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The deep-ocean carbon cycle is poorly quantified. An abyssal benthic rover was developed to make long time-series measurements of seafloor processes related to organic carbon remineralization and sequestration. Benthic Rover II (BR-II) is an autonomous dual-tracked vehicle that measures bottom water temperature and oxygen concentration, current velocity, and sediment community oxygen consumption (SCOC; respiration). BR-II is programmed to transit with low surface-contact pressure across the seafloor, photograph bottom conditions, and stop regularly to occupy respirometer incubation sites, with deployment periods up to 1 year. Now, continuously operational at a 4000-m station in the northeast Pacific over 5 years, substantial weekly, seasonal, annual, and episodic events have been recorded, which are critical to assessing the deep-ocean carbon cycle. There was a significant increase in phytodetritus cover (P < 0.01) arriving on the seafloor from the overlying water column between 2015 and 2020 that was negatively correlated with bottom water dissolved oxygen concentration (P < 0.01). Over the continuous 5-year monitoring period from November 2015 to November 2020, SCOC was positively correlated with phytodetritus cover (P < 0.01) and increased significantly from 2015 to 2020 (P < 0.01). These results show important influences of biological processes on the carbon cycle. The demonstrated success of BR-II now creates opportunities to expand the long-term monitoring of the deep sea to resolve the coupling of water column and benthic processes key to understanding the oceanic carbon cycle on a planet engulfed in a changing climate.

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Long time-series studies are critical to assessing impacts of climate change on the marine carbon cycle. A 27-year time-series study in the abyssal northeast Pacific (Sta. M, 4000 m depth) has provided the first concurrent measurements of sinking particulate organic carbon supply (POC flux) and remineralization by the benthic community. Sediment community oxygen consumption (SCOC), an estimate of organic carbon remineralization, was measured in situ over daily to interannual periods with four different instruments. Daily averages of SCOC ranged from a low of 5.0 mg C m-2 day-1 in February 1991 to a high of 31.0 mg C m-2 day-1 in June 2012. POC flux estimated from sediment trap collections at 600 and 50 m above bottom ranged from 0.3 mg C m-2 day-1 in October 2013 to 32.0 mg C m-2 day-1 in June 2011. Monthly averages of SCOC and POC flux correlated significantly with no time lag. Over the long time series, yearly average POC flux accounted for 63 % of the estimated carbon demand of the benthic community. Long time-series studies of sediment community processes, particularly SCOC, have shown similar fluctuations with the flux of POC reaching the abyssal seafloor. SCOC quickly responds to changes in food supply and tracks POC flux. Yet, SCOC consistently exceeds POC flux as measured by sediment traps alone. The shortfall of ~37 % could be explained by sediment trap sampling artifacts over decadal scales including undersampling of large sinking particles. High-resolution measurements of SCOC are critical to developing a realistic carbon cycle model for the open ocean. Such input is essential to evaluate the impact of climate change on the oceanic carbon cycle, and the long-term influences on the sedimentation record.

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Pelagic forms of the brown algae (Phaeophyceae) Sargassum spp. and their conspicuous rafts are defining characteristics of the Sargasso Sea in the western North Atlantic. Given rising temperatures and acidity in the surface ocean, we hypothesized that macrofauna associated with Sargassum in the Sargasso Sea have changed with respect to species composition, diversity, evenness, and sessile epibiota coverage since studies were conducted 40 years ago. Sargassum communities were sampled along a transect through the Sargasso Sea in 2011 and 2012 and compared to samples collected in the Sargasso Sea, Gulf Stream, and south of the subtropical convergence zone from 1966 to 1975. Mobile macrofauna communities exhibited changes in community structure and declines in diversity and evenness within a 6-month time period (August 2011-February 2012). Equivalent declines in diversity and evenness were recorded in the same region (Sargasso Sea, 25°-29°N) in 1972-1973. Recent community structures were unlike any documented historically, whether compared to sites of the same latitude range within the Sargasso Sea, or the broader historical dataset of sites ranging across the Sargasso Sea, Gulf Stream, and south of the subtropical convergence zone. Recent samples also recorded low coverage by sessile epibionts, both calcifying forms and hydroids. The diversity and species composition of macrofauna communities associated with Sargassum might be inherently unstable. While several biological and oceanographic factors might have contributed to these observations, including a decline in pH, increase in summer temperatures, and changes in the abundance and distribution of Sargassum seaweed in the area, it is not currently possible to attribute direct causal links.

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Global warming and its disproportionate impact on polar regions have led to increased iceberg populations. Southern Ocean studies in the northwest Weddell Sea have verified substantial delivery of terrestrial material accompanied by increased primary production and faunal abundance associated with free-drifting icebergs. It is hypothesized that input and utilization of macro- and micronutrients are promoted by conditions unique to free-drifting icebergs, leading to increased production, grazing, and export of organic carbon. In Arctic regions, increased freshwater input from meltwater acts to stratify and stabilize the upper water column. As has been observed in the Southern Ocean, Arctic-region icebergs should drive turbulent upwelling and reduce stratification, potentially leading to increased nitrate delivery to the local ecosystem. Increasing populations of icebergs in polar regions can potentially be important in mediating the drawdown and sequestration of CO(2) and can thus impact the oceanic carbon cycle.

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The metabolism of serine and glycine as studied in the plasma is abnormal in schizophrenics and psychotics. There is a concomitant abnormality of the enzyme serine hydroxymethyl transferase (SHMT). To study the status of serine-glycine metabolism in brains of schizophrenics and controls, frozen autopsied brain tissues were obtained from medial and lateral temporal lobes. The results show that the apparent Km of SHMT and the concentrations of serine and glycine are significantly higher only in the medial temporal lobe areas of schizophrenics when compared to controls. These findings are discussed in the context of the role of glycine and serine as enhancers of glutamatergic excitotoxicity and consequent development of morphological abnormalities in the brains of schizophrenics.

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Using synaptosomes prepared from whole rat brain, the spontaneous, calcium-independent, and calcium-dependent release of glutamate and GABA was assessed. Time intervals of 1-30 seconds were studied. Spontaneous release of glutamate (but not GABA) was elevated by 10 microM NMDA or AMPA by thirty seconds. This stimulation was partially calcium-dependent. Calcium-dependent release induced by 30 mM KCl was biphasic, confirming previous findings. This release was stimulated at all time periods by the presence of 10 microM NMDA or AMPA in an antagonist-sensitive manner. These data suggest that glutamate and GABA are released from vesicular stores in rat synaptosomes and that some of this release is modulated by presynaptic glutamate receptors.

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Previous studies from our laboratory indicated that the veratridine-induced release of glutamate and GABA from synaptosomes derived from brains of schizophrenics was decreased. In the present study, synaptosomes were prepared from frozen brain samples from schizophrenics and from controls. Stimulation by 10 mumol/L 2-amino-3-hydroxy-5-methoxylisoxazole-4-propionic acid (AMPA) produced equal glutamate release from both groups. Release induced by either 10 mumol/L kainic acid (KA) or n-methyl-d-asparate (NMDA) was reduced significantly in the preparations derived from schizophrenics. Similarly, the amount of GABA released by 50 mumol/L glutamate was also reduced in the schizophrenic-derived synaptosomes. However, in membranes derived from the crude synaptosomal pellet, no differences between the controls and schizophrenics were observed in measures of total glutamate binding or its displacement by NMDA. The data demonstrate a deficiency in NMDA (and possibly KA) receptor functioning schizophrenics and support the "second-generation" theories of schizophrenia as a glutamatergic deficiency disorder.

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Synaptosomes prepared by discontinuous Ficoll gradient centrifugation were either pre-incubated with glutamine or incubated with releasing agents in the presence of glutamine. Under both conditions, KCl and 4-aminopyridine (agents with specificity toward the calcium-dependent pool) produced elevated glutamate (but not GABA) release when glutamine was included. AMPA and veratridine produced the same glutamate release in the presence or absence of glutamine. These data support the hypothesis that glutamine utilization is involved in the release of glutamate from calcium-dependent pools.

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Studies of amino acid release were carried out using frozen sections from brains of schizophrenics and controls. Synaptosomes were prepared via differential centrifugation in Ficoll allowing the veratridine-induced release of aspartate, glutamate, glycine, and GABA to be measured. The release of glutamate and gamma-aminobutyric acid (GABA) was reduced in the synaptosomes from schizophrenics. This decrease could be reversed partially by pre-incubation of the synaptosomes with haloperidol. Additionally, the activity of glutamate decarboxylase was decreased and partially restored by haloperidol pre-incubation. These data are consistent with the hypothesis of a glutamatergic/GABAergic deficit in schizophrenia.

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We studied the kinetics of the enzyme serine hydroxymethyl transferase (SHMT) and the concentration of its metabolic substrates serine and glycine, in the postmortem brains of controls and schizophrenics. The Km of SHMT, and the concentration of serine and glycine were all significantly higher in the temporal lobes of brain tissues from schizophrenics than in those from controls. These differences were not observed in the frontal lobe specimens. Neuroleptics, age, sex and autolysis time did not contribute to these differences. The role of SHMT deficiency in schizophrenia is discussed in relation to the production of glycine and 1-carbon units from which purines and thereby adenosine is produced. Both glycine and adenosine are potent neuromodulatory substances for the release of dopamine and glutamate, neurotransmitters which have been implicated in the pathophysiology of schizophrenia.

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Male Sprague-Dawley rats were divided into four groups that were treated with various combinations of lithium, saline, and theophylline, i.e., saline/saline, saline/theophylline, lithium/theophylline, and lithium/saline. Neurobehavioral testing of cerebellar and neuromuscular functioning, and determination of the effect of the drug combinations on the animals' seizure threshold concluded that while theophylline increases lithium clearance, it does not exacerbate lithium neurotoxicity.

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Synaptosomes were prepared from whole rat brain by six different methods based on gradients of sucrose, Ficoll or Percoll. In these, the synthesis and calcium-specific release of amino acids were assessed by two different procedures. Preparations based on sucrose showed the least calcium-specific release, followed by Ficoll-derived synaptosomes. As previously described, Percoll gave two separate populations of synaptosomes, both very active in terms of release of aspartate, glutamate, and GABA. The data involving release and synthesis were not identical, but did agree in the following: in low-density synaptosomes, haloperidol blocked both the release and synthesis of glutamate, but was without effect in the heavier population. 2-chloroadenosine and 2-oxoglutarate affected both release and synthesis only in the high-density population. Dopamine blocked aspartate release and synthesis only in the high-density population. These results suggest that haloperidol interferes with glutamate release and synthesis via a mechanism which may not involve adenosine, serotonin, or dopamine.

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Phosphate-activated glutaminase was isolated from synaptosomes from three areas of rat brain. Glutamine utilization phosphate activation and inhibition by glutamate or ammonia were assessed in the absence or presence of haloperidol, chlorpromazine, or clozapine. All three drugs (at 1 micromolar concentration) elevated the Km for glutamine using preparations from the amygdala, hippocampus, or striatum. They interfered with phosphate activation only in the amygdala preparation. No drug affected end-product inhibition. The data suggest that neuroleptics may depress the release of glutamic acid from synaptosomes by interfering with the activation of glutaminase by phosphate.

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The effects of four inhibitors of glutamine hydrolysis on synaptosomes derived from several regions of the brain were studied. The calcium-specific release of endogenous glutamic acid was determined in the presence of varying concentrations of 6-diazo-5-oxo-norleucine (DON), N-ethyl-maleimide (NEM), 2-chloroadenosine (2-CA) or haloperidol. Both DON and NEM reduced the calcium-specific release in a concentration-dependent manner, equally in all regions tested. 2-Chloroadenosine also decreased release and the effect was most evident in the amygdala. As reported earlier, haloperidol blocked release of glutamic acid only in the amygdala. In synaptosomes from the amygdala, both DON and NEM failed to affect the calcium-specific release of aminobutyric acid (GABA), glycine or serotonin at concentrations which reduced release of glutamate by 50%; NEM, but not DON, elevated the release of dopamine. Dopamine itself affected neither the release of glutamate nor its blockade by haloperidol even in extremely large concentrations.

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The relationship between the free plasma concentration of nortriptyline and therapeutic response was examined. Eighteen depressed inpatients were treated for 21 days with steady state total nortriptyline plasma concentrations between 50-150 ng/ml. Steady state free nortriptyline concentrations were measured. The therapeutic nortriptyline response was measured by administering the Hamilton and the Carroll Rating scales at day zero and day 21. Statistical relationships between free levels of drug and clinical response were found to be insignificant. Qualitative assessment of the data suggest that free serum levels of nortriptyline in excess of 10 ng/ml may have an inhibitory effect on clinical response.

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The ability of several classes of neuroleptics to inhibit the activity of phosphate-activated glutaminase was studied in several brain regions. These agents decreased glutaminase activity only in the amygdala. Amphetamine elevated glutaminase activity in this region. This stimulation was not blocked by (-) butaclamol, but was blocked by (+) butaclamol, haloperidol, chlorpromazine or clozapine.

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This study compared two prospective pharmacokinetic dosing methods to predict steady-state concentrations of nortriptyline. One method required multiple determinations of the nortriptyline plasma concentration to estimate the drug's steady-state concentration. The second method required a single nortriptyline concentration drawn at a fixed time, preferably 36 hours, following a nortriptyline test dose. The 36-hour nortriptyline plasma concentrations (NTP 36h) were substituted into the straight-line equation of Cssav = 17.2 + 3.74 (NTP 36h), where Cssav is the average steady-state concentration for a 100 mg/day dose of nortriptyline. No differences were noted between the observed steady-state nortriptyline concentration of 121 +/- 19 ng/ml, the 36-hour single-point prediction mean concentration of 121 +/- 21 ng/ml, or the multiple-point prediction mean concentration of 122 +/- 19 ng/ml. Because of the similar findings between the two methods, the clinical advantages and disadvantages of each kinetic approach are discussed to put these prospective dosing protocols into their proper perspective.

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In studies designed to assess the pre-synaptic effects of neuroleptics in vitro, synaptosomes were prepared from several regions of rat brain. These preparations were incubated in the presence of a representative of each of the major classes of neuroleptic--chlorpromazine, haloperidol, or clozapine, or with (+) or (-)butaclamol. The calcium-specific release of endogenous glutamic acid was reduced only in synaptosomes derived from the amygdala. In this area, each of these agents [except (-)butaclamol] reduced the release of glutamic acid to a maximum of 40% in a concentration-dependent manner. When [3H]glutamine was included in the incubation media, a reduction in the released [3H]glutamate was present with 10(-8) M haloperidol, and 5 X 10(-8) M (+)butaclamol, clozapine, or chlorpromazine. (-)Butaclamol was inactive at 10(-5) M, a concentration producing complete blockade of the release of [3H]glutamic acid when active agents were included. Again, the effects were observed only in the amygdala. All agents, including (-)butaclamol blocked the uptake of [3H]glutamine into depolarized synaptosomes.

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Tardive dyskinesia is widely believed to be a state of relative hyperdopaminergic and hypocholinergic imbalance in the striatum of patients chronically treated with neuroleptics. However, not all patients with tardive dyskinesia respond to cholinergic drugs, which theoretically should restore the balance and improve the symptoms. We report a controlled, double-blind, crossover study of choline chloride in 11 patients with persistent tardive dyskinesia. Seven patients showed partial or minimal improvement, while two did not change and two deteriorated. The results are discussed in the light of other similar findings in the literature, and the implications for pharmacological subtypes of tardive dyskinesia using cholinergic probes are explored.

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