Accurate Plane Fat Grafting in Gluteal Augmentation: An Anatomic Study.

BACKGROUND: The safety of gluteal fat grafting is a global concern in plastic surgery. OBJECTIVE: The goal of this study was to test whether fat grafting to the buttocks with Auto Stop Reach (ASR) technology prevents penetration from the subcutaneous space into the fascia and muscle layers of the buttocks. METHODS: Fat transfer simulation was performed with blue dye on 8 fresh tissue cadaver buttocks by 3 board-certified plastic surgeons (S.S.K., S.C., B.W.). An open control was utilized to visualize the process in the different anatomic layers, and all of the other procedures were performed blindly, akin to live surgery. After blue dye transfer reached maximum capacity (ranging from 400-800 mL per buttock), dissection of the anatomical layers of the buttocks was performed to determine the plane(s) of injection. RESULTS: Blue dye fat transfer injection to the buttocks did not penetrate the gluteal fascia or muscle layers from the subcutaneous space while using ASR. CONCLUSIONS: Auto Stop Reach technology supports the safety of gluteal fat transfer in the subcutaneous space by board-certified plastic surgeons.

Proximity of percutaneous tibial nerve stimulation needle insertion to surrounding anatomic structures: a cadaveric study.

BACKGROUND: Percutaneous tibial nerve stimulation is a third-line treatment for overactive bladder and urgency urinary incontinence. During the procedure, a needle is inserted cephalad to the medial malleolus and posterior to the tibia. In recent years, permanent implants and leads have been developed for insertion into the medial ankle via a small incision. There are many important structures present in the medial compartment of the ankle, including the great saphenous vein, saphenous nerve, tibial nerve, posterior tibial vessels, and tendons of the posterior compartment leg muscles. OBJECTIVE: The primary objective of this study was to identify the proximity of the percutaneous tibial nerve stimulation needle placed per Food and Drug Administration-approved device instructions to nearby important anatomic structures. The secondary objectives were to identify the proximity of the tibial nerve to the needle site, identify clinically relevant ankle anatomic structures, and confirm the tibial nerve and posterior tibial vasculature by histologic analysis. STUDY DESIGN: Detailed medial ankle dissections were performed bilaterally on 10 female lightly embalmed anatomic donors (cadavers) obtained from the Willed Body Program at the University of Louisville. A pin was inserted at the percutaneous tibial nerve stimulation needle site, and the medial ankle was minimally dissected so the surrounding anatomic structures were visible but not disrupted. The shortest distance from the pin to the selected structures of the medial ankle region was measured. On completion of each dissection and set of measurements, tissue was harvested for histologic examination. The distances between the pin and each structure were assessed using means and standard deviations. A paired t test was used to assess the difference in the locations between the left and right ankles. Statistical analysis was performed on left-sided, right-sided, and combined measurements. An 80% prediction interval was found to represent the expected range of values for the measurement of a new cadaver or patient, and the 95% confidence interval of the mean was computed to characterize the average distance across all cadavers or patients. RESULTS: The medial ankle of 10 adult female lightly embalmed cadavers were examined bilaterally. Dissections were completed from October 2021 to July 2022. Of note, 80% prediction intervals for the tibial nerve, the posterior tibial artery or vein, and the flexor digitorum longus tendon had a lower range of 0.0 mm from the pin and extending to 12.1, 9.5, and 13.9 mm, respectively. Moreover, 2 of the structures were found to be asymmetrical between the right and left ankles. The great saphenous vein was further from the pin on the left (20.5 mm [standard deviation of 6.4 mm] on the left vs 18.1 mm [standard deviation of 5.3 mm] on the right; P=.04). The calcaneal (Achilles) tendon was further from the pin on the right side (13.2 mm [standard deviation of 6.8 mm] vs 7.9 mm [standard deviation of 6.7 mm]; P=.04). Tibial neurovascular structures were confirmed with microscopic analysis. CONCLUSION: The anatomic structures within the medial ankle lie unexpectedly close to the percutaneous tibial nerve stimulation needle site as noted per Food and Drug Administration-approved device instructions. There is a possibility that some medial ankle structures are not symmetrical. It is crucial that practitioners understand medial ankle anatomy when performing percutaneous tibial nerve stimulation or permanent device insertion.

Development of a safety zone for rectus abdominis fascia graft harvest based on dissections of the ilioinguinal and iliohypogastric nerves.

BACKGROUND: As a result of the vaginal mesh controversy, surgeons are performing more nonmesh, autologous fascia pubovaginal slings to treat stress urinary incontinence in women. The rectus abdominis fascia is the most commonly harvested site for autologous pubovaginal slings, so it is crucial that surgeons are familiar with the relationship between this graft harvest site and the ilioinguinal and iliohypogastric nerves, which can be injured during this procedure. OBJECTIVE: The aims of this study were as follows: (1) to estimate the safest area between the bilateral courses of the ilioinguinal and iliohypogastric nerves in which a rectus abdominis fascia graft could be harvested with minimal risk of injury to these nerves and (2) to determine the location and dimensions of a graft harvest site that maximized graft length while remaining close to the pubic symphysis. STUDY DESIGN: The ilioinguinal and iliohypogastric nerves were dissected bilaterally in 12 unembalmed female anatomical donors. The distances of these nerves to a 10 × 2 cm rectus abdominis fascia graft site located 4 cm above the pubic symphysis were measured. Nerve courses inferior to the graft site were determined for each donor by linearly extrapolating measurement points; analysis was performed with and without extrapolation. Average nerve trajectories were estimated assuming a linear regression function to predict the horizontal measurement as a quadratic function of the vertical distance; 95% confidence bands were also estimated. An estimated safety zone was determined to be the region between all credible nerve bounds. RESULTS: The largest safety zone that was closest to the pubic symphysis was located at 5.4 cm superior to the pubic symphysis. At this location, the inferior border of the graft could measure 9.4 cm in length (4.7 cm bilaterally from the midline). Extrapolated nerve courses below the study graft site yielded a smaller safety zone located 2.7 cm superior to the pubic symphysis, allowing for the inferior border of the graft to be 4.8 cm (2.4 cm bilaterally from the midline). CONCLUSION: A rectus abdominis fascia graft harvested 5.4 cm superior to the pubic symphysis with the inferior border of the graft measuring 9.4 cm in length should minimize injury to the ilioinguinal and iliohypogastric nerves. These dimensions allow for the longest graft while remaining relatively close to the pubic symphysis. The closer a graft is harvested to the pubic symphysis, the smaller in length the graft must be to avoid injury to the ilioinguinal and iliohypogastric nerves.

Repair of a large primary subtemporal encephalocele in a 3-year-old child: case report.

Primary encephaloceles (PEs) present only rarely in the temporal region; in the rare instance that they project through the floor of the middle fossa they are secondary. In this case report the authors report on the management of a giant PE extending through the floor of the middle fossa.An 8-month-old boy presented to the authors' service with a large PE projecting into his neck through a missing left middle fossa floor; the lesion was causing significant meta-, dys-, and hypoplasia of the structures of the anterolateral neck on that side. Surgical goals for this patient included the following: 1) removal of potentially epileptogenic and dysfunctional tissue; 2) preservation of cranial nerves; 3) prevention of cognitive decline or iatrogenic deficit; 4) prevention of CSF leak; 5) reconstruction of skull base; 6) prevention of airway and swallowing compromise; and 7) cosmesis. After a multidisciplinary evaluation with ENT, plastic surgery, and neurology, an operation was performed using a preauricular infratemporal approach when the patient was 3 years old. Gliotic tissue was resected and amygdala, hippocampus, and middle cerebral artery were preserved.The immediate results of the operation showed good immediate outcome. Seizure freedom and neurodevelopment outcomes remain to be seen at follow-up.

The Effect of Lithotomy Position on Nerve Stretch: A Cadaveric Study.

OBJECTIVE: The objective of our study was to design a method to measure nerve stretch in cadaveric subjects and then use the method to assess femoral nerve stretch in the lithotomy position with varying degrees of flexion and extension. METHODS: A university-based, cadaveric observational study of femoral nerve stretch was conducted. In 6 cadaveric subjects, femoral nerve near the inguinal ligament was dissected in each cadaveric subject. The nerve was marked, and digital images of the nerve were obtained in the supine position and lithotomy position in both flexion and extension. Distances were calculated using the ratio of pixels to millimeter specific for each image. The average distance for each set of images was then used to calculate the percent change from supine for each position. RESULTS: We were able to assess nerve stretch using photo-editing software. For extended position, all nerves showed some degree of stretch with the mean percent change in nerve length being 10.35%. For all other positions, most showed a decrease of nerve length. There was not a significant relation between degree of extension and stretch (Pearson r, P < 0.05). CONCLUSIONS: Hip extension between 10 and 20 degrees consistently stretches the femoral nerve greater than 5%. The potential for femoral nerve stretch and avoiding hip extension should be considered when positioning a patient in lithotomy for surgical procedures.

Anatomical Relationships of Burch Colposuspension Sutures.

OBJECTIVES: The prevalent use of minimally invasive midurethral slings for the treatment of stress urinary incontinence in the last several decades has resulted in fewer Burch procedures being performed and diminished surgical experience in performing the Burch colposuspension. However, recent antimesh media has resulted in more patients requesting nonmesh anti-incontinence procedures and a subsequent need for surgeons to refamiliarize themselves with the Burch procedure and its relevant anatomy. The objective of this study was to evaluate the relationships of Burch sutures to surrounding neurovascular anatomic structures in the human cadaver. METHODS: The retropubic space of 11 unembalmed female cadavers was dissected, and a Burch procedure performed. The distance from the Burch sutures' location through both Cooper's ligament and the vagina to the obturator neurovascular bundle and external iliac vessels was measured. RESULTS: The mean distance from the most lateral stitch in Cooper's ligament to the obturator bundle was 25.9 ± 7.6 mm and to the external iliac vessels was 28.9 ± 9.3 mm, and in some instances, these structures were less than 1.5 cm away. CONCLUSIONS: The obturator bundle and external iliac lie, on average, within 3 cm of sutures placed during a Burch colposuspension. Knowledge of these anatomical relationships is valuable when dissecting the space of Retzius and placing sutures for a Burch to avoid injury.

Surface and boney landmarks for sacral neuromodulation: a cadaveric study.

INTRODUCTION AND HYPOTHESIS: Standard external landmarks have been suggested as a guide for in-office percutaneous nerve evaluation (PNE), but validity of these landmarks has not been assessed. Our objective was to determine whether the standard 9 cm from the tip of the coccyx indicates the position of the S3 sacral foramen and whether other boney landmarks and measurements improved positioning. METHODS: Measurements and distances between external boney landmarks were obtained in 22 embalmed cadavers. Spinal needles were placed 9 cm superior to the coccyx and 2 cm lateral to midline bilaterally. After dissection, internal measurements relating to sacral length, position of S3, and location of the needle in relation to S3 were recorded. Correlations among measured variables were assessed using descriptive statistics. RESULTS: Mean distance from the tip of coccyx to S3 was 9.26 cm (±0.84), from S3 to midline 2.30 cm (±0.2); from needle to S3 1.25 cm, and needle placement was as likely to be placed above or below S3; and S2-S3 and S3-S4 interforamenal distance 1.48 cm (±0.30) and 1.48 cm (±0.24), respectively. Mean distance from S3 to sacroiliac joint (SIJ) was shorter than S2 to SIJ. All associations between external measurements and length from tip of coccyx to S3 were not significant. CONCLUSION: A distance 9 cm from the tip of the coccyx is a reasonable starting landmark for in-office blind PNE. However, given the variability in coccyx length, caution should be taken; also, sensory-motor response is necessary to confirm proper placement.

(±)3,4-methylenedioxymethamphetamine ("ecstasy") treatment modulates expression of neurotrophins and their receptors in multiple regions of adult rat brain.

(±)3,4-Methylenedioxymethamphetamine (MDMA), a widely used drug of abuse, rapidly reduces serotonin levels in the brain when ingested or administered in sufficient quantities, resulting in deficits in complex route-based learning, spatial learning, and reference memory. Neurotrophins are important for survival and preservation of neurons in the adult brain, including serotonergic neurons. In this study, we examined the effects of MDMA on the expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their respective high-affinity receptors, tropomyosin receptor kinase (trk)B and trkC, in multiple regions of the rat brain. A serotonergic-depleting dose of MDMA (10 mg/kg × 4 at 2-hour intervals on a single day) was administered to adult Sprague-Dawley rats, and brains were examined 1, 7, or 24 hours after the last dose. Messenger RNA levels of BDNF, NT-3, trkB, and trkC were analyzed by using in situ hybridization with cRNA probes. The prefrontal cortex was particularly vulnerable to MDMA-induced alterations in that BDNF, NT-3, trkB, and trkC mRNAs were all upregulated at multiple time points. MDMA-treated animals had increased BDNF expression in the frontal, parietal, piriform, and entorhinal cortices, increased NT-3 expression in the anterior cingulate cortex, and elevated trkC in the entorhinal cortex. In the nigrostriatal system, BDNF expression was upregulated in the substantia nigra pars compacta, and trkB was elevated in the striatum in MDMA-treated animals. Both neurotrophins and trkB were differentially regulated in several regions of the hippocampal formation. These findings suggest a possible role for neurotrophin signaling in the learning and memory deficits seen following MDMA treatment.

Effects of neonatal methamphetamine treatment on adult stress-induced corticosterone release in rats.

In rats, neonatal (+)-methamphetamine (MA) exposure and maternal separation stress increase corticosterone during treatment and result in learning and memory impairments later in life. Early-life stress also changes later responses to acute stress. We tested the hypothesis that neonatal MA exposure would alter adult corticosterone after acute stress or MA challenge. Rats were treated with MA (10 mg/kg × 4/day), saline, or handling on postnatal (P) days 11-15 or 11-20 (days that lead to learning and memory impairments at this dose). As adults, corticosterone was measured before and after 15 min forced swim (FS) or 15 min forced confinement (FC), counterbalanced, and after an acute MA challenge (10 mg/kg) given last. FS increased corticosterone more than FC; order and stress type interacted but did not interact with treatment; treatment interacted with FS but not with FC. In the P11-15 regimen, MA-treated rats showed more rapid increases in corticosterone after FS than controls. In the P11-20 regimen, MA-treated rats showed a trend toward more rapid decrease in corticosterone after FS. No differences were found after MA challenge. The data do not support the hypothesis that neonatal MA causes changes in adult stress responsiveness to FS, FC, or an acute MA challenge.

Electroencephalographic and convulsive effects of binge doses of (+)-methamphetamine, 5-methoxydiisopropyltryptamine, and (±)-3,4-methylenedioxymethamphetamine in rats.

The abuse of drugs such as methamphetamine (MA), 3,4-methylenedioxymethamphetamine (Ecstasy, MDMA), and 5-methoxydiisopropyltryptamine (5-MeO-DIPT; Foxy) is global. Symptoms from taking these drugs include tachycardia, agitation, hyperpyrexia, and sometimes seizures. We compared the EEG effects of these drugs in male Sprague-Dawley rats (~300 g) implanted with cortical electroencephalographic (EEG) electrodes prior to testing. Animals received four subcutaneous injections of MA, MDMA, or Foxy (10 mg/kg each as freebase, administered every 2 h), or saline as these doses produce lasting effects on learning, memory, and monoamines. EEG tracings were recorded before, during, and after treatment. Animals receiving MDMA showed no significant EEG abnormalities or myoclonus. MA treatment resulted in myoclonic activity and in brief (<10 s) EEG epileptiform activity in ~50% of the rats. Longer seizure activity (10 s to 5 min) was recorded in some MA-treated rats following the third and fourth doses. The onset of myoclonic activity following Foxy treatment occurred shortly after the first dose. All rats receiving Foxy showed seizures by the second dose and this continued throughout the treatment regimen. The results show that binge doses of MA and MDMA, which mimic the neurochemical changes seen in chronic users, increase EEG abnormalities after MA but not after MDMA. While the neurochemical effects of Foxy are not known in humans, this drug causes severe EEG abnormalities and overt seizures in 100% of tested animals.

Myelin, copper, and the cuprizone model of schizophrenia.

In recent years increasing evidence is pointing toward white matter abnormalities in schizophrenia and other psychiatric disorders. The present paper will provide an overview over the role of myelin in cognition and brain function, and its potential involvement in brain disorders. Furthermore, we will examine one particular experimental model for the study of dysmyelination, created by the administration of the toxin cuprizone. Cuprizone, a copper chelator, causes white matter abnormalities in rodents. The administration of cuprizone during specific developmental periods allows for the targeting of specific brain areas for dysmyelination. Thus, cuprizone can be used to study the pathogenesis and pathophysiology of myelin deficiencies in the central nervous system, and its effect on behaviors relevant to psychiatric disorders.

(+)-Methamphetamine-induced monoamine reductions and impaired egocentric learning in adrenalectomized rats is independent of hyperthermia.

Methamphetamine (MA) is widely abused and implicated in residual cognitive deficits. In rats, increases in plasma corticosterone and egocentric learning deficits are observed after a 1-day binge regimen of MA (10 mg/kg x 4 at 2-h intervals). The purpose of this experiment was to determine if adrenal inactivation during and following MA exposure would attenuate the egocentric learning deficits in the Cincinnati water maze (CWM). In the first experiment, the effects of adrenalectomy (ADX) or sham surgery (SHAM) on MA-induced neurotoxicity at 72 h were determined. SHAM-MA animals showed typical patterns of hyperthermia, whereas ADX-MA animals were normothermic. Both SHAM-MA- and ADX-MA-treated animals showed increased neostriatal glial fibrillary acidic protein and decreased monoamines in the neostriatum, hippocampus, and entorhinal cortex. In the second experiment, SHAM-MA- and ADX-MA-treated groups showed equivalently impaired CWM performance 2 weeks post-treatment (increased latencies, errors, and start returns) compared to SHAM-saline (SAL) and ADX-SAL groups with no effects on novel object recognition, elevated zero maze, or acoustic startle/prepulse inhibition. Post-testing, monoamine levels remained decreased in both MA-treated groups in all three brain regions, but were not as large as those observed at 72-h post-treatment. The data demonstrate that MA-induced learning deficits can be dissociated from drug-induced increases in plasma corticosterone or hyperthermia, but co-occur with dopamine and serotonin reductions.

Effect of a neurotoxic dose regimen of (+)-methamphetamine on behavior, plasma corticosterone, and brain monoamines in adult C57BL/6 mice.

RATIONALE: In rats, neurotoxic doses of methamphetamine (MA) induce astrogliosis, long lasting monoamine reductions, reuptake transporter down-regulation, and learning impairments. OBJECTIVE: We tested whether comparable effects occur in C57BL/6 mice. METHOD: C57BL/6 mice were treated with 10mg/kgs.c.x4 MA on a single day and evaluated at various intervals thereafter. RESULTS: The neurotoxic dose regimen of MA caused the predicted acute hyperthermia and increased striatal glial fibrillary acidic protein and reduced neostriatal dopamine. The MA-treated mice were hypoactive 24h later but not 48h later. MA-treated mice also showed exaggerated initial hyperactivity after a pharmacological dose of MA used to stimulate locomotion followed by a later phase of hypoactivity compared to saline-treated mice. No differences were observed on learning or memory tests (novel object recognition, egocentric, or spatial learning/memory). MA-treated mice showed a trend toward increased prepulse inhibition but not baseline acoustic startle reactivity. After testing, MA-treated mice showed reduced neostriatal dopamine and increased basal plasma corticosterone. CONCLUSIONS: A neurotoxic/binge regimen of MA in mice that produces the typical pattern of neurotoxic changes to those seen in rats, results in few behavioral changes. This may limit the utility of C57BL/6 mice for modeling the cognitive and behavioral effects described in human MA users who show such changes even after prolonged abstinence.

Glucose and corticosterone changes in developing and adult rats following exposure to (+/-)-3,4-methylendioxymethamphetamine or 5-methoxydiisopropyltryptamine.

The use of the club drugs 3,4-methylenedioxymethamphetamine (MDMA) and 5-methoxy-n,n-diisopropyltryptamine (Foxy) is of growing concern, especially as many of the effects, particularly during development, are unknown. The effects of these drugs upon homeostasis may be important since both are known to stimulate the hypothalamic-pituitary-adrenal axis. The purpose of this experiment was to examine alterations in rats in corticosterone and glucose following an acute exposure to these drugs at different stages of development: preweaning, juvenile, and adulthood. Both MDMA and Foxy increased corticosterone levels significantly at all ages examined, while glucose was elevated at all stages except at the juvenile time point (postnatal day 28). For both measures, there were no differences between the sexes with either drug. The data indicate that an acute exposure to these drugs alters CORT and glucose levels, raising the possibility that these changes may have effects on behavioral and cognitive function, as we and others have previously demonstrated.

Downregulation of oligodendrocyte transcripts is associated with impaired prefrontal cortex function in rats.

Abnormalities of brain white matter and oligodendroglia are among the most consistent findings in schizophrenia (Sz) research. Various gene expression microarray studies of post-mortem Sz brains showed a downregulation of myelin transcripts, while imaging and microscopy studies demonstrated decreases in prefrontal cortical (PFC) white matter volume and oligodendroglia density. Currently, the extent to which reduced oligodendrocyte markers contribute to pathophysiological domains of Sz is unknown. We exposed adolescent rats to cuprizone (CPZ), a copper chelator known to cause demyelination in mice, and examined expression of oligodendrocyte mRNA transcripts and PFC-mediated behavior. Rats on the CPZ diet showed decreased expression of mRNA transcripts encoding oligodendroglial proteins within the medial PFC, but not in the hippocampus or the striatum. These rats also displayed a specific deficit in the ability to shift between perceptual dimensions in the attentional set-shifting task, a PFC-mediated behavioral paradigm modeled after the Wisconsin Card Sorting Test (WCST). The inability to shift strategies corresponds to the deficits exhibited by Sz patients in the WCST. The results demonstrate that a reduction in oligodendrocyte markers is associated with impaired PFC-mediated behaviors. Thus, CPZ exposure of rats can serve as a model to examine the contribution of oligodendrocyte perturbation to cognitive deficits observed in Sz.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA) dose-dependently impairs spatial learning in the morris water maze after exposure of rats to different five-day intervals from birth to postnatal day twenty.

During postnatal days (PD) 11-20, (+/-)3,4-methylenedioxymethamphetamine (MDMA) treatment impairs egocentric and allocentric learning, and reduces spontaneous locomotor activity; however, it does not have these effects during PD 1-10. How the learning impairments relate to the stress hyporesponsive period (SHRP) is unknown. To test this association, the preweaning period was subdivided into 5-day periods from PD 1-20. Separate pups within each litter were injected subcutaneously with 0, 10, 15, 20, or 25 mg/kg MDMA x4/day on PD 1-5, 6-10, 11-15, or 16-20, and tested as adults. The 3 highest MDMA dose groups showed reduced locomotor activity during the first 10 min (of 60 min), especially in the PD 1-5 and 6-10 dosing regimens. MDMA groups in all dosing regimens showed impaired allocentric learning in the Morris water maze (on acquisition and reversal, all MDMA groups were affected; on the small platform phase, the 2 high-dose groups were affected). No effects of MDMA were found on anxiety (elevated zero maze), novel object recognition, or egocentric learning (although a nonsignificant trend was observed). The Morris maze results did not support the idea that the SHRP is critical to the effects of MDMA on allocentric learning. However, since no effects on egocentric learning were found, but were apparent after PD 11-20 treatment, the results show that these 2 forms of learning have different exposure-duration sensitivities.

Comparison of the developmental effects of 5-methoxy-N,N-diisopropyltryptamine (Foxy) to (+/-)-3,4-methylenedioxymethamphetamine (ecstasy) in rats.

RATIONALE: We have previously shown that (+/-)-3,4-methylenedioxymethamphetamine (MDMA) treatment from postnatal days (P)11 to P20 leads to learning and memory deficits when the animals are tested as adults. Recently, the club drug 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) has gained popularity. OBJECTIVE: Due to the similarities between MDMA and 5-MeO-DIPT and the substitution of 5-MeO-DIPT for MDMA, the purpose of this study was to compare the developmental effects of these drugs. METHODS: Within a litter, animals were treated from P11 to P20 with either MDMA, 5-MeO-DIPT, or saline. RESULTS: MDMA-treated animals showed increased anxiety in a measure of defensive marble burying, as well as deficits in spatial and path integration learning. 5-MeO-DIPT-treated animals showed spatial learning deficits; however, there were no deficits observed in spatial memory or path integration learning. 5-MeO-DIPT-treated animals also showed hyperactivity in response to a challenge dose of methamphetamine. CONCLUSIONS: The results show that treatment with either 5-MeO-DIPT or MDMA during development results in cognitive deficits and other behavioral changes but the pattern of effects is distinct for each drug.

(+/-)-3,4-Methylenedioxymethamphetamine treatment in adult rats impairs path integration learning: a comparison of single vs once per week treatment for 5 weeks.

3,4-Methlylenedioxymethamphetamine (MDMA) administration (4 x 15 mg/kg) on a single day has been shown to cause path integration deficits in rats. While most animal experiments focus on single binge-type models of MDMA use, many MDMA users take the drug on a recurring basis. The purpose of this study was to compare the effects of repeated single-day treatments with MDMA (4 x 15 mg/kg) once weekly for 5 weeks to animals that only received MDMA on week 5 and saline on weeks 1-4. In animals treated with MDMA for 5 weeks, there was an increase in time spent in the open area of the elevated zero maze suggesting a decrease in anxiety or increase in impulsivity compared to the animals given MDMA for 1 week and saline treated controls. Regardless of dosing regimen, MDMA treatment produced path integration deficits as evidenced by an increase in latency to find the goal in the Cincinnati water maze. Animals treated with MDMA also showed a transient hypoactivity that was not present when the animals were re-tested at the end of cognitive testing. In addition, both MDMA-treated groups showed comparable hyperactive responses to a later methamphetamine challenge. No differences were observed in spatial learning in the Morris water maze during acquisition or reversal but MDMA-related deficits were seen on reduced platform-size trials. Taken together, the data show that a single-day regimen of MDMA induces deficits similar to that of multiple weekly treatments.

Comparison of time-dependent effects of (+)-methamphetamine or forced swim on monoamines, corticosterone, glucose, creatine, and creatinine in rats.

BACKGROUND: Methamphetamine (MA) use is a worldwide problem. Abusers can have cognitive deficits, monoamine reductions, and altered magnetic resonance spectroscopy findings. Animal models have been used to investigate some of these effects, however many of these experiments have not examined the impact of MA on the stress response. For example, numerous studies have demonstrated (+)-MA-induced neurotoxicity and monoamine reductions, however the effects of MA on other markers that may play a role in neurotoxicity or cell energetics such as glucose, corticosterone, and/or creatine have received less attention. In this experiment, the effects of a neurotoxic regimen of (+)-MA (4 doses at 2 h intervals) on brain monoamines, neostriatal GFAP, plasma corticosterone, creatinine, and glucose, and brain and muscle creatine were evaluated 1, 7, 24, and 72 h after the first dose. In order to compare MA's effects with stress, animals were subjected to a forced swim test in a temporal pattern similar to MA administration [i.e., (30 min/session) 4 times at 2 h intervals]. RESULTS: MA increased corticosterone from 1-72 h with a peak 1 h after the first treatment, whereas glucose was only increased 1 h post-treatment. Neostriatal and hippocampal monoamines were decreased at 7, 24, and 72 h, with a concurrent increase in GFAP at 72 h. There was no effect of MA on regional brain creatine, however plasma creatinine was increased during the first 24 h and decreased by 72 h. As with MA treatment, forced swim increased corticosterone more than MA initially. Unlike MA, forced swim reduced creatine in the cerebellum with no change in other brain regions while plasma creatinine was decreased at 1 and 7 h. Glucose in plasma was decreased at 7 h. CONCLUSION: Both MA and forced swim increase demand on energy substrates but in different ways, and MA has persistent effects on corticosterone that are not attributable to stress alone.

Effect of +-methamphetamine on path integration learning, novel object recognition, and neurotoxicity in rats.

RATIONALE: Methamphetamine (MA) has been implicated in cognitive deficits in humans after chronic use. Animal models of neurotoxic MA exposure reveal persistent damage to monoaminergic systems but few associated cognitive effects. OBJECTIVES: Since questions have been raised about the typical neurotoxic dosing regimen used in animals and whether it adequately models human cumulative drug exposure, these experiments examined two different dosing regimens. MATERIALS AND METHODS: Rats were treated with one of the two regimens: one based on the typical neurotoxic regimen (4 x 10 mg/kg every 2 h) and one based on pharmacokinetic modeling (Cho AK, Melega WP, Kuczenski R, Segal DS Synapse 39:161-166, 2001) designed to better represent accumulating plasma concentrations of MA as seen in human users (24 x 1.67 mg/kg once every 15 min) matched for total daily dose. In two separate experiments, dosing regimens were compared for their effects on markers of neurotoxicity or on behavior. RESULTS: On markers of neurotoxicity, MA showed decreased dopamine (DA) and 5-HT, increased glial fibrillary acidic protein, and increased corticosterone levels regardless of dosing regimen 3 days post-treatment. Behaviorally, MA-treated groups, regardless of dosing regimen, showed hypoactivity, increased initial hyperactivity to a subsequent MA challenge, impaired novel object recognition, impaired learning in a multiple T water maze test of path integration, and no differences on spatial navigation or reference memory in the Morris water maze. After behavioral testing, reductions of DA and 5-HT remained. CONCLUSIONS: MA treatment induces an effect on path integration learning not previously reported. Dosing regimen had no differential effects on behavior or neurotoxicity.