Evaluation of a commercial orthopaedic metal artefact reduction tool in radiation therapy of patients with head and neck cancer.

OBJECTIVE: To assess the image quality and dosimetric effects of the Philips orthopaedic metal artefact reduction (OMAR) (Philips Healthcare System, Cleveland, OH) function for reducing metal artefacts on CT images of head and neck (H&N) patients. METHODS: 11 patients and a custom-built phantom with metal bead inserts (alumina, titanium, zirconia and chrome) were scanned. The image was reconstructed in two ways: with and without OMAR (OMAR and non-OMAR image). The mean and standard deviation values of CT Hounsfield unit (HU) for selected regions of interest of each case were investigated for both images. Volumetric modulated arc therapy plans were generated for all cases. Gamma analysis of each dose distribution pair in the patient (1%/1 mm criteria) and phantom (2%/2 mm and 3%/3 mm criteria) images was performed. The film measurements in phantom for two metal beads were conducted for evaluating the calculated dose on both OMAR and non-OMAR images. RESULTS: In the OMAR images, noise values were generally reduced, and the mean HU became closer to the reference value (measured from patients without metal implants) in both patient and phantom cases. Although dosimetric difference was insignificant for the eight closed-mouth patients (γ = 99.4 ± 0.5%), there was a large discrepancy in dosimetric calculation between OMAR and non-OMAR images for the three opened-mouth patients (γ = 91.1%, 94.8% and 96.6%). Moreover, the calculated dose on the OMAR image is closer to the real delivered dose on a radiochromic film than was the dose from the non-OMAR image. CONCLUSION: The OMAR algorithm increases the accuracy of CT HU and reduces the noise such that the entire radiation treatment planning process can be improved, especially for contouring and segmentation. ADVANCES IN KNOWLEDGE: OMAR reconstruction is appropriate for the radiotherapy planning process of H&N patients, particularly of patients who use a bite block.

The effect of MLC speed and acceleration on the plan delivery accuracy of VMAT.

OBJECTIVE: To determine a new metric utilizing multileaf collimator (MLC) speeds and accelerations to predict plan delivery accuracy of volumetric modulated arc therapy (VMAT). METHODS: To verify VMAT delivery accuracy, gamma evaluations, analysis of mechanical parameter difference between plans and log files, and analysis of changes in dose-volumetric parameters between plans and plans reconstructed with log files were performed with 40 VMAT plans. The average proportion of leaf speeds ranging from l to h cm s(-1) (Sl-h and l-h = 0-0.4, 0.4-0.8, 0.8-1.2, 1.2-1.6 and 1.6-2.0), mean and standard deviation of MLC speeds were calculated for each VMAT plan. The same was carried out for accelerations in centimetre per second squared (Al-h and l-h = 0-4, 4-8, 8-12, 12-16 and 16-20). The correlations of those indicators to plan delivery accuracy were analysed with Spearman's correlation coefficient (rs). RESULTS: The S1.2-1.6 and mean acceleration of MLCs showed generally higher correlations to plan delivery accuracy than did others. The highest rs values were observed between S1.2-1.6 and global 1%/2 mm (rs = -0.698 with p < 0.001) as well as mean acceleration and global 1%/2 mm (rs = -0.650 with p < 0.001). As the proportion of MLC speeds and accelerations >0.4 and 4 cm s(-2) increased, the plan delivery accuracy of VMAT decreased. CONCLUSION: The variations in MLC speeds and accelerations showed considerable correlations to VMAT delivery accuracy. ADVANCES IN KNOWLEDGE: As the MLC speeds and accelerations increased, VMAT delivery accuracy reduced.

Sedative and anxiolytic effects of zopiclone's enantiomers and metabolite.

We evaluated racemic zopiclone, its (S)- and (R)-enantiomers and a metabolite, (S)-desmethylzopiclone, for their actions on locomotor activity, rotarod performance, the elevated plus maze and the Vogel conflict test of anxiety, and electroconvulsive shock-induced seizures duration. Zopiclone and its (R)- and (S)-enantiomers reduced locomotor activity, and zopiclone and its (S)-enantiomer disrupted rotarod performance at 10 mg/kg. (S)-desmethylzopiclone did not alter these measures at doses of less than 200 mg/kg. (S)-desmethylzopiclone altered plus maze performance at the lowest dose of all the zopiclone derivatives tested, caused a dose-related effect on the Vogel conflict test and caused a dose-related reduction of electroconvulsive shock-induced seizure durations. The data indicate that (S)-desmethylzopiclone can bring about an anxiolytic effect without a substantial degree of central nervous system depression, and suggest that the agent may be particularly useful clinically in the treatment of anxiety.

Enantioselective behavioral effects of sibutramine metabolites.

The anti-obesity agent, racemic (RS)-sibutramine, has two active metabolites, desmethylsibutramine and didesmethylsibutramine. To the extent that sibutramine itself mediates some of its side effects, desmethylsibutramine and/or didesmethylsibutramine might be safer and just as therapeutically effective. Because both desmethylsibutramine and didesmethylsibutramine are also optically active, the present study assessed the anorexic effects (2.5-10 mg/kg, i.p., for all drugs), in rats, of the R(+)-and S(-)-enantiomers of both metabolites and compared them to the effects of racemic sibutramine. Locomotor activity (2.5-10 mg/kg, i. p., for all drugs), a dopamine dependent behavior, was also measured in view of some uncertainty regarding dopaminergic effects of sibutramine. In view of sibutramine's antidepressant profile in animal models, the same drugs were also tested in the Porsolt swim test (0.1-2.5 mg/kg, i.p., for all drugs). Lastly, the IC(50)s of all drugs to inhibit uptake in vitro of norepinephrine, serotonin and dopamine were determined. Both (R)-enantiomers had significantly greater anorexic effects than those of their respective (S)-enantiomers as well as of sibutramine. All of the agents increased locomotor activity and reduced immobilized time ("behavioral despair") in the swim test; again, the (R)-enantiomers were more potent than the (S)-enantiomers and sibutramine. However, the anorexic and locomotor effects could be dissociated from each other as well as from effects in the swim test. Both (R)-desmethylsibutramine and (R)-didesmethylsibutramine as well as sibutramine decreased food intake at a time (24-42 h post-treatment) when locomotor activity was unaffected. All of the drugs appeared to be more potent in the swim test than in the other tests and all of the drugs were more potent at inhibiting uptake of norepinephrine and dopamine than of serotonin. The results suggest that these enantioselective metabolites of sibutramine could be safe and effective treatments for obesity as well as possibly for depression.

Differential immune responses in mice with left- and right-turning preference.

Humoral and cell-mediated immune responses of inbred BALB/c male mice were assayed for differential reactivities associated with behavioral sidedness, which was evaluated by spontaneous rotational behavior in a circular cage model system. Mice with left-turning preference had lower in vivo primary IgM and IgG anti-Keyhole Limpet Hemocyanin (KLH) antibody responses, delayed-type hypersensitivity (DTH) responses, and host-resistance against the intracellular bacteria, Listeria monocytogenes, than mice with right-turning preference. The only immune parameter not shown to be associated with turning preference was the secondary humoral immune response to KLH. The weak innate immune response of left-turners for clearance of Listeria showed close intercorrelation with elevated serum IL-6 levels. Serum corticosterone and splenic norepinephrine levels were differentially increased and decreased by infection, respectively. We suggest that the observed differential immune reactivities of individual animals with same age, gender, and genetic background are associated with functional asymmetries within the brain, that the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic innervation are involved in the regulatory brain: immune interconnection after infection, and that the HPA axis and sympathetic nervous system are involved in the brain laterality effects on immune responses.

Left and right 6-hydroxydopamine lesions of the medial prefrontal cortex differentially affect voluntary ethanol consumption.

Dopaminergic projections to the medial prefrontal cortex (mPFC) were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) to examine how dopamine (DA) asymmetry in the mPFC influences voluntary ethanol consumption. Differences in nucleus accumbens (NAS) DA neurotransmission have been related to individual differences in locomotor activity and in the rewarding efficacy of ethanol. Therefore, differences in locomotor activity were used to further characterize the effects of unilateral mPFC 6-OHDA lesions on ethanol consumption. Male Long Evans rats were assessed for high versus low levels of spontaneous locomotor activity. DA terminals in the left or right mPFC were unilaterally lesioned with 6-OHDA, resulting in an average DA depletion of 54% and 50%, respectively. After a minimum seven-day recovery period, preference for a 10% ethanol solution vs. water was determined in a 24-h 2-bottle home-cage free-choice paradigm. Left mPFC 6-OHDA lesions increased and right lesions decreased ethanol consumption. These differential effects of left and right lesions were primarily attributable to rats exhibiting low locomotor activity prior to surgery. The present data suggest that right greater than left cortical DA asymmetry in combination with low endogenous NAS DA (predicted by low locomotor activity levels) may increase the vulnerability to abuse ethanol.

Rotation, locomotor activity and individual differences in voluntary ethanol consumption.

Spontaneous turning behavior and locomotor activity were evaluated for their ability to predict differences in the voluntary consumption of ethanol in male Long-Evans rats. Animals were assessed for their preferred direction of turning behavior and for high vs. low levels of spontaneous locomotor activity, as determined during nocturnal testing in a rotometer. Subsequently, preference for a 10% ethanol solution vs. water was determined in a 24-h two-bottle home-cage free-choice paradigm. Rats exhibiting a right-turning preference consumed more ethanol than rats showing a left-turning preference. While locomotor activity alone did not predict differences in drinking, turning and locomotor activity together predicted differences in ethanol consumption. Low-activity right-turning rats consumed more ethanol than all the other groups of rats. Previous studies from this laboratory have shown that individual differences in turning behavior are accompanied by different asymmetries in dopamine (DA) function in the medial prefrontal cortex (mPFC). Individual differences in locomotor activity are associated with differences in nucleus accumbens (NAS) DA function. The present data suggest that variations in mPFC DA asymmetry and NAS DA function may underlie differences in the voluntary consumption of ethanol.

Ethanol induced differences in medial prefrontal cortex dopamine asymmetry and in nucleus accumbens dopamine metabolism in left- and right-turning rats.

Ethanol (0.5 g/kg i.p.) 15 min prior to sacrifice increased homovanillic acid (HVA) levels in the left medial prefrontal cortex (mPFC) of left-turning rats and in the right mPFC of right-turning rats. In the nucleus accumbens (NAS), ethanol decreased dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and HVA levels in rats that exhibited low levels of locomotor activity but not in rats that exhibited high levels of locomotor activity. This laboratory has previously shown that rats exhibiting differences in turning and locomotor activity behavior display different preferences for ethanol. The present results suggest that ethanol-induced differences in mPFC and NAS DA activity may be related to individual differences in the susceptibility to abuse ethanol.

Paw preference, rotation, and dopamine function in Collins HI and LO mouse strains.

Mice have paw preferences that are consistent upon repeated measurement. The Collins HI and LO strains are two populations of mice that have been selectively bred to differ markedly in the degree of paw preference. They represent a unique genetic model of functional cerebral lateralization. Rotation (or circling) behavior in normal unlesioned animals reflects an endogenous lateralization of the functioning brain dopamine (DA) systems. In the present study, rotational behavior and lateralized brain DA neurochemistry were assessed in the Collins HI and LO strain mice. Confirming Collins findings, HI strain mice exhibited stronger paw preferences than LO strain mice. HI strain mice also showed stronger percent directional preferences during nocturnal tests of spontaneous rotation. Neurochemical differences were also apparent between the strains. DA and its metabolites were measured in the medial prefrontal cortex (PFC), nucleus accumbens (NAS), and striatum. Degrees of rotational and paw preference in HI, but not LO, mice were correlated with PFC asymmetries in DA and the DA metabolite dihydroxyphenyl acetic acid (DOPAC), respectively. Hemisphere, paw preference, turning preference, and strain interacted in a complex way to determine measures of DA utilization in the NAS and striatum. Even though the directions of paw preference and rotation were not correlated, HI and LO mice of differing paw and rotational directional preferences showed differences in DA neurochemistry in the NAS and striatum.

Effects of prenatal cocaine exposure on the mesocorticolimbic dopamine system: an in vivo microdialysis study in the rat.

Microdialysis studies were conducted on prenatally saline-treated and prenatally cocaine-treated rats, either as pups (10-30 days old) or young adults (40-190 days old), to study the effects of prenatal cocaine exposure on the mesolimbic dopamine (DA) system. In the n. accumbens of saline-treated rats, basal dialysate concentrations of DA were similar in pups and adults; however, the levels of DA metabolites, DOPAC, HVA, and the serotonin metabolite, 5-HIAA, were markedly lower in pups. In pups, prenatal cocaine exposure led to basal dialysate levels of DA in the n. accumbens that were twice control levels; however, there was no difference in response to a period of intermittent tail pinch or an acute injection of cocaine (20 mg/kg). In the adult, basal levels of DA, DOPAC, HVA and 5-HIAA in n. accumbens did not differ across prenatal treatments. However, in prenatally cocaine-treated adults a cocaine injection led to an enhanced rise in extracellular DA compared to controls. In frontal cortex of adult rats, basal levels of DA, DOPAC and HVA did not differ across prenatal treatments; however, basal levels of 5-HIAA in this region were significantly elevated in prenatal-cocaine rats. No group differences were observed in the frontal cortex in response to either tail pinch or cocaine. Thus prenatal cocaine exposure produces an increase in basal extracellular DA in the n. accumbens of pups which returns to normal with aging. While this initial difference normalizes, prenatal cocaine exposure induces other persistent changes in adulthood.

Left and right 6-hydroxydopamine lesions of the medial prefrontal cortex differentially alter subcortical dopamine utilization and the behavioral response to stress.

The effects of left and right prefrontal cortical dopamine (DA) depletion on circling behavior, stress-escape behavior and subcortical DA function were examined in rats exhibiting left or right turning biases. 6-Hydroxydopamine lesions of the medial prefrontal cortex (PFC) caused significant DA depletions when assessed in separate studies at 3 days and 3-4 weeks. However, depletions were smaller at 3-4 weeks and there was a significant increase in DA concentration on the left side following right lesions. Significant increases in striatal DA content were observed following lesions of either side at 3-4 weeks, but not at 3 days. No changes in DA concentration were observed in the nucleus accumbens septi (NAS). Left circling rats significantly increased their circling behavior following right sided lesions and showed disrupted footshock-escape behavior following left sided lesions. Performance of the footshock-escape task exerted an effect on striatal and NAS DA utilization as indicated by the ratio of 3,4-dihydroxyphenylacetic acid (DOPAC) to DA. The effects of footshock on NAS DA utilization were greater following left PFC lesions as compared to the right lesion and sham conditions. These lesion effects were also greater in left- than in right-turning animals. The data indicate that an intrinsic asymmetry in brain DA systems interacts with left and right PFC lesions to differentially determine subcortical DA function and behaviors that it subserves.

Enhanced cocaine self-administration in adult rats prenatally exposed to cocaine.

Rats that had been prenatally exposed to either cocaine or saline were examined as adults using continuous reinforcement (FR1) cocaine self-administration. Initially these rats were water-deprived and trained to bar-press for water; no differences across prenatal treatments were observed during this training phase. After complete rehydration and implantation of an intravenous cannula into the external jugular vein, animals were introduced to cocaine self-administration with a nocturnal and subsequent 3 h exposure. During daily test sessions rats were allowed to self-administer cocaine for 1 h/day. Prenatal cocaine exposure led to a marked and stable enhancement of the rates of self-administration for up to 13 days, the longest time point examined. These results suggest that prenatal cocaine exposure can alter cocaine reinforcement in adult animals.

Chronic antidepressant drug treatment reduces turning behavior and increases dopamine levels in the medial prefrontal cortex.

The effects of chronic administration of the antidepressant drugs desipramine, nortryptiline and paroxetine (PAR) (10 mg/kg/day, 21 days) on changes in turning (circling) behavior and on norepinephrine (NE), dopamine (DA) and serotonin and their metabolites 3,4-dihydroxyphenylacetic acid and 5-hydroxyindole acetic acid (5-HIAA) in the medial prefrontal cortex (PFC), nucleus accumbens and striatum were evaluated in rats. All three drugs eliminated turning biases in right turning rats. All drugs increased DA concentrations in the PFC while PAR increased NE in the PFC and reduced 5-HIAA in all three structures. The results are discussed with reference to previous findings involving brain asymmetry in depression.

Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum.

Ibogaine, a naturally occurring alkaloid, has been claimed to be effective in treating addiction to opioid and stimulant drugs and has been reported to decrease morphine and cocaine self-administration in rats. The present study sought to determine if other iboga alkaloids, as well as the chemically related harmala alkaloid harmaline, would also reduce the intravenous self-administration of morphine and cocaine in rats. Because both ibogaine and harmaline induce tremors, an effect that may be causally related to neurotoxicity in the cerebellar vermis, the temorigenic activities of the other iboga alkaloids were assessed. Lastly, in view of the involvement of the dopaminergic mesolimbic system in the actions of drugs of abuse, the effects of some of the iboga alkaloids on extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum were determined. All of the tested alkaloids (i.e., ibogaine, tabernanthine, R- and S-coronaridine, R- and S-ibogamine, desethylcoronaridine, and harmaline) dose-dependently (2.5-80 mg/kg) decreased morphine and cocaine intake in the hour after treatment; decreases in morphine and cocaine intake intake were also apparent the day after administration of some but not all of these alkaloids (i.e., ibogaine, tabernanthine, desethylcoronaridine, and the R-isomers of coronaridine and ibogamine). In some rats, there were persistent decreases in morphine or cocaine intake for several days after a single injection or after two or three weekly injections of one or another of these alkaloids; R-ibogamine produced such effects more consistently than any of the other alkaloids.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurochemical predisposition to self-administer cocaine in rats: individual differences in dopamine and its metabolites.

Using in vivo microdialysis, this study attempted to determine whether a neurochemical predisposition to self-administer cocaine could be identified. Estimated extracellular levels of dopamine and its metabolites were measured bilaterally in the mesocorticolimbic and nigrostriatal systems of naive rats that were subsequently trained to self-administer cocaine intravenously. There were several significant relationships between dopamine and dopamine metabolite (3,4-dihydroxyphenylacetic acid and homovanillic acid) levels and rates of cocaine self-administration during both acquisition and asymptotic phases of testing. Dopamine levels in the nucleus accumbens were non-monotonically related to rates of self-administration during both phases: low to moderate dopamine levels were positively correlated with self-administration rates whereas moderate to high dopamine levels were negative correlated with self-administration rates. Dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) levels in the striatum were inversely correlated with self-administration rates during the acquisition phase. DOPAC and HVA levels in the left and right sides of the medial prefrontal cortex were positively and negatively correlated, respectively, with self-administration rates during the asymptotic phase; left/right asymmetrics in cortical metabolite levels were also correlated with asymptotic rates. There were no significant relationships between any neurochemical indices and rates of bar-pressing for water. These results suggest that the normal variability in drug seeking behavior is at least in part attributable to individual differences in the activity of brain dopamine systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimating extracellular concentrations of dopamine and 3,4-dihydroxyphenylacetic acid in nucleus accumbens and striatum using microdialysis: relationships between in vitro and in vivo recoveries.

It is common practice in microdialysis studies for probes to be "calibrated" in artificial CSF and in vitro recoveries determined for all substances to be measured in vivo. Dialysate concentrations of such substances are then "corrected" for in vitro recoveries to provide "estimates" of extracellular concentrations. At least for dopamine, in vitro and in vivo recoveries are significantly different and, therefore, an estimate of extracellular dopamine based on correction for in vitro recovery is likely to be erroneous. Generally, however, the relative relationships of such estimates among animals are of interest rather than the "true" extracellular values. Such relationships would be valid to the extent that estimated values are correlated with or predictive of true values. Using the "no net flux" procedure, the present study sought to determine, for both dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), whether in vitro and in vivo recoveries would correlate with each other as well as whether respective estimated and true (no net flux) values of these substances would correlate with each other. Probes (3 mm; BAS/CMed MF-5393), previously calibrated, were lowered into both the nucleus accumbens and striatum of freely moving rats the day before sample collection was begun. In vitro and in vivo recoveries were not significantly correlated (r = 0.1-0.3), for either dopamine or DOPAC. For both dopamine and DOPAC, however, there were significant correlations (r = 0.7-0.8) between estimated and true values. Surprisingly, when using these commercial probes, absolute dialysate levels for both substances were even better correlated (r = 0.9-0.95) with true values.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of prenatal cocaine exposure on the nigrostriatal dopamine system: an in vivo microdialysis study in the rat.

Pregnant rats were given injections of saline (0.5 ml/kg) or cocaine (10 mg/kg, 20 mg/ml, s.c.) twice daily between gestational days 7-21. Offspring were examined by microdialysis between postnatal days 10-125 to study the effects of prenatal cocaine exposure on the nigrostriatal dopamine (DA) system. Twenty-min dialysis samples were collected and assayed for DA, DOPAC and HVA. After four baseline samples, the rat was exposed to 20 min of intermittent tail pinch and monitored for four samples; then each rat received an acute injection of cocaine (20 mg/kg, i.p.) and six additional samples were collected. Basal dialysate concentrations of all DA markers, estimated from pre-implantation calibration of the probes, were markedly reduced in young rats ('pups', 10-30 days old) as compared with adult rats (40-125 days old). Compared to control pups, basal DA, as well as DOPAC and HVA, were elevated in the prenatal-cocaine pups. Tail pinch (a mild stressor) produced a significant increase in DA only in the pups prenatally exposed to cocaine. The increase in basal DA induced by an acute cocaine injection (20 mg/kg) was also greater and more prolonged in the prenatal-cocaine pups. In older rats (40-125 days) there were no group differences in any of the DA parameters. Thus prenatal exposure to cocaine produces an activation of the DA system which persists after birth but returns to normal in older rats.

Lateralized changes in prefrontal cortical dopamine activity induced by controllable and uncontrollable stress in the rat.

Exposure to stressors that are not controlled results in a variety of changes in behavior and in brain chemistry. Among these is the activation of dopamine-containing neuronal systems projecting to the medial prefrontal cortex (PFC), to a lesser extent the nucleus accumbens (NAC) and, in a few studies, the striatum. Previous data have shown that stressor evoked PFC activation is asymmetrical. The present experiments were designed to assess the effects of controlled and uncontrolled stressors on these DA systems using the procedures of the learned helplessness (LH) model. In a first experiment, 80 trials of either a controllable (ESC) or identical uncontrollable footshock stressor (YOK) caused an activation, as indicated by increased metabolite concentrations of DA in the PFC, NAC and striatum. In the PFC, YOK caused a bilateral DA depletion, relative to ESC and control animals, and a right > left increase in DOPAC/DA which was not seen in ESC animals. These findings suggested a preferential effect of YOK in the right PFC. A second experiment used rats that had been grouped according to their turning behavior, YOK right-biased rats showed an increase in DOPAC on the right side of the PFC and YOK left-biased rats displayed a similar increase on the left side in response to a brief (5 min) controllable footshock stressor. Since right-turning rats had been shown to be more sensitive to a LH behavioral phenomenon, the data suggested that right PFC activation is responsible for the greater LH sensitivity. A final experiment evaluated the neurochemical and behavioral responses to a prolonged footshock stressor 24 h after uncontrolled footshock. Right-biased YOK animals displayed depressed footshock escape behavior and a right > left depletion in PFC DA and HVA. Across-groups footshock escape performance was correlated with DA and HVA concentrations on the right but not on the left side of the PFC. Thus a disturbance of right PFC DA utilization was again associated with compromised coping behavior. The data suggest that the inability to control a stressor causes a lateralized alteration of PFC DA and this results in a disruption of the ability to respond to a new stressor. These findings indicate that the two sides of the PFC are differentially specialized for responding to a stressor.

Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor.

Because of the claim that ibogaine suppresses the symptoms of "narcotic withdrawal" in humans, the effect of ibogaine on naltrexone-precipitated withdrawal signs in morphine-dependent rats was assessed. Morphine was administered subcutaneously through implanted silicone reservoirs for 5 days. Ibogaine (20, 40 or 80 mg/kg, i.p.) or saline was administered 30 min prior to challenge with naltrexone (1 mg/kg, i.p.) and withdrawal signs were counted for the following 2 hr. Ibogaine (40 and 80 mg/kg) significantly reduced the occurrence of four signs (wet-dog shakes, grooming, teeth chattering and diarrhea) during naltrexone-precipitated withdrawal; three other signs (weight loss, burying and flinching) were unaffected. Ibogaine induces head and body tremors lasting for 2-3 hr and the tremors might have interfered with the expression of opioid withdrawal. To examine this issue, another experiment was conducted in which ibogaine (40 mg/kg) or saline was administered 4 hr prior to challenge with naltrexone. Although there was a complete absence of tremors, ibogaine still significantly reduced the occurrence of the same four signs of withdrawal.

Within-subject sensitization of striatal dopamine release after a single injection of cocaine: an in vivo microdialysis study.

Repeated microdialysis measurements, conducted 1 week apart at the same tissue site, were used to investigate the changes in basal and cocaine-stimulated extracellular dopamine (DA) levels after a single prior exposure to either saline or cocaine. Dialysis probes were placed into rats previously implanted with guide cannulas and basal levels of dopamine (DA), and its metabolites (DOPAC and HVA) were estimated in 20-min fractions of the dialysate. Basal levels in the extracellular fluid (ECF), estimated from pre-implantation calibration of the probes, were 7.9 +/- 0.7 nM DA, 4.9 +/- 0.8 microM DOPAC, and 3.6 +/- 0.6 microM HVA. After a stable baseline was obtained saline (1 ml/kg, i.p.) or cocaine (20 mg/kg, i.p.) was injected. Saline produced no significant changes in any of the neurochemical markers. A cocaine injection produced a sixfold increase in DA, while DOPAC and HVA were unchanged. One week later the same procedure was repeated except this time both groups received cocaine. In rats that had received cocaine 1 week earlier, basal DA levels in the ECF were doubled, whereas they were unchanged in rats that received saline a week earlier. Furthermore, the dopamine release in response to acute cocaine during the second week was elevated in animals which had been previously exposed to cocaine. Rotation was also measured during both weeks and, while a tendency toward behavioral sensitization was observed, it did not reach significance.(ABSTRACT TRUNCATED AT 250 WORDS)