Comparative Analysis of Clinical and Patient-Reported Outcomes of a New Enhanced Monofocal IOL and a Conventional Monofocal IOL.

Purpose: To compare the outcomes of the Tecnis Eyhance ICB00 IOL, designed to enhance intermediate vision, to a conventional Tecnis Monofocal ZCB00 IOL. Methods: This retrospective analysis compared two cohorts of patients undergoing lens replacement surgery with bilateral implantation of the Tecnis ICB00 or the Tecnis ZCB00 IOL (383 patients in each group). Monocular and binocular uncorrected distance (UDVA), intermediate (UIVA; 66cm), and near (UNVA; 40cm) visual acuities, refractive predictability, and patient-reported outcomes were compared. A sub-analysis of patients with the Eyhance IOL was performed to compare patients who achieved bilateral emmetropia to those with mini-monovision. One-month postoperative outcomes were analyzed. Results: Both groups had comparable UDVA outcomes. On average, both monocular and binocular UIVAs were approximately one Snellen line better in patients implanted with Eyhance IOL (monocular UIVA: ICB00 0.23 ± 0.18 logMAR, ZCB00 0.33 ± 0.19 logMAR; binocular UIVA: ICB00 0.18 ± 0.18 logMAR, ZCB00 0.26 ± 0.20 logMAR, p < 0.01). Likewise, the mean UNVA was also one Snellen line better with the ICB00 model (monocular UNVA: ICB00 0.51 ± 0.20 logMAR, ZCB00 0.61 ± 0.18 logMAR; binocular UNVA: ICB00 0.42 ± 0.19 logMAR, ZCB00 0.51 ± 0.22 logMAR, p < 0.01). There was no difference between the two groups in overall satisfaction or visual phenomena. A subgroup of patients who achieved mini-monovision with Eyhance IOL had, on average, one Snellen line better UIVA and UNVA compared to patients with bilateral emmetropia. Conclusion: Patients receiving the enhanced monofocal IOL had better intermediate and near vision compared to those receiving the conventional monofocal IOL, with similar levels of patient-reported photic phenomena in both groups.

Intense pulsed light improves signs and symptoms of dry eye disease due to meibomian gland dysfunction: A randomized controlled study.

PURPOSE: To compare the safety and efficacy of intense pulsed light (IPL) followed by meibomian gland expression (MGX), against monotherapy of MGX. METHODS: Patients with moderate to severe meibomian gland dysfunction (MGD) were 1:1 randomized to 4 sessions of intense pulse light + MGX at 2-week intervals, or 4 sessions of Sham + MGX at 2-week intervals. Both patients and examiners were blinded to the allocation. Outcome measures, evaluated at the baseline (BL) and at a follow-up (FU) conducted 4 weeks after the last IPL session, included fluorescein tear breakup time (TBUT) as the primary outcome measure, OSDI (Ocular Surface Disease Index) questionnaire, Eye Dryness Score (EDS, a visual analog scale (VAS)-based questionnaire), Meibomian gland score (MGS, a score of meibum expressibility and quality in 15 glands on the lower eyelid), daily use of artificial tears, and daily use of warm compresses. In addition, during each treatment session, the number of expressible glands was counted in both eyelids, the predominant quality of meibum was estimated in both eyelids, and the level of pain/discomfort due to MGX and IPL was recorded. RESULTS: TBUT increased from 3.8±0.2 (µ±standard error of mean (SEM)) to 4.5±0.3 seconds in the control arm, and from 4.0±0.2 to 6.0±0.3 in the study arm. The difference between arms was statistically significant (P < .01). Other signs/symptoms which improved in both arms but were greater in the study arm included MGS (P < .001), EDS (P < .01), the number of expressible glands in the lower eyelids (P < .0001) and upper eyelid (P < .0001), the predominant meibum quality in the lower eyelid (P < .0001) and upper eyelid (P < .0001), and the level of pain due to MGX (P < .0001). Outcome measures which improved in both arms with no significant differences between the two were OSDI (P = .9984), and the daily use of artificial tears (P = .8216). Meibography, daily use of warm compresses, and severity of skin rosacea did not show statistically significant changes in either arm. No serious adverse events were observed. There was a slight tendency for more adverse events in the control group (P = 0.06). CONCLUSIONS: The results of this study suggest that, in patients with moderate to severe symptoms, combination therapy of intense pulse light (IPL) and meibomian gland expression (MGX) could be a safe and useful approach for improving signs of dry eye disease (DED) due to meibomian gland dysfunction (MGD). Future studies are needed to elucidate if and how such improvements can be generalized to different severity levels of MGD.

Evaluation of Visual and Subjective Outcomes with Mix-and-Match of Three One-Piece Tecnis Multifocal IOLs of Varying Add Powers.

PURPOSE: To evaluate visual and subjective outcomes after bilateral mix-and-match implantation of one-piece diffractive multifocal IOLs in different near add powers (+2.75 D, +3.25 D, +4.0 D). SETTING: Four US clinics. DESIGN: Prospective, multi-center, parallel comparison clinical study design. PATIENTS AND METHODS: Two treatment groups received implantation with either the +3.25 D (ZLB00) or the +4.00 D (ZMB00) Tecnis® Multifocal 1-piece IOL in their non-dominant eye, and the +2.75 D (ZKB00) Tecnis Multifocal 1-piece IOL in their dominant eye (Abbott Medical Optics, Inc., Santa Ana, CA). Each study patient underwent the same routine cataract extraction procedures for each eye, with the second eye scheduled to undergo cataract extraction within 7 to 30 days after the 1st eye surgery. Visual and subjective outcomes were evaluated at 90 days after 2nd eye surgery for the two groups: +3.25D/+2.75D (n=41) and +4.00D/+2.75D (n=36). RESULTS: Mean binocular uncorrected distance visual acuities at 90 days postop were 0.02 ± 0.082 (+3.25D/+2.75D) vs 0.07 ± 0.128 (+4.00D/+2.75D) (p=0.025). Mean binocular uncorrected intermediate visual acuities at 90 days postop were 0.14 ± 0.185 (+3.25D/+2.75D) vs 0.26 ± 0.261 (+4.00D/+2.75D) (p=0.024). Mean binocular uncorrected near visual acuities at 90 days postop were 0.06 ± 0.098 (+3.25D/+2.75D) vs 0.19 ± 0.286 (+4.00D/+2.75D) (p=0.018). Over 88% of patients reported "none" for visual symptoms of glare, halos, starburst, or other. Freedom from glasses or contacts was reported by groups +3.25D/+2.75D and +4.00D/+2.75D as follows: distance (95.1% vs 97.1%), intermediate (92.7% vs 94.1%), and near activities (82.9% vs 64.7%). CONCLUSION: At 90 days postoperatively, both groups demonstrated good visual and subjective outcomes; however, differences in near and intermediate outcomes favored the +3.25/+2.75 IOL combination. CLINICALTRIALSGOV REGISTRATION: NCT02863159 (08/11/2016).

The hippocampus, prefrontal cortex, and perirhinal cortex are critical to incidental order memory.

Considerable research in rodents and humans indicates the hippocampus and prefrontal cortex are essential for remembering temporal relationships among stimuli, and accumulating evidence suggests the perirhinal cortex may also be involved. However, experimental parameters differ substantially across studies, which limits our ability to fully understand the fundamental contributions of these structures. In fact, previous studies vary in the type of temporal memory they emphasize (e.g., order, sequence, or separation in time), the stimuli and responses they use (e.g., trial-unique or repeated sequences, and incidental or rewarded behavior), and the degree to which they control for potential confounding factors (e.g., primary and recency effects, or order memory deficits secondary to item memory impairments). To help integrate these findings, we developed a new paradigm testing incidental memory for trial-unique series of events, and concurrently assessed order and item memory in animals with damage to the hippocampus, prefrontal cortex, or perirhinal cortex. We found that this new approach led to robust order and item memory, and that hippocampal, prefrontal and perirhinal damage selectively impaired order memory. These findings suggest the hippocampus, prefrontal cortex and perirhinal cortex are part of a broad network of structures essential for incidentally learning the order of events in episodic memory.

Intense pulsed light for evaporative dry eye disease.

There is a clear association between dry eye disease (DED) and skin inflammatory diseases occurring in close proximity to the eyelids, such as facial skin rosacea. Intense pulsed light (IPL) is widely accepted as a treatment for skin rosacea. A number of recent studies demonstrated that, in patients suffering from meibomian gland dysfunction (MGD), IPL therapy also reduces signs and symptoms of DED. Despite these encouraging results, in the context of DED and MGD, the mechanisms of action of IPL are not well understood. The purpose of this review was to raise the potential mechanisms of action and to discuss their plausibility.

Prospective evaluation of intense pulsed light and meibomian gland expression efficacy on relieving signs and symptoms of dry eye disease due to meibomian gland dysfunction.

PURPOSE: The aim of this study was to estimate the efficacy of intense pulsed light (IPL), followed by meibomian gland expression (MGX), for reducing the number and severity of signs and symptoms of dry eye disease (DED) secondary to meibomian gland dysfunction (MGD). PATIENTS AND METHODS: In a prospective study conducted in two sites, 40 subjects (80 eyes) with moderate to severe MGD were enrolled. Major inclusion criteria consisted of at least two of the following measures being compatible with DED in both eyes: tear breakup time (TBUT), meibomian gland score (MGS), corneal fluorescein staining (CFS), Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire, and tear film osmolarity (TFO). Enrolled patients underwent four treatment sessions, 3 weeks apart. Each treatment included the administration of 10-15 pulses of IPL on the cheeks and nose, followed by MGX of the upper and lower eyelids. TBUT, MGS, CFS, SPEED, TFO, and lipid layer thickness (LLT) were measured at baseline (BL) and at 9, 12, and 15 weeks after BL. RESULTS: Due to different staining methods used for TBUT measurements, TBUT and CFS were analyzed separately for each site. From BL to the final follow-up, the number of signs compatible with DED decreased from 3.3±0.1 to 1.4±0.1. TBUT improved by +93% (n=38; P<0.0001) and +425% (n=42; P<0.0001) for sites 1 and 2, respectively. SPEED, MGS, and CFS improved by -55% (n=80; P<0.0001), -36% (n=80; P<0.0001), and -58% (n=38; P<0.0001), respectively. In 20 eyes with abnormally elevated TFO at BL, TFO improved by -7% (n=20; P<0.005). LLT did not change (n=38; P=0.88). CONCLUSION: In subjects with moderate to severe MGD, IPL combined with MGX reduced the number and severity of symptoms and signs of DED. Except for LLT, all examined outcome measures significantly improved after 15 weeks. These results support the efficacy of IPL + MGX in relieving both signs and symptoms of DED secondary to MGD.

Retrieval-induced NMDA receptor-dependent Arc expression in two models of cocaine-cue memory.

The association of environmental cues with drugs of abuse results in persistent drug-cue memories. These memories contribute significantly to relapse among addicts. While conditioned place preference (CPP) is a well-established paradigm frequently used to examine the modulation of drug-cue memories, very few studies have used the non-preference-based model conditioned activity (CA) for this purpose. Here, we used both experimental approaches to investigate the neural substrates of cocaine-cue memories. First, we directly compared, in a consistent setting, the involvement of cortical and subcortical brain regions in cocaine-cue memory retrieval by quantifying activity-regulated cytoskeletal-associated (Arc) protein expression in both the CPP and CA models. Second, because NMDA receptor activation is required for Arc expression, we investigated the NMDA receptor dependency of memory persistence using the CA model. In both the CPP and CA models, drug-paired animals showed significant increases in Arc immunoreactivity in regions of the frontal cortex and amygdala compared to unpaired controls. Additionally, administration of a NMDA receptor antagonist (MK-801 or memantine) immediately after cocaine-CA memory reactivation impaired the subsequent conditioned locomotion associated with the cocaine-paired environment. The enhanced Arc expression evident in a subset of corticolimbic regions after retrieval of a cocaine-context memory, observed in both the CPP and CA paradigms, likely signifies that these regions: (i) are activated during retrieval of these memories irrespective of preference-based decisions, and (ii) undergo neuroplasticity in order to update information about cues previously associated with cocaine. This study also establishes the involvement of NMDA receptors in maintaining memories established using the CA model, a characteristic previously demonstrated using CPP. Overall, these results demonstrate the utility of the CA model for studies of cocaine-context memory and suggest the involvement of an NMDA receptor-dependent Arc induction pathway in drug-cue memory interference.

Running wheel exercise before a binge regimen of methamphetamine does not protect against striatal dopaminergic damage.

Repeated administration of methamphetamine (mAMPH) to rodents in a single-day "binge" dosing regimen produces long-lasting damage to forebrain dopaminergic nerve terminals as measured by decreases in tissue dopamine (DA) content and levels of the plasmalemmal DA transporter (DAT). However, the midbrain cell bodies from which the DA terminals arise survive, and previous reports show that striatal DA markers return to control levels by 12 months post-mAMPH, suggesting long-term repair or regrowth of damaged DA terminals. We previously showed that when rats engaged in voluntary aerobic exercise for 3 weeks before and 3 weeks after a binge regimen of mAMPH, exercise significantly ameliorated mAMPH-induced decreases in striatal DAT. However, these data left unresolved the question of whether exercise protected against the initial neurotoxicity from the mAMPH binge or accelerated the repair of the damaged DA terminals. The present experiments were designed to test whether exercise protects against the mAMPH-induced injury. Adult male Sprague-Dawley rats were allowed to run in wheels for 3 weeks before an acute binge regimen of mAMPH or saline, then placed into nonwheel cages for an additional week before autoradiographic determination of striatal DAT binding. The autoradiographic findings showed that prior exercise provided no protection against mAMPH-induced damage to striatal DA terminals. These results, together with analyses from our previous experiments, suggest that voluntary exercise may accelerate the repair of mAMPH-damaged DA terminals and that voluntary exercise may be useful as therapeutic adjunct in the treatment mAMPH addicts.

Methamphetamine influences on brain and behavior: unsafe at any speed?

Methamphetamine damages monoamine-containing nerve terminals in the brains of both animals and human drug abusers, and the cellular mechanisms underlying this injury have been extensively studied. More recently, the growing evidence for methamphetamine influences on memory and executive function of human users has prompted studies of cognitive impairments in methamphetamine-exposed animals. After summarizing current knowledge about the cellular mechanisms of methamphetamine-induced brain injury, this review emphasizes research into the brain changes that underlie the cognitive deficits that accompany repeated methamphetamine exposure. Novel approaches to mitigating or reversing methamphetamine-induced brain and behavioral changes are described, and it is argued that the slow spontaneous reversibility of the injury produced by this drug may offer opportunities for novel treatment development.

Running wheel exercise ameliorates methamphetamine-induced damage to dopamine and serotonin terminals.

Repeated administration of methamphetamine (mAMPH) to rodents in a single-day "binge" produces long-lasting damage to dopaminergic and serotonergic terminals. Because previous research has demonstrated that physical activity can ameliorate nigrostriatal injury, this study investigated whether voluntary exercise in rats can alter the monoaminergic damage resulting from a neurotoxic mAMPH binge. Adult male rats were allowed constant access to running wheels or kept in nonwheel cages for three weeks, then given a binge dosing regimen of mAMPH or saline. The rats were returned to their original environments for three additional weeks post-mAMPH. [(125) I]RTI-55 binding and autoradiography was used to quantify dopamine transporters (DAT), and radioimmunocytochemistry was used to quantify striatal tyrosine hydroxylase (TH). Binge mAMPH treatment significantly reduced striatal DAT and TH in a regionally specific pattern; with greatest effects in ventral caudate-putamen (CP) and relative sparing of the nucleus accumbens septi (NAc). The effects of mAMPH on striatal DAT and TH were ameliorated in the running, compared to the sedentary, animals. Also, mAMPH was found to reduce [(125) I]RTI-55 binding to serotonin transporters (SERT) in frontoparietal cortex, and this too was significantly attenuated by exercise. Additional correlational analyses showed that the post-mAMPH running of individual animals predicted the amelioration of striatal DAT and TH as well as frontoparietal SERT. Overall, voluntary exercise significantly diminished mAMPH-induced forebrain monoaminergic damage. The significant correlations between post-mAMPH exercise and markers of monoaminergic terminal integrity provide novel evidence that voluntary exercise may exert beneficial effects on behavior in recovering mAMPH addicts.

A neurotoxic regimen of methamphetamine impairs novelty recognition as measured by a social odor-based task.

Repeated administration of methamphetamine (mAMPH) to rodents in a single-day "binge" regimen damages forebrain monoaminergic nerve terminals and produces subsequent cognitive deficits. Here we investigate performance on a social odor-based task, demonstrating enduring mAMPH-induced deficits in recognition memory. Three weeks after a neurotoxic mAMPH regimen, singly-housed male Long-Evans rats had four wooden beads placed in their home cage: three beads containing odors from their home cage (HC beads) and one bead from a cage of a rat not present in the colony room (N1 bead). Exploration times for each bead were recorded during three 1-min habituation trials separated by 1-min intertrial intervals. Twenty-four hours later, a 1-min memory test was conducted, in which animals were presented with two HC beads, one N1 bead, and one bead from another novel animal (N2). Saline- and mAMPH-treated rats showed similar, progressive decreases in exploration time for the N1 bead during the habituation trials, indicating equivalent short-term olfactory habituation to the novel odor. By contrast, during the subsequent memory test, saline-treated rats showed a strong preference for the N2 bead over the N1 bead while mAMPH-treated rats showed no preference. The use of the rats' primary sensory modality (olfaction) coupled with the social significance (from conspecifics) of the odors produces strong, long-lasting memories. Our results show that prior treatment with a neurotoxic regimen of mAMPH impairs long-term memory for the previously experienced odors. As compared with previously employed object recognition tasks, this test may be advantageous for investigating mAMPH-induced memory impairments in rodents.

Randomized comparison of postoperative use of hydrogel ocular bandage and collagen corneal shield for wound protection and patient tolerability after cataract surgery.

PURPOSE: To compare the safety and efficacy of a hydrogel bandage and a collagen corneal shield in providing wound protection and relief of pain/discomfort in the acute period after uneventful unilateral clear corneal phacoemulsification cataract surgery with foldable intraocular lens (IOL) implantation. SETTING: Seventeen investigational sites in the United States. DESIGN: Prospective randomized single-masked parallel study. METHODS: The study comprised patients scheduled to have unilateral clear corneal cataract surgery with posterior chamber intraocular lens implantation. The patients were examined preoperatively and frequently for 30 days postoperatively. The design was a noninferiority study of the 2 primary endpoints, device performance and maximum reported postoperative pain. RESULTS: The device performance success was 78.6% (228/290) for the hydrogel bandage and 26.5% (26/98) for the corneal shield (P<.0001 for noninferiority). Analyses indicated that the hydrogel bandage was superior to the corneal shield in device performance (P<.001; difference = 52.1%; 95% confidence interval, 41.6%-61.4%). The maximum postoperative pain/discomfort score of the hydrogel bandage (mean 1.3 ± 1.8 [SD]; scale 0 to 10) was noninferior to that of the corneal shield (1.1 ± 1.6) in the first 4 hours after surgery (P<.001). Adverse events in the cataract surgeries were reported in 22.2% (70/316) and 36.5% (38/104) of hydrogel bandage patients and corneal shield patients, respectively (P = .0045). CONCLUSION: The hydrogel bandage was safe and effective for ocular surface protection and relief of pain/discomfort when applied topically to clear corneal incisions used in cataract or IOL implantation surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. Additional disclosures are found in the footnotes.

Neurotoxic methamphetamine regimens produce long-lasting changes in striatal G-proteins.

Animals repeatedly dosed with methamphetamine during a single day suffer damage to brain dopamine and serotonin terminals and show behavioral deficits. These methamphetamine regimens also produce long-term reductions in dopamine agonist-stimulated immediate-early gene responses both in striatum and several cortical areas, but the mechanism(s) underlying these long-lasting effects of methamphetamine remain uncertain. Six weeks after a neurotoxic regimen of methamphetamine (4 × 4 mg/kg) or saline, α subunit levels of striatal G-proteins that couple dopamine receptors to second messenger systems were measured. Because the damage to striatal monoamine terminals produced by methamphetamine is regionally heterogeneous, we used radioimmunocytochemistry, which combines quantification with regional resolution. We found significant increases in G(iα) and G(olfα) expression in the ventral striatum (but not in the dorsolateral striatum or nucleus accumbens) of methamphetamine-pretreated rats, a regional pattern similar to that reported for methamphetamine effects on dopamine terminal markers. By contrast, G(qα) expression was unaffected in all striatal subregions. The central roles of G(i) and G(olf) in modulating the activity of a series of interlinked intracellular signaling pathways suggest that methamphetamine-induced changes in G(i) and G(olf) can have lasting effects on striatal neuronal function.

A sensitizing D-amphetamine dose regimen induces long-lasting spinophilin and VGLUT1 protein upregulation in the rat diencephalon.

Numerous studies in this lab and others have reported psychostimulant-induced alterations in both synaptic protein expression and synaptic density in striatum and prefrontal cortex. Recently we have shown that chronic D-amphetamine (D-AMPH) administration in rats increased synaptic protein expression in striatum and limbic brain regions including hippocampus, amygdala, septum, and paraventricular nucleus of the thalamus (PVT). Potential synaptic changes in thalamic nuclei are interesting since the thalamus serves as a gateway to cerebral cortex and a nodal point for basal ganglia influences. Therefore we sought to examine drug-induced differences in synaptic protein expression throughout the diencephalon. Rats received an escalating (1-8 mg/kg) dosing regimen of D-AMPH for five weeks and were euthanized 28 days later. Radioimmunocytochemistry (RICC) revealed significant upregulation of both spinophilin and the vesicular glutamate transporter, VGLUT1, in PVT, mediodorsal (MD), and ventromedial (VM) thalamic nuclei as well as in lateral hypothalamus (LH) and habenula. Strong positive correlations were observed between VGLUT1 and spinophilin expression in PVT, medial habenula, MD, VM and LH of D-AMPH-treated rats. No significant D-AMPH effect was seen in sensorimotor cortices for either protein. Additionally, no significant differences in the general vesicular protein synaptophysin were observed for any brain region. These findings add to evidence suggesting that long-lasting stimulant-induced synaptic alterations are widespread but not ubiquitous. Moreover, they suggest that D-AMPH-induced synaptic changes may occur preferentially in excitatory synapses.

Reversal-specific learning impairments after a binge regimen of methamphetamine in rats: possible involvement of striatal dopamine.

A growing body of evidence indicates that protracted use of methamphetamine (mAMPH) causes long-term impairments in cognitive function in humans. Aside from the widely reported problems with attention, mAMPH users exhibit learning and memory deficits, particularly on tasks requiring response control. Although binge mAMPH administration to animals results in cognitive deficits, few studies have attempted to test behavioral flexibility in animals after mAMPH exposure. The aim of this study was to evaluate whether mAMPH would produce impairments in two tasks assessing flexible responding in rats: a touchscreen-based discrimination-reversal learning task and an attentional set shift task (ASST) based on a hallmark test of executive function in humans, the Wisconsin Card Sort. We treated male Long-Evans rats with a regimen of four injections of 2 mg/kg mAMPH (or vehicle) within a single day, a dosing regimen shown earlier to produce object recognition impairments. We then tested them on (1) reversal learning after pretreatment discrimination learning or (2) the ASST. Early reversal learning accuracy was impaired in mAMPH-treated rats. MAMPH pretreatment also selectively impaired reversal performance during ASST testing, leaving set-shifting performance intact. Postmortem analysis of [(125)I]RTI-55 binding revealed small (10-20%) but significant reductions in striatal dopamine transporters produced by this mAMPH regimen. Together, these results lend new information to the growing field documenting impaired cognition after mAMPH exposure, and constitute a rat model of the widely reported decision-making deficits resulting from mAMPH abuse seen in humans.

Long-term changes in dopamine-stimulated gene expression after single-day methamphetamine exposure.

Methamphetamine (mAMPH) is a highly addictive psychostimulant drug that injures monoaminergic neurons and results in behavioral impairments in humans and animals. Although evidence exists for changes in cortical volume, metabolism, and blood oxygenation levels in human mAMPH abusers, animal models have instead emphasized this drug's long-lasting influence on ascending monoaminergic (dopamine, serotonin) projections. The aim of this study was to investigate cortical and subcortical function in rats long after administration of a single-day mAMPH regimen known to damage monoaminergic systems, at a time point when behavioral impairments are still evident. Rats were given either saline or a neurotoxic (4 x 4 mg/kg, sc) mAMPH regimen. Five weeks later, they were given pharmacological treatments that stimulate cortical gene expression: either the dopaminergic agonist apomorphine (3 mg/kg, sc) or the muscarinic acetylcholine agonist pilocarpine (25 mg/kg, ip). Cortical and subcortical immediate early gene (IEG) responses were measured by immunocytochemical analysis of Fos or JunB, protein products of the IEGs, c-fos and junB. Compared with saline-pretreated controls, mAMPH-pretreated animals had about 50-70% fewer Fos- and JunB-immunoreactive cells in anterior cingulate, infralimbic, orbital, somatosensory, and rhinal cortices as well as caudate-putamen and nucleus accumbens, 90 min after apomorphine challenge. By contrast, mAMPH-pretreated rats had no reductions in the numbers of Fos or JunB-positive cells following pilocarpine challenge. This study demonstrates the profound and enduring effects of mAMPH administration on dopamine-stimulated cortical function in animals.

Methamphetamine influences on recognition memory: comparison of escalating and single-day dosing regimens.

Methamphetamine (mAMPH) is an addictive drug that produces memory and recall impairments in humans. Animals subjected to a binge mAMPH dosing regimen that damages brain dopamine and serotonin terminals show impairments in an object recognition (OR) task. Earlier research demonstrated that preceding a single-day mAMPH binge regimen with several days of increasing mAMPH doses greatly attenuates its neurotoxicity in rats. The escalating dose (ED) paradigm appears to mimic the human pattern of escalating drug intake. The current aim was to test whether an ED plus binge mAMPH regimen produces OR impairments. In addition to its translational value, this experiment helps address whether monoaminergic neurotoxicity accounts for OR impairments seen after mAMPH administration. To further address this issue, a separate experiment investigated both OR impairments and monoamine transporter integrity in groups of rats treated with a range of mAMPH doses during a single day. An ED mAMPH regimen attenuated the acute hyperthermic response to the subsequent mAMPH binge and prevented the OR impairments and reductions in [125 I]RTI-55 binding to monoamine transporters in striatum, hippocampus (HC), and perirhinal cortex (pRh) that otherwise occur 1 week after the mAMPH binge. Single-day mAMPH regimens (4 x 1mg/kg to 4 x 4 mg/kg, s.c.) dose-dependently produced acute hyperthermia and, 1 week post-mAMPH, produced dose-dependent impairments in OR and reductions in monoamine transporter binding. The OR impairments of single-day mAMPH-treated rats correlated with monoaminergic transporter loss in ventral caudate-putamen, HC, and pRh. In aggregate, these findings suggest a correspondence between mAMPH-induced monoaminergic injury and the resulting OR deficits.

Methamphetamine-induced neural and cognitive changes in rodents.

AIMS: Although psychostimulant drug abuse carries with it several potential health risks, the chronic abuse of amphetamines carries the danger of permanent brain injury. The purpose of these experiments is to develop animal models to understand the long-lasting influences of methamphetamine exposure on cerebral cortex and cognitive function. METHODS: The approach taken is to administer a regimen of methamphetamine known to be neurotoxic to dopamine and serotonin nerve terminals in the rat, and to investigate the influences of that dosing regimen on (i) cortical neuron integrity and function using anatomical stains and (ii) novel object recognition memory. RESULTS: In rodents, repeated administration of methamphetamine during a single day produces long-lasting damage to striatal dopamine and forebrain serotonin terminals as well as degeneration of somatosensory cortical neurons. The degeneration of somatosensory cortical neurons may represent only the most visible form of long-term deleterious effects on cerebral cortex, as exposure of rats to methamphetamine can reduce the immediate early gene responses of neurons in widespread cortical areas, even long after exposure to the drug. Together with the death and long-lasting functional impairments of cortical neurons, rats exposed to methamphetamine have impaired cognitive function. When tested for object recognition memory, methamphetamine-treated rats show deficiencies lasting for at least 3 weeks after drug exposure. CONCLUSIONS: Using a rodent model, these findings provide an avenue to study the cortical influences of methamphetamine and their cognitive sequelae.