Biomedical subjects

Alvin V Terry

Publications and source records attributed to Alvin V Terry.

At least 19 recordsLinked to original sources

PubMed2006

Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine.

Cotinine is the major metabolite of nicotine in humans, and the substance greatly outlasts the presence of nicotine in the body. Recently, cotinine has been shown to exert pharmacological properties of its own that include potential cognition enhancement, anti-psychotic activity, and cytoprotection. Since the metabolite is generally less potent than nicotine in vivo, we considered whether part of cotinine's efficacy could be related to a reduced ability to desensitize nicotinic receptors as compared with nicotine. Rats freely moving in their home cages were instrumented to allow ongoing measurement of mean arterial blood pressure (MAP). The ganglionic stimulant dimethylphenylpiperazinium (DMPP) maximally increased MAP by 25mmHg. Slow (20min) i.v. infusion of nicotine (0.25-1micromol) produced no change in resting MAP, but the pressor response to subsequent injection of DMPP was significantly attenuated in a dose-dependent manner by up to 51%. Pre-infusion of equivalent doses of cotinine produced the same maximal degree of inhibition of the response to DMPP. Discrete i.v. injections of nicotine also produced a dose dependent increase in MAP of up to 43mmHg after the highest tolerated dose. In contrast, injection of cotinine produced no significant change in MAP up to 13 times the highest dose of nicotine. These results illustrate the disconnection between nicotinic receptor activation and receptor desensitization, and they suggest that cotinine's pharmacological actions are either mediated through partial desensitization, or through non-ganglionic subtypes of nicotinic receptors.

Animals↗

PubMed2006

Chlorpyrifos, chlorpyrifos-oxon, and diisopropylfluorophosphate inhibit kinesin-dependent microtubule motility.

Diisopropylfluorophosphate, originally developed as a chemical warfare agent, is structurally similar to nerve agents, and chlorpyrifos has extensive worldwide use as an agricultural pesticide. While inhibition of cholinesterases underlies the acute toxicity of these organophosphates, we previously reported impaired axonal transport in the sciatic nerves from rats treated chronically with subthreshold doses of chlorpyrifos. Those data indicate that chlorpyrifos (and/or its active metabolite, chlorpyrifos-oxon) might directly affect the function of kinesin and/or microtubules--the principal proteins that mediate anterograde axonal transport. The current report describes in vitro assays to assess the concentration-dependent effects of chlorpyrifos (0-10 microM), chlorpyrifos-oxon (0-10 microM), and diisopropylfluorophosphate (0-0.59 nM) on kinesin-dependent microtubule motility. Preincubating bovine brain microtubules with the organophosphates did not alter kinesin-mediated microtubule motility. In contrast, preincubation of bovine brain kinesin with diisopropylfluorophosphate, chlorpyrifos, or chlorpyrifos-oxon produced a concentration-dependent increase in the number of locomoting microtubules that detached from the kinesin-coated glass cover slip. Our data suggest that the organophosphates-chlorpyrifos-oxon, chlorpyrifos, and diisopropylfluorophosphate-directly affect kinesin, thereby disrupting kinesin-dependent transport on microtubules. Kinesin-dependent movement of vesicles, organelles, and other cellular components along microtubules is fundamental to the organization of all eukaryotic cells, especially in neurons where organelles and proteins synthesized in the cell body must move down long axons to pre-synaptic sites in nerve terminals. We postulate that disruption of kinesin-dependent intracellular transport could account for some of the long-term effects of organophosphates on the peripheral and central nervous system.

Animals↗

PubMed2006

Galantamine and donepezil attenuate pharmacologically induced deficits in prepulse inhibition in rats.

Acetylcholinesterase inhibitors (AChEIs) are currently being evaluated as adjunctive therapy for the cognitive dysfunction of schizophrenia. This core symptom of schizophrenia has often been attributed to impaired attention and abnormal sensory motor gating, features that are also found in Huntington's Disease, autism, and several other psychiatric and neurological disorders. The ability to improve prepulse inhibition (PPI) of the acoustic startle response may predict the efficacy of compounds as cognitive enhancers. In this study, PPI was disrupted in Wistar rats in three pharmacologic models: dopamine receptor agonism by apomorphine, NMDA receptor antagonism by MK801, or muscarinic acetylcholine receptor antagonism by scopolamine. We then evaluated the commonly used AChEIs, donepezil (0.5, 1.0, or 2.0mg/kg) and galantamine (0.3, 1.0, or 3.0mg/kg) for the capacity to improve PPI in each model. Under vehicle conditions, the prepulse stimuli (75, 80 and 85dB) inhibited the startle response to a 120dB auditory stimulus in a graded fashion. Galantamine (depending on dose) improved PPI deficits in all three PPI disruption models, whereas donepezil ameliorated PPI deficits induced by scopolamine and apomorphine, but was not effective in the MK801 model. These results indicate that some AChEIs may have the potential to improve cognition in schizophrenia by improving auditory sensory gating.

Acoustic Stimulation↗

PubMed2006

Time-dependent cognitive deficits associated with first and second generation antipsychotics: cholinergic dysregulation as a potential mechanism.

Although cognitive dysfunction is considered one of the more debilitating symptoms of schizophrenia, there is a fundamental gap in our knowledge of how the primary pharmacologic treatments of this disease, first- and second-generation antipsychotics (FGAs and SGAs, respectively), affect cognition, particularly over extended periods of time. Moreover, it has been known for decades that chronic treatment with FGAs can lead to imbalances in cholinergic function in the striatum that result in movement disorders; however, there is a growing body of evidence to suggest that both FGAs and SGAs can lead to cholinergic alterations in brain areas more traditionally considered as memory-related, such as cortical and hippocampal regions. Data from our laboratories in rodents indicate that some SGAs (if administered for sufficient periods of time) can be associated with impairments in memory-related task performance as well as alterations in the cholinergic enzyme choline acetyltransferase, the vesicular acetylcholine transporter, and nicotinic (alpha(7)) and muscarinic (M(2)) acetylcholine receptors. Given the well documented importance of central cholinergic function to information processing and cognitive function, it is important that the mechanisms for such chronic antipsychotic effects be identified. In this review, two potential mechanisms for long-term antipsychotic-related cholinergic alterations in the central nervous system are discussed: 1) antipsychotic antagonist activity at dopaminergic-D(2) receptors on cholinergic neurons and 2) antipsychotic effects on neurotrophins that support cholinergic neurons, such as nerve growth factor and brain derived growth factor. Novel strategies to optimize the therapeutics of schizophrenia and maintain cognitive function via adjunctive cholinergic compounds and antipsychotic crossover approaches are also discussed.

Animals↗

PubMed2006

Time-dependent effects of haloperidol and ziprasidone on nerve growth factor, cholinergic neurons, and spatial learning in rats.

In this rodent study, we evaluated the effects of different time periods (7, 14, 45, and 90 days) of oral treatment with haloperidol (HAL; 2.0 mg/kg/day) or ziprasidone (ZIP; 12.0 mg/kg/day) on nerve growth factor (NGF) and choline acetyltransferase (ChAT) levels in the hippocampus, and we subsequently assessed water maze task performance, prepulse inhibition (PPI) of the auditory gating response, and several NGF-related proteins and cholinergic markers after 90 days of treatment. Seven and 14 days of treatment with either HAL or ZIP resulted in a notable increase in NGF and ChAT immunoreactivity in the dentate gyrus (DG), CA1, and CA3 areas of the hippocampus. After 45 days, NGF and ChAT immunoreactivity had abated to control levels in ZIP-treated animals, but it was markedly reduced in HAL-treated subjects. After 90 days of treatment, NGF and ChAT levels were substantially lower than controls in both antipsychotic groups. Furthermore, after 90 days of treatment and a drug-free washout period, water maze performance (but not PPI) was impaired in both antipsychotic groups, although the decrement was greater in the HAL group. Several NGF-related and cholinergic proteins were diminished in the brains of subjects treated with either neuroleptic as well. These data support the premise that, although ZIP (given chronically) seems somewhat superior to HAL due to less pronounced behavioral effects and a more delayed appearance of neurochemical deficits, both antipsychotics produce time-dependent deleterious effects on NGF, cholinergic markers (i.e., important neurobiological substrates of memory), and cognitive function.

Animals↗

PubMed2006

Long-term antipsychotic treatments and crossover studies in rats: differential effects of typical and atypical agents on the expression of antioxidant enzymes and membrane lipid peroxidation in rat brain.

Short-term (<45 days) treatment studies in rats have reported increased oxidative stress and oxidative (i.e., oxygen free radical-mediated) neural cell injury with typical antipsychotics such as haloperidol, but not with the atypicals such as clozapine, olanzapine or risperidone. However, now these and several other atypical antipsychotics that differ in their neurotransmitter receptor affinity profiles are being used for a long-term treatment of schizophrenia. Therefore, understanding of their long-term treatment effects on the expression of antioxidant enzymes and oxidative neural cell injury in rats may be important to explain the possible differential mechanisms underlying their long-term clinical and side effects profiles. The effect of 90 and 180 day exposure to haloperidol (HAL, 2mg/kg/day), a representative typical antipsychotic was compared to exposure to chlorpromazine (CPZ, 10mg/kg/day), ziprasidone (ZIP, 12mg/kg/day), risperidone (RISP, 2.5mg/kg/day), clozapine (CLOZ, 20mg/kg/day) or olanzapine (OLZ, 10mg/kg/day) on the expression of antioxidant defense enzymes and levels of lipid peroxidation in the rat brain. The drug-induced effects on various antioxidant defense enzymes; manganese-superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT) were assessed by determination of their enzymatic activity and protein content. Immunohistochemical analysis was also carried out to assess the cellular levels of MnSOD and CuZnSOD and cellular morphology. The oxidative membrane damage was assessed by determination of levels of the lipid peroxidation product, hydroxyalkanals (HAEs) in the rat brain. Both 90 and 180 days of HAL treatment very significantly decreased the levels of MnSOD (50%) and CuZnSOD (80%) and increased the levels of HAEs compared to vehicle treatment. Smaller reduction was found in CAT (25%) and no change in the glutathione peroxidase (GSHPx). The levels of enzymatic activity correlated generally well with the levels of enzyme protein indicating that the changes were in the expression of net protein. Though atypical antipsychotics like ZIP, RISP and OLZ did not show any change in the HAEs levels up to 90 days, further treatment up to 180 days resulted in significantly increased levels of HAEs in CPZ, ZIP and RISP, but not in OLZ treated rats. Post-treatment with several atypical antipsychotics (OLZ=CLOZ>RISP) for 90 days after 90 day of HAL treatment significantly restored the HAL-induced loss in MnSOD and CuZnSOD activities and increase in lipid peroxidation products as well as cellular morphology. These data may be very helpful in planning long-term use as well as switch over of these antipsychotics for the management of schizophrenia.

Animals↗

PubMed2006

Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus.

The results of mostly short-term treatment studies in human patients and animals suggest that second-generation antipsychotics (SGAs) such as risperidone (RISP) and olanzapine (OLZ) compared to first-generation antipsychotics (FGAs) such as haloperidol (HAL) and chlorpromazine (CPZ) have neuroprotective effects. The animal studies indicate that these effects are probably mediated through increased expression of neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). However, since antipsychotics are commonly used for very long-term treatment periods, particularly in schizophrenic patients, it is important to measure the effects of chronic administration of antipsychotic drugs on the aforementioned growth factors. This study determined the effects of 90- and 180-day treatments with two FGAs, HAL and CPZ, and two SGAs, RISP and OLZ, on the levels of NGF and BDNF protein in hippocampus and striatum of rat. Furthermore, since a preliminary study showed that 90-day treatment of HAL caused significant reductions in the expression of both NGF and BDNF the HAL-treated animals were then switched to SGAs for the next 90 days to assess the potential for restoration of trophic factor levels. After the 90-day treatment, NGF levels in the hippocampus were reduced by 60-70% with HAL or CPZ, and by only 25-30% with RISP or OLZ compared to levels with vehicle only. After the 180-day treatment, NGF levels were further reduced with HAL, RISP, and OLZ, but not with CPZ. The magnitude of the NGF decreases in the striatum was larger (70-90%) with all the antipsychotics compared to the hippocampus. However, the pattern of BDNF changes in the hippocampus differed significantly from the striatum after 90- or 180-day treatment with the antipsychotics. In hippocampus, compared to controls, BDNF levels remained unchanged with OLZ both after 90 and 180 days of treatment. Whereas, larger decreases in BDNF levels were observed with HAL or CPZ and intermediate decreases were observed with RISP after 90 days of treatment that continued to decline up to 180 days. Furthermore, switching HAL animals after 90 days of treatment to either RISP or OLZ for the next 90 days significantly restored levels of both NGF and BDNF in both the brain regions. These data indicate that SGAs compared to FGAs induce less deleterious effects on neurotrophic factor levels in the brain and may also offer ability to reverse the more pronounced negative effects of FGAs as well. These data may have significant clinical implications for long-term antipsychotic selection as well as the common practice of antipsychotic switchover.

Animals↗

PubMed2006

Determination of chlorpyrifos and its metabolites in rat brain tissue using coupled-column liquid chromatography/electrospray ionization tandem mass spectrometry.

A method has been developed to quantify chlorpyrifos (O,O-diethyl-O-[3,5,6,-trichloro-2-pyridyl] phosphorothionate) and its metabolites chlorpyrifos-oxon (O,O-diethyl-O-[3,5,6,trichloro-2-pyridinyl] phosphate) and TCP (3,5,6,-trichloro-2-pyridinol) in rat brain tissue by coupled-column liquid chromatography/electrospray ionization tandem mass spectrometry (LC/LC/ESI-MS/MS). Rat brains were homogenized and treated by protein precipitation using ice-cold acetonitrile. The supernatant was directly injected onto the coupled-column system. Sample clean-up was achieved on a Zorbax Extend-C(18) column (2.1 x 50 mm, 5 microm) using a mobile phase of acetonitrile/water with 0.0025% formic acid (40:60, v/v). The compounds were separated isocratically on a Zorbax Eclipse XDB C(8) column (2.0 x 150 mm, 5 microm) using a mobile phase of acetonitrile/water with 0.0025% formic acid (75:25, v/v). Chlorpyrifos and chlorpyrifos-oxon were detected in positive ion mode using multiple reaction monitoring (MRM). TCP was detected in negative ion mode using precursor-to-precursor transition monitoring. The method was validated and the specificity, linearity, limit of quantitation (LOQ), precision, accuracy, stability, and recoveries were determined. Calibration curves for all three analytes yielded correlation coefficients of 0.993 or greater. The LOQs were 25.3 ng/g for chlorpyrifos and 6.3 ng/g for chlorpyrifos-oxon and TCP. All precision relative standard deviations (RSDs) were less than 16% for the LOQ and less than 11% for the other QC samples. This method was successfully applied to six rats that were injected subcutaneously with chlorpyrifos.

Animals↗

PubMed2005

ELISA methods to measure cholinergic markers and nerve growth factor receptors in cortex, hippocampus, prefrontal cortex, and basal forebrain from rat brain.

The central cholinergic system has a fundamental role in normal cognitive function, and in diseases that exhibit cognitive dysfunction. The purpose of this study was to design ELISA methods to measure proteins that have essential functions in the central cholinergic system. We were particularly interested in quantifying proteins that respond directly or indirectly to nerve growth factor (NGF). ELISAs offer advantages over Western blot analyses and other methods, such as increased sensitivity, decreased assay variability, increased efficiency, and decreased cost. We developed indirect ELISA methods for: choline acetyltransferase (ChAT); the vesicular acetylcholine transporter (VAChT); the high affinity choline transporter (HACT/CHT); TrkA, the high affinity NGF receptor; the p75 neurotrophin receptor (p75(NTR)). A sandwich ELISA was developed to measure tyrosine-phosphorylated TrkA in brain lysates. We used these ELISAs to compare levels of the above proteins in important memory-related brain regions--basal forebrain, hippocampus, cortex, and prefrontal cortex--from old and young rats. We identified age-related differences in the levels of the aforementioned proteins (e.g., VAChT and HACT/CHT in hippocampus). Thus, these ELISA methods should be particularly useful for comparing the effects of age, disease, drugs, and toxicants on brain levels of key cholinergic and growth factor-related proteins.

Acetylcholine↗

PubMed2005

Effect of repeated nicotine exposure on high-affinity nicotinic acetylcholine receptor density in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHRs) are often used as a model of attention deficit hyperactivity disorder (ADHD) and to investigate the effects of hypertension on cognitive function. Further, they appear to have reduced numbers of central nicotinic acetylcholine receptors (nAChRs) and, therefore, may be useful to model certain aspects of Alzheimer's disease (AD) and other forms of dementia given that a decrease in nAChRs is thought to contribute to cognitive decline in these disorders. In the present study, based on reports that chronic nicotine exposure increases nAChRs in several mammalian models, we tested the hypothesis that repeated exposures to a relatively low dose of the alkaloid would ameliorate the receptor deficits in SHR. Thus, young-adult SHRs and age-matched Wistar-Kyoto (WKY) control rats were treated with either saline or nicotine twice a day for 14 days (total daily dose = 0.7 mg/kg nicotine base) and then sacrificed. Quantitative receptor autoradiography with [125I]-IPH, an epibatidine analog, revealed: (1) that high-affinity nAChRs were higher in saline-treated WKY (control) rats compared to saline-treated SHRs in 18 of the 19 brain region measured, although statistically different only in the mediodorsal thalamic nuclei, (2) that nicotine significantly increased nAChR binding in WKY rats in six brain areas including cortical regions and the anterior thalamic nucleus, (3) that there were no cases where nicotine significantly increased nAChR binding in SHRs. These results indicate that subjects deficient in nAChRs may be less sensitive to nAChR upregulation with nicotine than normal subjects and require higher doses or longer periods of exposure.

Animals↗

PubMed2005

Cotinine, a neuroactive metabolite of nicotine: potential for treating disorders of impaired cognition.

The pharmacological effects of the tobacco-derived alkaloid nicotine have been widely studied in humans and animals for decades. However, relatively little attention has been given to the potential actions of its major metabolite, cotinine. After nicotine consumption the duration of cotinine's presence in blood and brain greatly exceeds that of nicotine. Therefore, cotinine could mediate the more protracted pharmacological effects of nicotine. The studies described in this report were thus designed to further investigate certain neuropharmacological actions of cotinine. Behavioral tests (e.g., delayed matching-to-sample) were conducted in aged rhesus monkeys to assess the effects of cotinine on working memory and attention. In rats a prepulse inhibition (PPI) procedure was used to assess the effects of the compound on auditory gating - a method for predicting the potential antipsychotic properties of drugs. Cotinine exhibited significant effectiveness in these tasks. The drug was also cytoprotective in differentiated PC-12 cells with a potency equivalent to that of nicotine. The effects of chronic cotinine treatment on the expression of nicotinic and muscarinic acetylcholine receptors in rat brain were measured by [125I]epibatidine, [125I]alpha-bungarotoxin ([125I]BTX), [3H]pirenzepine ([3H]PRZ), and [3H]AFDX-384 ([3H]AFX) autoradiography. Unlike nicotine, cotinine failed to upregulate the expression of brain nicotinic receptors. Based on its relative safety in man, cotinine should prove useful in the treatment of diseases of impaired cognition and behavior without exhibiting the toxicity usually attributed to nicotine.

Aging↗

PubMed2004

Selective serotonin 5-HT2A receptor antagonist EMD 281014 improves delayed matching performance in young and aged rhesus monkeys.

RATIONALE: The superior cognitive effects of atypical neuroleptics over typical agents reported in the schizophrenia literature are often attributed to the more prominent antagonist activity of the atypical drugs at serotonin 5HT(2A) receptors. However, atypical neuroleptics also have activity at many additional neurotransmitter receptors and few studies have specifically (and prospectively) tested the hypothesis that 5HT(2A) antagonism alone results in enhanced cognitive function. OBJECTIVES: The purpose of this study was to evaluate the selective 5-HT(2A) antagonist, 7-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl}-1H-indole-3-carbonitrile HCl (EMD 281014) in young and aged monkeys in a test designed to assess working memory function. METHODS: Four oral doses (0.1, 1.0, 3.0, and 10.0 mg/kg) of EMD 281014 were evaluated in six young adult (mean age=9.2 years) and eight aged rhesus macaques (mean age=24.9 years) trained to perform a computer-assisted delayed matching-to-sample (DMTS) task. RESULTS: Depending on dose, EMD 281014 improved DMTS accuracy in young and aged monkeys primarily at either the medium or long retention intervals. While the latencies associated with incorrect color selections (choices latencies) tended to be longer than those associated with correct selections (particularly in the aged subjects) under baseline conditions, there were no significant effects of EMD 281014 on either sample or choice latencies in either age group. In addition, no adverse effects were observed across the range of doses evaluated in either cohort of animals. CONCLUSION: These experiments, conducted in a non-human primate model, suggest that selective 5HT(2A) antagonists such as EMD 281014 could offer therapeutic benefit to younger and older psychiatric patients by improving working memory function.

Aging↗

PubMed2004

The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys.

IDRA 21, a positive allosteric modulator of the glutamate AMPA receptor, produced a concentration-dependent inhibition of glutamate-induced inactivation of membrane currents in recombinant HEK 293 (human embryonic kidney) cells stably transfected with human GluR1/2 flip receptors. IDRA 21 doubled the charge transfer at a concentration of 70 microM, suggesting that this compound can facilitate excitatory neurotransmission via GluR 1/2 receptors. We next sought to exploit this mechanism of action by examining the drug as a potential cognition-enhancing agent in non-human primates. Oral administration of IDRA 21 produced a highly significant improvement in the performance of a delayed matching-to-sample (DMTS) task by young adult rhesus monkeys. The pattern of task improvement over the dose range 0.15-10 mg/kg was maintained to 48 hr after the single dose administration. For sessions run after administration of the individualized Best Dose of IDRA 21, task accuracy for Long delay (most difficult) trials was increased by 34% of vehicle. Animals were randomly assigned fixed doses of IDRA 21 to determine whether the positive mnemonic response could be maintained. The repeated doses were separated by 3 days, thus allowing for potential cumulative effects. IDRA 21 produced a gradual increase in task accuracy that was maintained on average above vehicle performance levels over an intermittent dosing schedule during a total period of 3 weeks. A separate group of aged monkeys (>20 y) were, as a group, impaired (during vehicle testing) in DMTS performance efficiency relative to the young cohort. IDRA 21 also improved task accuracy by aged rhesus monkeys over the same dose range, but the responses were not as robust as those exhibited by young animals. Aged subjects also appeared to be more individually sensitive to drug dose, and they exhibited shorter task latencies than did the young group. Despite these differences, when the individualized Best Doses were considered, IDRA 21 produced a robust increase in DMTS accuracy of up to 18% of vehicle for trials associated with Medium delay intervals. For both study groups, no obvious untoward effects of IDRA 21 were noted. These findings support the use of AMPA modulators like IDRA 21 in the treatment of cognitive/memory disorders, including those associated with aging. They also indicate that the drug is associated with long-term effects that could limit dosing regimens to one dose every two or three days. The nature of the protracted mnemonic effects produced by the compound remains to be elucidated.

Aging↗

PubMed2004

Donepezil-induced improvement in delayed matching accuracy by young and old rhesus monkeys.

Donepezil (Aricept), a long-acting cholinesterase inhibitor, is widely used in the treatment of Alzheimer's disease to improve cognition and memory. Many drugs within the class of cognition-enhancing agents, both currently approved medications and those under development, have clinical indications narrowly relegated to Alzheimer's disease. The purpose of this study was to determine whether the efficacy attributed to donepezil in its ability to improve delayed matching accuracy by monkeys was independent of age. Male and female rhesus monkeys (n = 17) ranging from 9to 29 yr of age were administered donepezil (10, 25, 50, and 100 microg/kg, im) during 4 discrete test days. Donepezil treatment improved average task accuracy, but intersubject variability prohibited statistical significance. When animals were considered individually, the most effective dose of donepezil was associated with a highly significant increase in group task performance that was consistent with enhanced recall during testing. The variability associated with the dose-response analysis was attributable primarily to subject age, such that older monkeys required higher doses of donepezil. Yet at doses that were effective in all subjects, there was no relationship between age and the improvement in task accuracy. Likewise, there was no association between baseline task proficiency and improvement in task accuracy.

Age Factors↗

PubMed2004

Novel analogs of choline as potential neuroprotective agents.

The ability of choline to serve as a full, though low potency agonist for the alpha7 nicotinic receptor has provided the impetus to develop analogs that exhibit levels of potency and effectiveness suitable for use as therapeutic agents. Seven analogs of choline were synthesized based on previous work with the analog pyrrolidinecholine. The drugs were administered to differentiated PC-12 cells 24 hr prior to growth factor withdrawal which itself induced cytotoxicity in 30-40% of the cells. Three of 7 choline analogs exhibited potency and efficacy similar to that for nicotine as cytoprotective agents. Despite being tertiary amines, 4 of the choline analogs were more potent than choline in inhibiting [(3)H]choline uptake into cultured fibroblasts transfected with the high affinity, sodium-dependent choline transporter. One of the most effective analogs JAY 2-21-29 was shown to produce a potent (EC50 approximately 30 nM) cytoprotective action that was blocked by pretreatment with the alpha7 nicotinic receptor selective antagonist methyllycaconitine, but not by thealpha2 subtype-preferring antagonist dihydro-beta-erythroidin. These preliminary studies support the further neurochemical characterization of these compounds 1) as selectivealpha7 nicotinic receptor agonists and, 2) based on their interaction with the choline transporter, as potential cholinergic false neurotransmitters as has been demonstrated for pyrrolidinecholine.

Aconitine↗

PubMed2003

Modulation of nerve growth factor and choline acetyltransferase expression in rat hippocampus after chronic exposure to haloperidol, risperidone, and olanzapine.

RATIONALE: Recently, we reported that compared to haloperidol, chronic exposure to either the risperidone (RISP) or olanzapine (OLZ) resulted in superior effects on spatial learning performance as well as the cholinergic neurons, although the mechanism for these effects was not addressed. OBJECTIVES: The objective of this study was to investigate one plausible mechanism whereby RISP and OLZ exert superior effects on cholinergic neurons, i.e. positive effects on nerve growth factor (NGF), which is known to regulate the brain cholinergic activity as well as cognitive function. Therefore, the effects of chronic exposure to HAL, RISP, or OLZ on the expression of NGF and choline acetyltransferase (ChAT) in the hippocampus (i.e. a brain area well known to be involved in cognitive function and known to receive major cholinergic projections from the medial septum) were compared. METHODS: Rats were treated with HAL (1 or 2 mg/kg per day), RISP (1.25 or 2.5 mg/kg per day), or OLZ (5 or 10 mg/kg per day) for 45 days in drinking water. NGF and ChAT were measured by immunohistochemistry and NGF protein was also measured by an enzyme-linked ImmunoSorbent assay. RESULTS: Compared to controls, HAL exposure resulted in a marked reduction in NGF immunoreactivity in the hippocampal dentate gyrus (DG), CA1 and CA3 areas. In contrast, RISP did not alter, while OLZ significantly increased levels of NGF. These changes in NGF levels corresponded well with changes in ChAT immunoreactivity in the hippocampus and the medial septum. CONCLUSIONS: These preclinical data, combined with previously published behavioral results, support the premise that OLZ and RISP, in contrast to HAL, preserve cholinergic pathways and cognitive function via superior effects on NGF expression and are thus therapeutically superior for extended use.

Administration, Oral↗

PubMed2003

Enhanced attention in rhesus monkeys as a common factor for the cognitive effects of drugs with abuse potential.

RATIONALE: One of the common neurochemical features of many drugs of abuse is their ability to directly or indirectly enhance dopaminergic activity in the brain, particularly within the ventral tegmental-nucleus accumbens pathway. Dopaminergic pathways in the frontal and limbic cortex also may be targets for these agents, where pharmacological effects could result in heightened attention and/or support self-administration behavior. OBJECTIVES: The purpose of this study was to determine whether drugs from differing pharmacological classes that exhibit abuse potential would share the ability to counter distractability in the delayed matching task. METHODS: Well trained mature macaques performed a computer-assisted delayed matching-to-sample task which included trials associated with three delay intervals and randomly interspersed task-relevant distractors. Drug regimens included four to five doses and subjects were tested no more than twice per week. RESULTS: All but one of the six compounds (tomoxetine), on average, increased task accuracy for either non-distractor or distractor trials. It was evident that for several compounds, doses required to improve accuracy for non-distractor trials were routinely greater than the doses required to improve accuracy for distractor trials. Data for the individualized Best dose (based upon the subject's optimal level of accuracy during distractor trials) revealed statistically significant distractor-related improvements in task accuracy for the same five compounds. The relative efficacy for reversing distractor-induced decrements in task accuracy was estimated by the level of improvement with respect to baseline: nomifensine (31%)>nicotine (22%) approximately morphine (19%) approximately caffeine (19%) approximately methylphenidate (22%) >tomoxetine (9%). Tomoxetine (noradrenergic preferring) was the only compound that did not produce a significant improvement in accuracy. CONCLUSIONS: These results provide pharmacological support for the concept that attentional mechanisms may play an important role in the "environmental" associative aspects of drug seeking behavior, and as such they may provide the basis for treatment strategies aimed at preventing relapse in detoxified addicts.

Animals↗

PubMed2003

The potential role of cotinine in the cognitive and neuroprotective actions of nicotine.

Cotinine is a primary metabolite of nicotine that has been suggested in many studies in animals and in humans to exert measurable effects on aspects of on-going behavior or on cognitive function. Much of the interest in cotinine derives from its long pharmacological half-life (15-19 hours) relative to nicotine (2-3 hours). Despite decades of study focusing on nicotine as the predominant behaviorally active component of tobacco, there continue to be aspects of the pharmacology of the drug that have yet to be explained. For example, nicotine can evoke a protracted behavioral response, i.e., in great excess of the presence of the drug in the plasma. Also, there is often a striking differential between the potency for nicotine-induced behavioral responses in humans and animals, and its potency as a cholinergic agonist, neurochemically. One possibility that may explain one or more of these properties of nicotine is the presence of a long-lived bioactive metabolite or breakdown product of nicotine such as cotinine. Preliminary data in support of this hypothesis are consistent with the ability of cotinine to improve performance accuracy on delayed matching task by macaque monkeys, and in reversing apomorphine-induced deficits in prepulse inhibition of acoustic startle in rats. The drug also was shown to be as potent as nicotine in the ability to act as a cytoprotective agent in cells that express a neuronal cholinergic phenotype. This new appreciation for the role of cotinine in nicotine's actions, and as a pharmacological agent in its own right, particularly in aspects of cognitive function and for neuroprotection, ultimately may be applied towards the treatment of Alzheimer's disease and related disorders, and for various psychiatric syndromes.

Animals↗