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PubMed1995

Changes in periwinkle (Littorina littorea) populations following the ban on TBT-based antifoulings on small boats in the United Kingdom.

In 1987 the UK Government banned the use of tributyl tin (TBT)-based antifouling paints on small boats of less than 25 m. Following initial control measures taken in 1986, a program of research was started to monitor concentrations of TBT residues in estuarine waters and sediments and to observe faunistic changes in highly contaminated estuaries. As part of this program, the size-frequency and abundance of Littorina littorea populations have been recorded in the estuaries of the rivers Crouch (Essex) and Hamble (Hampshire). Since the TBT ban, the concentration of TBT residues in water and sediments has been steadily declining. In both L. littorea populations, the frequency of O-group individuals has increased markedly, and there has been a simultaneous decrease in TBT residues in L. littorea tissues. Furthermore, plankton surveys of the River Crouch show that the numbers of L. littorea eggs and veliger larvae have progressively increased, suggesting that TBT may have impaired periwinkle reproduction and/or survival of the eggs and larvae. Subsequent laboratory experiments have indeed shown that reduced egg production was the probable mechanism of action, but the imposex associated with exposure to TBT in dogwhelks (Nucella lapillus) has not been seen.

Animals↗
PubMedDate not supplied

Cytoskeleton alterations by tributyltin (TBT) in tunicate phagocytes.

The effects of tributyltin chloride (TBT) on cytoskeletal components, as possible cell targets of toxicity, were examined on cultured hemocytes of the colonial ascidian Botryllus schlosseri by means of indirect immunofluorescence. The immunotoxic effect of 10 microM TBT (sublethal concentration) consists of (1) inhibition of yeast phagocytosis, Ca2+ ATPase activity, and respiratory burst; (2) increase in intracellular Ca2+ concentration; and (3) alterations in cell morphology. After 60 min, TBT-exposed amebocytes become spherical, withdrawing their long pseudopodia, and lose motility. Their microfilaments assemble in clusters around the peripheric cytoplasm, indicating massive disassembly, with the exception of unaltered adhesion plaques. Analogously, their microtubules reveal extensive disaggregation, being scattered in the cytoplasm and not recognizable as single filaments, whereas the microtubule organizing center (MTOC) is still visible. Treatment together with 20 micrograms/ml calmodulin (CaM) can partially restore the cytoskeleton architecture. These results suggest a relationship between TBT and Ca2+ homeostasis in ascidian hemocytes. By interfering with Ca2+ ATPase activity through CaM inhibition, either directly or indirectly, TBT induces an excess of intracellular Ca2+ accumulation, which first causes internal disorganization of cytoskeletal proteins and consequently inhibition of phagocytosis, beginning from chemotaxis and particle adhesion.

Animals↗
PubMed1998

Mesocosm study of Mytilus edulis larvae and postlarvae, including the settlement phase, exposed to a gradient of tributyltin.

In a mesocosm study, the effects of a gradient of tributylin (TBT) (nominal TBT concentrations of 0.3, 2.3, 18.5, 146, and 1150 ng Sn liter-1) on Mytilus edulis larvae and postlarvae, including the settlement phase, were investigated over 15 days. Effects of TBT on mortality, growth measured as increase in shell length, shell dimensions, and settlement were evaluated. In general, mortality was high in all mesocosms including the control; during the first 24 h of the experiment, mortality was 63% at the highest TBT concentration (26% in the control). An LC50 (24 h) of 254 ng Sn liter-1 was estimated. The mortality rate of larvae/postlarvae increased 40% at 18.5 ng Sn liter-1 (0.41 day-1) compared with the control (0.30 day-1). For postlarvae, the growth rate decreased with increasing TBT concentration. The mean shell length at 2.3 ng Sn liter-1 was significantly reduced in comparison to the control on Day 15. Then EC10 (15 days) for shell growth was estimated to be 5.4 ng Sn liter-1. This is the lowest effect concentration ever reported in the literature. For postlarvae, shell dimensions in terms of shell length-shell width relations were affected by TBT at 1150 ng Sn liter-1, because the reduced growth led to the failure of adult mussels to secret a dissochonch shell. During the first days of exposure, the settlement monitored on polyethylene settling strips was stimulated by TBT, after which the settlement decreased due to the high mortality. Only a small portion of the population survived to the end of the test period. By comparison of the biotic conditions (in terms of larval abundance and particle concentration reflecting larval food) in the control mesocosm with those in the cove where the experiment was conducted, it was concluded that the mesocosm had successfully simulated the field conditions.

Animals↗
PubMed2000

Changes in the metabolic elimination profile of testosterone following exposure of the crustacean Daphnia magna to tributyltin.

The biocide tributyltin has been found to cause the development of pseudohermaphroditic conditions in some neogastropod species. These abnormalities of the reproductive system have adversely affected the fecundity of some field populations of gastropods, resulting in local population declines. Current evidence suggests that tributyltin elicits these effects by interfering with the biotransformation of testosterone to other steroid derivatives, resulting in an elevation in endogenous testosterone or some of its bioactive derivatives. The purpose of the present study was to determine whether tributyltin altered testosterone metabolism in daphnids (Daphnia magna), a species commonly used in ecotoxicology testing. Exposure of daphnids to 1.2 microg (tin)/L caused a general increase in the rate of elimination of oxido-reduced, hydroxylated, and glucose-conjugated derivatives of testosterone. However, tributyltin exposure had no significant effect on the rate of elimination of the glucose-conjugated forms of the various oxido-reduced and hydroxylated derivatives of testosterone. As a result, the percentage of the oxido-reduced and hydroxylated metabolites of testosterone eliminated as glucose conjugates decreased with increasing tributyltin exposure levels. These results demonstrate that tributyltin causes alterations in testosterone metabolism in daphnids that would result in an increase in the production of oxido-reduced derivatives. These products are preferentially retained in the tissues of daphnids and are variously androgenic in vertebrates. The increased production of oxido-reduced derivatives of testosterone may be mechanically responsible for the masculinizing effects of tributyltin in some species and suggests that daphnids may be a suitable surrogate for evaluating the potential of chemicals to elicit this form of toxicity.

Androstane-3,17-diol↗
PubMed2002

Evaluation of tributyltin subchronic effects in tropical freshwater fish (Astyanax bimaculatus, Linnaeus, 1758).

Tributyltin (TBT) is widely used as a biocide in antifouling paints. Astyanax bimaculatus adult fish were acclimatized in a laboratory and isolated in groups of eight individuals. Two groups were used as a control (similar handling and corn oil control) and one group was exposed to TBTCI dissolved in corn oil (0.0688 +/- 0.0031 microg TBT.g(-1)) every 6 days for 32 days. Light and transmission electron microscopy were used to investigate the morphological effects on liver. A muscle fragment was excised for the determination of the acetylcholinesterase activity and blood smears were obtained for differential white cell counts. The results indicated nuclear irregular shapes, chromatin condensation, presence of intranuclear lipid bodies, and degenerative nuclei. Acetylcholinesterase activity was not affected by TBT exposure. The increasing number of neutrophils may represent cytotoxic and stress conditions facilitating the invasion of opportunist organisms. According to the authors' data, TBT was confirmed as a powerful aquatic contaminant to fish in tropical ecosystem.

Acetylcholinesterase↗
PubMed2002

Comparing sensitivity of ecotoxicological effect endpoints between laboratory and field.

Extrapolating toxicant effects with a fixed application factor (AF) approach or one of the species sensitivity distribution (SSD) models presumes that toxicant effects on single, individual-level endpoints reflect effects at the ecosystem level. Measured effect concentrations on plankton from multispecies field tests using tributyltin (TBT) and linear alkylbenzene sulfonates (LAS) were compared with published laboratory single-species test results and measured in situ concentrations. Extrapolation methods were evaluated by comparing predicted no-effect concentrations (PNECs), calculated by AF and SSD models with NOECs and E(L)C(50)s obtained from field studies. Overall, structural parameters were more sensitive than functional ones. Measured effect concentrations covered approximately the same range between laboratory and field experiments. Both SSD and AF approaches provide PNECs that appear to be protective for ecosystems. The AF approach is simpler to apply than the SSD models and results in PNECs that are no less conservative. Calculated PNEC values and the lowest field effect concentrations were lower than measured environmental concentrations for both substances, indicating that they may pose a risk to marine ecosystems.

Alkanesulfonic Acids↗
PubMed1997

Effect of in vitro exposure to tributyltin on generation of oxygen metabolites by oyster hemocytes.

Mollusks depend chiefly on hemocyte-mediated cytotoxic mechanisms such as reactive oxygen species (ROS) to defend against pathogenic microorganisms. The effect of in vitro tributyltin chloride (TBT) exposure on ROS generation by oyster (Crassostrea virginica) blood phagocytes is quantified in this study. Luminol-augmented chemiluminescence (LCL) was used to measure ROS activity of resting and zymosan-stimulated cells after 1 or 20 hr TBT exposure. LCL is thought to measure primarily the activity of the myeloperoxidase/hydrogen peroxide/ halide antimicrobial pathway. Hemocytes in TBT-free medium (controls) produced low level LCL, which was markedly stimulated by the addition of zymosan particles. Both resting and zymosan-stimulated LCL values were significantly inhibited by > or = 80 ppb TBT after either 1 or 20 hr of exposure. Exposure to < or = 2 ppb TBT concentrations for 20 hr produced slightly enhanced LCL activity, suggesting a hormesis-like effect. Partial reversibility of TBT suppression of LCL took place when previously exposed cells were put in TBT-free medium. The TBT concentrations used in these studies were not cytolethal in vitro and were considerably less than oyster tissue levels recorded after chronic, sublethal in vitro exposures. The data suggest that the common aquatic contaminant TBT can interact rapidly with C. virginica hemocytes to produce a partially reversible immunotoxicological lesion. Xenobiotic-induced suppression of ROS production by hemocytes may increase host susceptibility to infectious diseases.

Animals↗
PubMed1994

Comparison of cellular and nuclear flow cytometric techniques for discriminating apoptotic subpopulations.

We compared cellular flow cytometric methods employing carboxyfluorescein (CF), Höechst 33342, and Höechst 33258 with a nuclear method in their ability to discriminate apoptotic subpopulations in rat thymocyte cultures exposed to dexamethasone or tributyltin. In the nuclear technique, apoptotic cells appeared as a single population containing reduced DNA content, while in the cellular techniques, apoptotic cells appeared as two or more subpopulations exhibiting increased fluorescence. Of these subpopulations, early apoptotic cells [which excluded propidium iodide (PI), indicating maintenance of membrane integrity] exhibited higher fluorescence but the same level of axial light loss (i.e., size/refractive index) as viable cells; late apoptotic and dead cells (which incorporated PI) exhibited decreased axial light loss. However, while the Höechst dyes allowed discrimination of late apoptotic from dead cells, CF did not. In comparing sensitivity to staining conditions, Höechst 33258 fluorescence was the most stable over time, Höechst 33342 the least, and CF fluorescence not only varied with time, but with tri-n-butyltin methoxide concentration. Comparison of single-parameter analyses revealed that axial light loss was sensitive only to late apoptotic changes; nuclear fluorescence was a better indicator of apoptotic subpopulations, but still underestimated the total percentage of affected cells, and Höechst 33342 distinguished early apoptotic cells as those with elevated fluorescence. Early apoptotic cells stained with Höechst 33258 also exhibited increased fluorescence, but could not be distinguished from late apoptotic and dead cells without a second parameter. These findings indicate that of the methods investigated, the method of choice for detecting apoptosis depends on the goal of analysis: Höechst 33258 was best for discriminating apoptotic subpopulations, and CF was best for assessing alterations of membrane fluidity. For single-parameter analyses, Höechst 33258 was best for determining the total percentage of affected cells, while Höechst 33342 could be used to determine the percentage in early apoptosis.

Animals↗
PubMed2002

Neurotoxicologic sequelae of tributyltin intoxication in rats.

Tributyltin oxide (TBTO) is a commonly used biocide. The purpose of this study is to correlate the toxicity of TBTO with the alterations of brain neurotransmitters and ATPases. TBTO was given by stomach tube to rats at either 37.5 or 75 mg x kg (-1)for 3 consecutive days. Nervous signs appeared in treated animals and the mortality reached 12 and 30%, respectively. The levels of brain dopamine, norepinephrine and serotonin decreased in a dose-dependent manner. The activities of brain total ATPase, Mg (2+)-ATPase and Na (+)/K (+)- ATPase were suppressed. The activity of Na (+)/K (+)- ATPase was more severely affected than that of Mg (2+)-ATPase. Histopathological changes in brain included hyperaemia, focal haemorrhages in vacuolated myelinated fibres, chromatolysis, or complete necrosis of neurons, degenerative changes, or complete absence of purkinje cells in the cerebellum.

Adenosine Triphosphatases↗
PubMed1993

Apoptosis as a mechanism of tributyltin cytotoxicity to thymocytes: relationship of apoptotic markers to biochemical and cellular effects.

Recent in vitro studies have suggested that activation of apoptosis could account for the profound depletion of cortical thymocytes, which characterizes tributyltin (TBT) immunotoxicity. However, it has also been shown that TBT disrupts macromolecular synthesis and cellular energetics to an extent that might be expected to interfere with the initiation of apoptosis. The purpose of these studies was to further evaluate the morphological and biochemical characteristics of thymocyte killing by TBT and to relate this to key cellular processes. Ex vivo thymocyte cultures from immature rats were treated with bis(tri-n-butyltin) oxide (TBTO) at concentrations ranging from those which rapidly produced necrosis (5-10 microM), down to cytotoxic but subnecrotic concentrations (0.1-2 microM). In cells exposed to TBTO concentrations that caused a rapid and near maximal inhibition of protein synthesis, it remained possible to demonstrate the stereotypic internucleosomal DNA cleavage and morphological changes indicative of apoptosis. Further confirmation that apoptosis was occurring independently from protein synthesis was provided by the absence of a protective effect following cycloheximide pretreatment. Apoptosis still occurred in TBTO-treated thymocytes although intracellular ATP levels were depressed to 20% or less of control values. Cytoprotective effects were noted with the intracellular Ca2+ chelators BAPTA-AM and Quin-2 AM, and also with zinc. Cell killing by TBTO occurred without overt disturbance of thymocyte cell cycle parameters. These results indicate that thymocyte apoptosis stimulated by TBT exposure occurs independently of a requirement for protein synthesis and does not require fully conserved cellular energetics.

Adenosine Triphosphate↗
PubMed1994

Tributyltin and dexamethasone induce apoptosis in rat thymocytes by mutually antagonistic mechanisms.

The nuclei of apoptotic thymocytes can be identified by flow cytometry as a subpopulation exhibiting reduced DNA content. We observed that rat thymocyte cultures exposed to 1.0-2.5 microM tri-n-butyltin methoxide (TBT) exhibited a rapid time- and concentration-dependent induction of apoptosis, with > 85% of cells exhibiting reduced DNA content within 1 hr after exposure to 2.0-2.5 microM TBT. In contrast, exposure to 1.0 microM dexamethasone phosphate (DEX) resulted in a gradual time-dependent increase to approximately 45% induction of apoptosis by 6 hr versus approximately 15% spontaneous induction in controls. However, simultaneous exposure to TBT and DEX resulted in a decreased response: although TBT concentrations between 0.1 and 0.5 microM did not induce apoptosis, they reduced the ability of DEX to initiate apoptosis; while at TBT concentrations > or = 1.0 microM, simultaneous exposure to DEX substantially decreased the extent of TBT-induced apoptosis and cytotoxicity. Furthermore, while treatment with the protein synthesis inhibitor cycloheximide or the protein kinase C inhibitor H-7 completely blocked DEX-induced apoptosis, neither significantly reduced induction of apoptosis by TBT. Taken together, the toxicant-specific differences in the timing and extent of apoptotic induction and the dissimilar responses to CHX and H-7 suggest that TBT and DEX initiate endonuclease-mediated apoptotic cell death through different mechanisms. Moreover, the ability of each agent to retard the action of the other suggests that these mechanisms are directly or indirectly antagonistic.

Analysis of Variance↗
PubMed1996

Endogenous interleukin-1 alpha associated with skin irritation induced by tributyltin.

Tributyltin (TBT) salts are well-known skin irritants in both human and rodents. This study investigated the role of interleukin-1alpha (IL-1alpha) in the process in mice and in murine keratinocytes. The ears of Balb/c mice were painted with different amounts of TBT (67-536 nmol in acetone) or with acetone alone. Two hours later there was dose-related production of IL-1alpha along with ear swelling and accumulation of skin water, all of which were partially prevented by intraperitoneal injection of antibody against murine IL-1alpha. By reverse transcription-polymerase chain reaction we were able to show that the neutralizing antibody also partially prevented TBT-induced in vivo IL-6 expression but no TBT-induced TNF-alpha expression, suggesting a paracrine effect of IL-1alpha on IL-6 production but not TNF-alpha expression and indicating that other inflammatory mediators are involved. TBT induced both intracellular production of IL-1alpha and its release into culture medium in a murine keratinocyte cell line (HEL30). IL-1alpha production was inhibited by addition of a neutralizing antibody against IL-1alpha, which suggests an autocrine effect of IL-1alpha on its own production. The intracellular production of IL-1alpha could he significantly inhibited by prior treatment with antioxidants, which strongly suggests a role for oxidative species in the mechanism of action of TBT in IL-1alpha induction. The complex-1 inhibitor rotenone also significantly inhibits IL-1alpha production. Since TBT causes disturbances in the respiratory chain in mitochondria, the mechanism of its action may be the production of reactive oxygen intermediates at the ubiquinone site, which activate transcription factors and promote IL-1alpha synthesis.

Animals↗
PubMed1997

Role of mitochondria and calcium ions in tributyltin-induced gene regulatory pathways.

Tributyltin (TBT) salts are potent skin irritants both in humans and rodents. Data in the literature indicate mitochondria as target of TBT effects. Here, we investigate the early intracellular molecular events that follow TBT treatment and the relevance of calcium ions and mitochondria in gene-regulatory signaling pathways. Confluent HEL30 cells were treated with increasing doses of TBT (0-5 microM). At different times thereafter, the level of intracellular Ca2+, the cellular oxidative activity, nuclear factor-kappaB (NF-kappaB) activation, and IL-1alpha production were measured. TBT induced a dose-related increase of intracellular Ca2+ that reached the plateau 4 min following treatment. The increase of intracellular Ca2+ was followed by an increase in cellular oxidative activity as measured by DCFH oxidation (15 min) that preceded NF-kappaB activation (30 min) and IL-1alpha production (4 hr). All these events can be almost completely abrogated by BAPTA, an intracellular Ca2+ chelator. Furthermore, the modulation of cellular oxidative activity induced by TBT observed with rotenone, an inhibitor of the electron entry from complex I to ubiquinone, or after prolonged treatment with ethidium bromide, an inhibitor of mitochondrial DNA and RNA synthesis, indicates mitochondria as an important intracellular source of reactive oxygen species. These findings indicate the rise in intracellular Ca2+ as the starting event and indicate the role of mitochondria as the source of second messenger molecules essential for TBT-induced NF-kappaB activation and IL-1alpha production.

Analysis of Variance↗
PubMed1999

Suppression of calcium oscillation by tri-n-butyltin chloride in cultured rat hepatocytes.

The effects of tri-n-butyltin chloride (TBT), an environmental pollutant, on cytoplasmic free calcium ion concentration ([Ca2+]i) were investigated in primary cultured rat hepatocytes. A high concentration (4.0 microM) of TBT increased resting levels of [Ca2+]i and then induced cell blebs resulting in cell death within 2 h. The increase in [Ca2+]i, but not the cell death, depended on the presence of extracellular Ca2+, suggesting that the increase in [Ca2+]i is not critical for the cytotoxicity of TBT. A low concentration (0.1 microM) of TBT did not have any toxic effect (decrease in ATP content, decrease in viability, and shape change) on cultured hepatocytes and did not change [Ca2+]i. However, the calcium responses induced by phenylephrine, [Arg8]-vasopressin, and ATP were suppressed in the cells pretreated with 0.1 microM TBT for 30 min. The suppression was not observed in the cells pretreated with 0.1 microM TBT for only 1 min. Pretreatment with 0.1 microM TBT for 30 min had no effect on the inositol 1,4,5-triphosphate content or its increase in response to hormonal stimulation. These results suggest that TBT suppresses hormone-induced calcium responses at nontoxic low concentrations.

Animals↗
PubMed2006

5,6-Dichloro-1-methylgramine, a non-toxic antifoulant derived from a marine natural product.

The laboratory culture of the barnacle, Balanus amphitrite has made it possible to supply cypris larvae for antifouling assays all year round. The settlement of cyprids obtained from cultured B. amphitrite was indistinguishable from cyprids reared from field-collected barnacles. In laboratory cyprid settlement assays of extracts from marine sessile organisms, antifouling activity was expressed as the 99% inhibitory concentration (IC99), and toxicity as the 30% lethal concentration (LC30). The lipophilic extract of the marine bryozoan, Zoobotryon pellucidum, which showed promising antifouling activity, yielded 2,5,6-tribromo-1-methylgramine (TBG) by bioassay-guided isolation. The inhibitory activity of TBG was 6 times as strong as that of bis-(n-butyltin)oxide (TBTO), while its toxicity to cypris larvae was one-tenth that of TBTO. A structure-activity relationship study with 155 indole derivatives led to the discovery of the non-toxic antifoulant candidates 5,6-dichlorogramine, 5-chloro-2-methylgramine, and 5,6-dichrolo-1-methylgramine (DCMG), the latter being selected as the antifouling paint ingredient for performance evaluation tests (panel tests) following the results of a preliminary safety tests. A silicone-based antifouling paint containing 5-10% of DCMG was prepared and tested in the field; the painted surfaces remained almost barnacle-free for 1.5 years similar to silicone coatings such as Biox. Since the leaching rate of DCMG from the paint surface could be controlled by the addition of an acrylic acid-styrene copolymer (ASP), the life of the antifouling performance is expected to be improved. Thus, an extremely non-toxic silicone-based antifouling paint containing DCMG is under development.

Alkaloids↗
PubMed1998

Immunotoxicology: extrapolation from animal to man--estimation of the immunotoxicologic risk associated with TBTO exposure.

Bis(tri-n-butyltin)oxide (TBTO) has been shown to be immunotoxic in rodents, resulting in decreased resistance to infections. The no-effect level assessed by estimating effects on host resistance in rats has been found to lie between 0.5 and 5.0 mg TBTO/kg food (0.025 and 0.25 mg/kg body weight). For risk assessment such animal data need to be extrapolated to the human situation. In risk assessment procedures uncertainty factors are used to account for interspecies variation (extrapolation from animal to man) and for variation within the human species. For both factors a value of 10 is often used, based on international guidelines. Hence, exposures below 0.00025 mg/kg body weight should not pose a risk for the human population. In the present study we have taken an alternative approach. We have produced dose-response curves for the effect of TBTO exposure on resistance to Trichinella spiralis. To extrapolate this curve to the human situation, we produced additional dose response data concerning in vitro effects of TBTO exposure on the mitogen responsiveness of both rat lymphoid cells and human blood cells. Using regression analyses of these dose-response data, we calculated a factor that accounts for interspecies variation (IEV) and a factor that accounts for intraspecies variation (IAV) within the human samples. Using these factors, we estimated the dose that decreases resistance in man to an infection. We choose 10% increase of the infectious load as a reference point which in our view is of biological significance. Based on these considerations, we estimated the dose that may affect resistance in adult humans at 0.04 mg/kg body weight. Pre- and postnatal exposure will probably result in effects at lower concentrations, due to the vulnerability of the developing immune system.

Adult↗
PubMed1987

Selective learning impairment of delayed reinforcement autoshaped behavior caused by low doses of trimethyltin.

The organometal neurotoxin trimethyltin (TMT), induces impaired learning and memory for various tasks. However, administration is also associated with other "non-specific" behavioral changes which may be responsible for effects on conditioned behaviors. To determine if TMT treatment causes a specific learning impairment, three experiments were done using variations of a delay of reinforcement autoshaping task in which rats learn to associate the presentation and retraction of a lever with the delivery of a food pellet reinforcer. No significant effects of TMT treatment were found with a short (4 s) delay of reinforcement, indicating that rats were motivated and had the sensorimotor capacity for learning. When the delay was increased to 6 s, 3.0 or 6.0 mg TMT/kg produced dose-related reductions in behaviors directed towards the lever. Performance of a group given 7.5 mg TMT/kg, while still impaired relative to controls, appeared to be better than the performance of groups given lower doses. This paradoxical effect was investigated with a latent inhibition paradigm, in which rats were pre-exposed to the Skinner boxes for several sessions without delivery of food reinforcement. Control rats showed retardation of autoshaping when food reinforcement was subsequently introduced. Rats given 7.5 mg TMT/kg exhibited elevated levels of lever responding during pre-exposure and autoshaping sessions. The results indicate that 7.5 mg TMT/kg produces learning impairments which are confounded by hyperreactivity to the environment and an inability to suppress behavior toward irrelevant stimuli. In contrast, low doses of TMT cause learning impairments which are not confounded by hyperreactivity, and may prove to be useful models for studying specific associational dysfunctions.

Animals↗