasmic reticulum in hepatocytes were seen in rats and dogs: “no-effect” diet levels were 250 and 300 ppm, respectively. Chlorinated paraffin accumulates primarily in the abdominal fat of rats at concentrations which never exceed those in diet (unlike certain other chlorinated organic compounds); its half-life in abdominal fat is about 8 weeks, when untreated diet is offered. On the currently available evidence, in view of their slight toxicity and the low human dietary levels in comparison to the maximum “no-effect” levels in rats and dogs, it is concluded that chlorinated paraffins present no toxicological risk to man despite their continued manufacture and widespread low-level occurrence in the environment.

Striatal synaptophysin levels are not indicative of dopaminergic supersensitivity

Recent evidence suggests that behavioral supersensitivity to dopamine (DA) agonists observed in chronic neuroleptic-treated animals might be related to changes in synaptic morphology and density. The aim of this study was to test this hypothesis using Western blotting to determine the striatal synaptophysin levels in rats chronically treated with haloperidol followed by sub-acute administration of a DA agonist. Chronic haloperidol treatment (1 mg/kg/day for 21 days) produced an 88% increase in striatal synaptophysin levels and a 73% increase in apomorphine-induced stereotypes. Sub-acute administration of the DA D-1 receptor agonist SKF38393 (10 mg/kg/day for 5 days) or the DA D-2 receptor agonist quinpirole (1 mg/kg/day for 5 days) did not modify the haloperidol-induced increase in striatal synaptophysin levels. However, sub-acute administration of SKF38393 attenuated (62%) haloperidol-induced stereotypies. We conclude that there is no direct relationship between stereotyped behavior and synaptophysin levels indicating that striatal synaptophysin levels are not a good marker of dopaminergic supersensitivity.

The effects of the 5-HT 1A agonist flesinoxan, in three paradigms for assessing antidepressant potential in the rat

5-HT 1A receptor agonists have been shown to be effective clinically in the treatment of depression and anxiety. Flesinoxan is an example which is highly selective for the 5-HT 1A receptor subtype. The objective of this study was to appraise the antidepressant potential of flesinoxan (1 and 3 mg/kg s.c.) in three tests which are indicative of antidepressant activity. These are (1) the forced swim test, following sub-acute administration, (2) `open field' activity in the olfactory bulbectomised (OB) rat, following chronic administration, and (3) 8-OH-DPAT-induced hypothemia following chronic treatment. Both doses of flesinoxan significantly reduced the immobility time in the sham and OB groups when compared to their respective controls. In the `open field', there was a significant increase in the ambulation of the OB control group. The higher dose of flesinoxan significantly reduced this deficit. In addition both doses of flesinoxan significantly attenuated the 8-OH-DPAT-induced hypothermic response. These effects of flesinoxan are quantitatively similar to those seen following the chronic administration of antidepressants. These studies illustrate the potential antidepressant properties of flesinoxan, and hence further emphasise the role of the 5-HT 1A receptor in the pathogenesis of depression.

Differential regulation by methylenedioxymethamphetamine of 5-hydroxytryptamine1A receptor density and mRNA expression in rat hippocampus, frontal cortex, and brainstem: the role of corticosteroids.

The present study examined the effects of repeated administration to rats of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") on 5-hydroxytryptamine1A (5-HT1A) receptor density and mRNA expression in the hippocampus, frontal cortex, and brainstem. As expected, 7 days after subacute MDMA administration (20 mg/kg i.p. twice daily for 4 consecutive days) 5-HT content was markedly reduced (-70%) in the hippocampus and the frontal cortex. 5-HT1A receptor density was increased in the frontal cortex by 23% and decreased in the hippocampus and the brainstem by 25%. These changes correlated with an enhanced or diminished 5-HT1A receptor mRNA expression in the three regions studied. To examine the influence of corticosteroids on these changes, adrenalectomized (ADX) rats received the same dosage regimen as above. Adrenalectomy by itself did not modify 5-HT content in the brain regions examined and increased 5-HT1A receptor density in the hippocampus (+20%) but produced no change in the frontal cortex and brainstem. Adrenalectomy also prevented MDMA-induced changes in receptor number in the hippocampus and brainstem but not in the frontal cortex. Dexamethasone (1 mg/kg/day i.p.) administered for 7 consecutive days reversed the effects of adrenalectomy in the hippocampus but not in the frontal cortex. In the brainstem, MDMA no longer reduced 5-HT1A receptor number in ADX rats, but a significant reduction was restored when ADX animals received the glucocorticoid treatment. The present data show that MDMA may affect 5-HT1A receptors in a regionally dependent manner, notably through a drug effect on corticosterone release, which attenuates 5-HT1A receptor gene transcription selectively in the hippocampus.

Comparison of the toxicity profiles of ISIS 1082 and ISIS 2105, phosphorothioate oligonucleotides, following subacute intradermal administration in Sprague-Dawley rats

The systemic toxicity of two phosphorothioate oligonucleotides specific for herpes simplex viruses (ISIS 1082) and human papiloma virus (ISIS 2105) were evaluated following repeated intradermal injections of vehicle control, 0.33, 2.17, or 21.7 mg/kg daily to Sprague-Dawley rats (10/sex/group) for 14 days. Animals were sacrificed 1 day after the last dose, except for a portion of the ISIS 1082-treated animals (5/sex/group) which were maintained for an additional 14-day recovery period. The profile of alterations noted for both compounds was very similar. Other than local signs of irritation at the site of injection, there were no clinical signs of toxicity or treatment-related mortality, but there was a slight decrease in body weight gain for the 21.7 mg/kg dose groups. Alterations in hematology parameters included dose-dependent thrombocytopenia and anemia. Alterations in serum chemistry parameters were suggestive of mild alterations in hepatic metabolism, with increases in liver transaminases and bilirubin, along with decreases in albumin and cholesterol. Both spleen and liver weights were significantly elevated in a dose-dependent fashion. Histopathological alterations noted in liver, kidney, lung, injection site skin, and spleen were characterized as perivascular and interstitial infiltrates of macrophages and monocytes. Additional microscopic alterations in the spleen included mild lymphoid hyperplasia (seen in lymph nodes as well), and extramedullary hematopoiesis. Treatment-related cytopenias were likely related to mild, focal hypocellularity in the bone marrow. Alterations in ISIS 1082-treated animals were only partially reversed following the 14-day treatment-free period. In conclusion, repeated intradermal administration of ISIS 1082 and ISIS 2105 produced a similar spectrum of toxicities, with liver, kidney, spleen, and bone marrow being identified as target tissues. Copyright

Effects of the subacute administration of nefiracetam on abnormal behavior in aged rats

We investigated the effects of nefiracetam on learning and memory by the Morris water maze task and water-finding test, and on emotional behavior by forced swimming, hole-board and open-field tests in old male Kbl Wistar rats aged 90 and 108 weeks. In the water maze task, the acquisition of the task in aged rats was slower than that in young rats. Subacute administration of nefiracetam (1 and 3 mg/kg daily) for 24 days tended to shorten the goal latency to escape onto the platform in a dose-dependent manner in the retention test, conducted 24 days after acquisition training. Nefiracetam (1 mg/kg) administration for 49 days decreased the duration of immobility in aged rats in the forced swimming test. Locomotor activity in young rats during the dark period was significantly higher than that during the light period, while there was no difference in Locomotor activity between the light and dark periods in aged rats, suggesting that Locomotor activity during the dark period and nocturnal habits may be impaired in aged rats. Subacute administration of nefiracetam for 14 days significantly increased the Locomotor activity during the dark, but not light, period in a dose-dependent manner. In addition, nefiracetam given for 38 days, significantly shortened the increased time elapsed before animals started exploring the environment in aged rats compared with young rats in the water-finding tests. These findings suggest that nefiracetam may improve the impaired nocturnal habits and some of emotional behavior in aged rats.

Effect of polymeric nanoparticle administration on the clearance activity of the mononuclear phagocyte system in mice.

We investigated the consequences of acute and subacute administration of mice with polyisobutylcyanoacrylate (PIBCA), polyisohexylcyanoacrylate (PIHCA), poly(D,L-lactic) acid (PLA), and polystyrene (PS) nanoparticles on the mononuclear phagocyte system phagocytic function. This was done by measuring the clearance rate of colloidal carbon. Single administration of PIBCA and PIHCA (but not PLA and PS) nanoparticles reduced carbon clearance in both a time- and dose-dependent fashion. Since clearance of preopsonized carbon was normal, it was assumed that PIBCA and PIHCA nanoparticles deplete opsonins specific for carbon recognition. A decrease in plasma fibronectin levels resulting from nanoparticle administration suggested its implication in their removal from blood. However, fibronectin does not seem to be responsible for PIBCA and PIHCA blockade. Phagocytic function was preserved after repeated treatment with nanoparticles, probably as a result of increased Kupffer cell phagocytic activity and the contribution of spleen macrophages. Neither toxicity nor effects due to nanoparticle hepatic accumulation were observed.

Striatal c-fos levels do not correlate with haloperidol-induced behavioral supersensitivity.

Striatal c-fos levels and stereotyped behavior have been evaluated in chronically haloperidol-treated rats which received subsequent subacute dopamine (DA) agonist treatment to investigate the possible relationship between striatal c-fos and behavioral supersensitivity. Haloperidol treatment (1 mg/kg/day for 21 days) increased apomorphine-induced stereotypies but did not modify striatal c-fos levels. The subacute administration of the DA D-1 agonist SKF38393 (10 mg/kg/day for 5 days) and the combination of the D-1 agonist with the D-2 agonist quinpirole (1 mg/kg/day for 5 days) attenuated apomorphine-induced stereotypies after haloperidol pretreatment. The administration of quinpirole alone, however, did not modify the response to haloperidol. All DA agonists significantly increased c-fos levels after apomorphine injection. The dissociation between haloperidol-induced behavioral supersensitivity and striatal c-fos levels observed in this study suggests that mechanisms different from striatal c-fos induction might be involved, and that striatal c-fos levels are not a good marker of behavioral supersensitivity expression.

Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: A preliminary double-blind placebo-controlled study

Objective: To determine the effect of subacute administration of methylphenidate on recovery from moderate to moderately severe closed head injury. Design: Double-blind placebo-controlled with random assignment. Patients were enrolled when their Galveston Orientation and Amnesia Test score was at least 65. Drug/placebo treatment began the day following baseline cognitive assessment and continued for 30 consecutive days. Follow-up evaluations were conducted at 30 and 90 days after baseline, after discontinuation of drug/placebo. Setting: A level I trauma center. Patients: Twenty-three patients ranging in age from 16 to 64 years. Head injury severity ranged from moderately severe (Glasgow Coma Score [GCS] ≤ 8, no intracranial pressure monitor) to “complicated mild” (GCS from 13 to 15 with positive computed tomography brain scan). Thirty-day follow-up was based on 12 patients, whereas 90-day evaluation was based on 9 patients, with complicated mild head injuries excluded from the analyses. Interventions: Methylphenidate administered twice daily at a dose of .30 mg/kg; placebo administered according to the same schedule in identical pill form. Main Outcome Measures: The Disability Rating Scale (DSR) and tests of attention, memory, and vigilance. Results: The methylphenidate group was significantly better at 30 days on the DRS ( p < .02), and on tests of attention ( p < .03) and motor performance ( p, .0.5). No significant differences were noted between groups at 90 days. Conclusions: Subacute administration of methylphenidate after moderately severe head injury appeared to enhance the rate but not the ultimate level of recovery as measured by the DRS and tests of vigilance. Problems with possible selection bias and small sample size limit generalization of results.