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Biomedical subjects

R D Smith

Publications and source records attributed to R D Smith.

At least 163 records · Page 9Linked to original sources
PubMed1997

Reduction of dizocilpine and scopolamine-induced deficits in avoidance responding by SCH 54388, a metabolite of felbamate.

Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a novel antiepileptic agent with a unique structure and mechanism of action, possibly involving binding sites at the N-methyl-D-aspartate receptor (NMDA) complex. A monocarbomate metabolite of felbamate (SCH 54388) was compared to felbamate using a mouse passive-avoidance paradigm (PAR). SCH 54388 was markedly free of toxic side effects up to doses of 300 mg/kg, sc. SCH 54388 reduced the deficit-producing effects of either scopolamine, a cholinergic antagonist, or dizocilpine (MK-801), an NMDA receptor channel blocker, in a dose-dependent manner. The effective dose range of SCH 54388 was between 0.01 and 10 mg/kg, sc. SCH 54388 was also orally active at doses between 0.1 and 10 mg/kg. Felbamate also reduced scopolamine and dizocilpine antagonism, but was less potent than SCH 54388, reducing scopolamine-induced deficits at 1 to 3 mg/kg, sc. in a dose-dependent manner and reducing deficits induced by dizocilpine at doses of 0.1 and 3 mg/kg, SC. The reduction of dizocilpine-induced deficits by felbamate was not dose dependent. These results suggest that SCH 54388 has a mechanism of action involving either directly or indirectly, glutaminergic and cholinergic central neuronal systems.

Animals↗
PubMed1997

Racial differences in the renal response to blood pressure lowering during chronic angiotensin-converting enzyme inhibition: a prospective double-blind randomized comparison of fosinopril and lisinopril in older hypertensive patients with chronic renal insufficiency.

This study was undertaken to compare the effects of chronic angiotensin-converting enzyme (ACE) inhibition on blood pressure (BP) and renal hemodynamics in older black and nonblack hypertensive patients with chronic renal insufficiency. A multicenter, placebo lead-in double-blind, parallel group study was performed to compare the antihypertensive efficacy and renal hemodynamic response to the once-daily ACE inhibitor fosinopril (n = 14) and lisinopril (n = 13) over a 22-week period. The study goal was to lower diastolic blood pressure (DBP) to 90 mm Hg or less. Furosemide was added after 6 weeks if blood pressure goal was not achieved. At outpatient clinics at university medical centers, 27 older hypertensive patients (> or = 45 years; 12 blacks, 15 nonblacks; 19 male, eight female) with DBP of 95 mm Hg or higher and 4-hour creatinine clearance 20 to 70 mL/min/1.73 m2 were studied. Changes (delta) from baseline in BP, glomerular filtration rate (GFR), and renal plasma flow (RPF) were measured. Mean systolic blood pressure (SBP) and DBP decreased significantly and to a similar extent in randomized groups: fosinopril (mean +/- SEM) delta DBP at 6 weeks was -13 +/- 2 (P < 0.0001; 95% CI, -16 to -9) and at 22 weeks was -12 +/- 2 (P < 0.0001; 95% CI, -16 to -9); lisinopril delta DBP at 6 weeks was -14 +/- 6 (P < 0.0001; 95% CI, -10 to -18) and at 22 weeks was -16 +/- 2 (P < 0.0001; 95% CI, -12 to -21). GFR and RPF did not change significantly in either group. BP was significantly reduced and to a similar extent in blacks and nonblacks: for blacks, delta DBP at 6 weeks was -11 +/- 3 (P < 0.05; 95% CI, -0.01 to -9) and at 22 weeks was -16 +/- 2 (P < 0.0001; 95% CI, -11 to -20); for nonblacks, delta DBP at 6 weeks was -14 +/- 1 (P < 0.0001; 95% CI, -12 to -17) and at 22 weeks was -12 +/- 2 (P < 0.0001; 95% CI, -16 to -8). Eight patients (five blacks and three nonblacks) required an addition of furosemide after 6 weeks to reach the DBP goal of < or = 90 mm Hg at 22 weeks. GFR was not significantly altered for either racial group at 6 weeks; however, at 22 weeks; however, at 22 weeks, GFR decreased significantly in blacks (delta GFR, -16 +/- 5; P < 0.006; 95% CI, -26 to -5) and tended to increase in nonblacks (delta GFR, 7 +/- 6; P > 0.25). delta GFR correlated directly with the delta RPF (delta GFR = 0.0611* delta RPF -2.35 +; r = 0.68; P < 0.003). There was no correlation between delta MAP and delta GFR or delta RPF in blacks or nonblacks. We conclude that chronic ACE inhibition with fosinopril and lisinopril alone or in combination with furosemide lowers BP in older blacks and nonblacks with hypertension and chronic renal insufficiency. Racial differences in the renal hemodynamic response to chronic ACE inhibition were noted and appear to be independent of diuretic use and the magnitude of BP lowering.

Aged↗
PubMed1997

Assessment of a new self-rating scale for post-traumatic stress disorder.

BACKGROUND: In post-traumatic stress disorder (PTSD) there is a need for self-rating scales that are sensitive to treatment effects and have been tested in a broad range of trauma survivors. Separate measures of frequency and severity may also provide an advantage. METHODS: Three hundred and fifty-three men and women completed the Davidson Trauma Scale (DTS), a 17-item scale measuring each DSM-IV symptom of PTSD on 5-point frequency and severity scales. These subjects comprised war veterans, survivors of rape or hurricane and a mixed trauma group participating in a clinical trial. Other scales were included as validity checks as follows: Global ratings, SCL-90-R, Eysenck Scale, Impact of Event Scale and Structured Clinical Interview for DSM-III-R. RESULTS: The scale demonstrated good test-retest reliability (r = 0.86), internal consistency (r = 0.99). One main factor emerged for severity and a smaller one for intrusion. In PTSD diagnosed subjects, and the factor structure more closely resembled the traditional grouping of symptoms. Concurrent validity was obtained against the SCID, with a diagnostic accuracy of 83% at a DTS score of 40. Good convergent and divergent validity was obtained. The DTS showed predictive validity against response to treatment, as well as being sensitive to treatment effects. CONCLUSIONS: The DTS showed good reliability and validity, and offers promised as a scale which is particularly suited to assessing symptom severity, treatment outcome and in screening for the likely diagnosis of PTSD.

Adult↗
PubMed1997

Variations in seroprevalence and host factors for bovine anaplasmosis in Illinois.

The modified card agglutination test (MCAT) was used to detect antibodies to Anaplasma marginale in 4994 samples collected from market cattle through the Brucellosis Eradication Program in Illinois. The MCAT reactor rate in the sample was 6.4%. The statewide prevalence estimate increased to between 7.1% and 10.7% when corrected for sampling distribution and test sensitivity and specificity. While the sample reactor rate measures the proportion of infected cattle moving through the market system and into new herds, consideration of the sampling proportions and test characteristics is important when estimating the overall prevalence. Cows were found to be at decreased risk relative to male cattle in lower-prevalence areas, but the risk was similar in higher-prevalence areas. In both higher- and lower-prevalence areas, the risk for seropositivity increased from 1 year of age onwards, but the rate of increase with age was greater in the higher-prevalence areas. Calves, however, had higher seroprevalence levels than 1-2-year-old animals. The risk was highest for Angus and Angus-Hereford cross cattle, while dairy cattle showed a decreased risk in the whole sample, but not when the analyses were stratified by prevalence level. There was a higher concentration of dairy cattle in areas with lower prevalence levels.

Age Factors↗
PubMed1997

Mobile element 297 in the Abd-B gene of Drosophila melanogaster, not Delta 88, is responsible for the tuh-3 mutation.

The tumorous-head-3 (tuh-3) mutation has been associated with the insertion of mobile element Delta 88 at +200 on the bithorax complex (BX-C) DNA map, 5' of all Abdominal-B (Abd-B) transcripts. Different phenotypes of tuh-3 are regulated by the tumorous-head-1 (tuh-1) maternal effect locus. In the presence of the recessive tuh-1h maternal effect, tuh-3 offspring produce homeotic abdominal and genital tissue in the head. In the presence of the dominant tuh-1g maternal effect, tuh-3 offspring have normal heads but now show genital defects. One other mutant, I127B, produces flies with identical defects to that of tuh-3 in the presence of both maternal effects. Molecular analysis of I127B revealed the insertion of mobile element 297 in the Abd-B gene, approximately 25 kb downstream of the Delta 88 insertion in tuh-3. No other abnormalities were detected. Reexamination of our tuh-3 strain revealed a 297 insertion in an identical region to that of I127B, in addition to the Delta 88 insertion. Recombinants of tuh-3, carrying 297 only, produced homeotic head defects and genital defects in the presence of the tuh-1h and tuh-1g maternal effects, respectively. Recombinants of tuh-3, carrying Delta 88 only, failed to produce any defects in the presence of either maternal effect. Based upon these results, we propose that it is the 297 insertion in the Abd-B gene, not Delta 88, that is responsible for the tuh-3 mutation.

Animals↗
PubMed1997

Increased hepatic iron in the acquired immunodeficiency syndrome: an autopsy study.

Abnormalities in iron metabolism have been reported in patients with acquired immunodeficiency syndrome (AIDS). To assess the frequency of abnormal hepatic iron deposition in these patients and to examine potential causes of iron overload, we analyzed the amount of iron at different cellular sites in liver sections obtained at autopsy of 78 patients with AIDS. Quantitation of serum iron and transferrin levels and estimation of total iron binding capacity was obtained using serum from 63 patients. The number of whole blood/packed red blood cell transfusions and opportunistic infections was recorded. Of the 78 patients, 25 (32%) showed a Grade 3 or 4 (0-4 scale) iron level, distributed in three patterns, i.e., in hepatocytes only, in hepatocytes and Kupffer cells, and in Kupffer cells only. In these 25 livers, 4 had cirrhosis, with no documented cause; the mean number of transfusions was 12.5; and 16 (64%) had Mycobacterium avium-Mycobacterium intracellulare infection. In the 53 livers with little or no iron, 5 had cirrhosis, with 3 of those 5 listing alcoholic liver disease or hepatitis as the cause; the mean number of transfusions was 1.4; and 18 (34%) had Mycobacterium avium-Mycobacterium intracellulare infection. Transferrin saturation was more than 50% in 6 (29%) of 21 cases with increased hepatic iron levels and in 6 (14%) of 42 cases with little or no hepatic iron. These results indicate that hepatic iron overload in patients with AIDS is associated with blood transfusions, an elevated transferrin saturation, and Mycobacterium avium-Mycobacterium intracellulare infection. Significant hepatic iron deposition in patients with AIDS with no other apparent cause of cirrhosis suggests an etiologic role for iron in hepatic injury. The increase in hepatic iron levels in these patients has potentially adverse clinical effects related to the use of transfusions, iron supplements, and iron-containing drugs.

AIDS-Related Opportunistic Infections↗
PubMed1996

Characterization of PCR products from bacilli using electrospray ionization FTICR mass spectrometry.

A procedure for rapid purification of polymerase chain reaction (PCR) products allowing precise molecular weight determination using electrospray ionization-Fourier transform ion cyclotron resonance (ESI-FTICR) mass spectrometry is described. PCR amplification utilized the DNA polymerase from Pyrococcus furiosus (Pfu) which, unlike Taq, does not incorporate a nontemplated terminal deoxyadenosine phosphate. An 89-base pair nucleotide portion of the spacer region between the 16S and 23S ribosomal rRNA genes was amplified from the genome of three members of Bacillus cereus group and a 114 nucleotide region from the Bacillus subtilis. PCR involves polymerization of nucleotide precursors using two oligonucleotide primers and an amplification enzyme, as well as the presence of metal ions. Mass spectrometric analysis greatly benefits from removal of the oligonucleotide primers (15- and 17-mers in this instance) and nucleotide precursors since they adversely affect sensitivity and metal ion adduction results in an inaccurate molecular weight determination. In the presence of guanidinium hydrochloride the PCR products bind preferentially to a silica resin, allowing removal of other components (i.e., dNTP's primers, and salts). Further removal of metal ions was accomplished using a microdialysis device, allowing samples to be pumped through a hollow cellulose fiber with external countercurrent flow of 2.5 mM ammonium acetate. Prior to injection into the mass spectrometer, the sample buffer was adjusted to 50 vol % acetronitrile, 25 mM piperidine, and 25 mM imidazole, which enhanced signal intensity. The molecular weights of the PCR products determined by nucleotide sequence and MS analysis were in excellent agreement, and several PCR products were analyzed where mass differences corresponding to single base substitutions could be accurately assigned. These assignments were possible due to the high mass precision, accuracy, and resolution FTICR inherently affords. This constitutes the first report demonstrating the ionization and detection of PCR products by mass spectrometry with mass precision and accuracy for assignment of such modifications or substitutions.

Bacillus↗
PubMed1996

On-line microdialysis sample cleanup for electrospray ionization mass spectrometry of nucleic acid samples.

A major limitation of electrospray ionization mass spectrometry (ESI-MS) for oligonucleotide analysis arises due to sodium adduction, a problem that increases with molecular weight. Sodium adduction can preclude useful measurements when limited sample sizes prevent off-line cleanup. A novel and generally useful on-line microdialysis technique is described for the rapid (approximately 1-5 min) DNA sample cleanup for ESI-MS. Mass spectra of oligonucleotides of different size and sequence showing no significant sodium adduct peaks were obtained using the on-line microdialysis system with sodium chloride concentrations as high as 250 mM. Signal-to-noise ratios were also greatly enhanced compared to direct infusion of the original samples. By using ammonium acetate as the dialysis buffer, it was also found that the noncovalent association of double-stranded oligonucleotides could be preserved during the microdialysis process, allowing analysis by ESI-MS.

Base Sequence↗
PubMed1996

Diabetic nephropathy after renal transplantation. Clinical and pathologic features.

The histologic diagnosis of diabetic glomerulosclerosis was made in 14 renal transplant recipients. All 14 had insulin-dependent diabetes mellitus, which was the original cause of end-stage renal disease in 12; one patient had membranoproliferative glomerulonephritis and another patient had membranous nephropathy as the cause of end-stage renal disease. Insulin-dependent diabetes mellitus was diagnosed at an average age of 18.5 years (range, 8-41 years), and the mean duration of diabetes prior to transplantation was 15 years (range, 2-25 years). All patients were recipients of first kidney transplants (six living related donors and eight cadavers). The histologic diagnosis of diabetic glomerulosclerosis was made on average, 97 months after transplantation (range 41-154 months). All 14 patients had proteinuria (mean 5.3 g/24 hr; range 1.1-12 g/24 hr) and renal dysfunction (mean serum creatinine level, 2.8 mg/dl). Patient and graft survival rates at 1 year, 5 years, and 10 years after transplantation were 100%, 92%, and 59%, and 100%, 92%, and 34%, respectively. Graft failure was due to diabetic nephropathy in seven patients, diabetic nephropathy and membranous nephropathy in one patient, and death due to a cerebrovascular accident in one patient. A total of five patients are alive with a functioning kidney. Of the eight patients who returned to dialysis, four are alive, three remain on dialysis, and 1 had a combined kidney and pancreas transplant. Histologic findings were as follows: 9/14 had moderate or severe diffuse glomerular basement membrane thickening and 2/14 had nodular glomerulosclerosis. Arteriolar lesions were prominent in all cases and was graded moderate or severe in 11 cases. The development of allograft diabetic nephropathy is associated with a high rate of allograft failure.

Adult↗
PubMed1996

Mass spectrometric characterization of sequence-specific complexes of DNA and transcription factor PU.1 DNA binding domain.

Electrospray ionization mass spectrometry (ESI-MS) has been used to study the noncovalent interaction of the 13.5-kDa DNA binding domain of PU.1 (PU.1-DBD) with specific double-stranded DNA (dsDNA) target molecules. Mixtures of PU.1-DBD protein and wild-type target DNA sequence yielded ESI-MS spectra showing only protein-dsDNA complex ions of 1:1 stoichiometry and free dsDNA. When PU.1-DBD protein, wild type target DNA, and a mutant target DNA lacking the consensus sequence were mixed, only the 1:1 complex with the wild-type DNA was observed, consistent with gel electrophoresis mobility shift assay results, demonstrating the observation of sequence-specific protein-dsDNA complexes using ESI-MS.

Binding Sites↗
PubMed1996

Direct measurement of oligonucleotide binding stoichiometry of gene V protein by mass spectrometry.

The binding stoichiometry of gene V protein from bacteriophage f1 to several oligonucleotides was studied using electrospray ionization-mass spectrometry (ESI-MS). Using mild mass spectrometer interface conditions that preserve noncovalent associations in solution, gene V protein was observed as dimer ions from a 10 mM NH4OAc solution. Addition of oligonucleotides resulted in formation of protein-oligonucleotide complexes with stoichiometry of approximately four nucleotides (nt) per protein monomer. A 16-mer oligonucleotide gave predominantly a 4:1 (protein monomer: oligonucleotide) complex while oligonucleotides shorter than 15 nt showed stoichiometries of 2:1. Stoichiometries and relative binding constants for a mixture of oligonucleotides were readily measured using mass spectrometry. The binding stoichiometry of the protein with the 16-mer oligonucleotide was measured independently using size-exclusion chromatography and the results were consistent with the mass spectrometric data. These results demonstrate, for the first time, the observation and stoichiometric measurement of protein-oligonucleotide complexes using ESI-MS. The sensitivity and high resolution of ESI-MS should make it a useful too] in the study of protein-DNA interactions.

Base Sequence↗
PubMed1996

Mechanism of NO-induced oxidation of myoglobin and hemoglobin.

Nitric oxide (NO) has been implicated as mediator in a variety of physiological functions, including neurotransmission, platelet aggregation, macrophage function, and vasodilation. The consumption of NO by extracellular hemoglobin and subsequent vasoconstriction have been suggested to be the cause of the mild hypertensive events reported during in vivo trials of hemoglobin-based O2 carriers. The depletion of NO from endothelial cells is most likely due to the oxidative reaction of NO with oxyhemoglobin in arterioles and surrounding tissue. In order to determine the mechanism of this key reaction, we have measured the kinetics of NO-induced oxidation of a variety of different recombinant sperm whale myoglobins (Mb) and human hemoglobins (Hb). The observed rates depend linearly on [NO] but show no dependence on [O2]. The bimolecular rate constants for NO-induced oxidation of MbO2 and HbO2 are large (k.ox,NO = 30-50 microM-1 s-1 for the wild-type proteins) and similar to those for simple nitric oxide binding to deoxygenated Mb and Hb. Both reversible NO binding and NO-induced oxidation occur in two steps: (1) bimolecular entry of nitric oxide into the distal portion of the heme pocket and (2) rapid reaction of noncovalently bound nitric oxide with the iron atom to produce Fe(2+)-N=O or with Fe(2+)-O-O delta- to produce Fe(3+)-OH2 and nitrate. Both the oxidation and binding rate constants for sperm whale Mb were increased when His(E7) was replaced by aliphatic residues. These mutants lack polar interactions in the distal pocket which normally hinder NO entry into the protein. Decreasing the volume of the distal pocket by replacing Leu(B10) and Val(E11) with aromatic amino acids markedly inhibits NO-induced oxidation of MbO2. The latter results provide a protein engineering strategy for reducing hypertensive events caused by extracellular hemoglobin-based O2 carriers. This approach has been explored by examining the effects of Phe(B10) and Phe(E11) substitutions on the rates of NO-induced oxidation of the alpha and beta subunits in recombinant human hemoglobin.

Animals↗
PubMed1996

Molecular weight determination of plasmid DNA using electrospray ionization mass spectrometry.

Ionization and molecular weight (MW) determination of megadalton size plasmid DNA has been achieved using electrospray ionization (ESI) with Fourier transform ion cyclotron resonance (FTICR) mass spectrometry. DNA molecules were shown to remain intact through electrospray ionization by collection on a specially prepared surface, followed by agarose gel electrophoresis. Individual highly charged ions of plasmid DNA produced by ESI were trapped in an FTICR cell for up to several hours and reacted with acetic acid to induce charge state shifts. Measurements of mass-to-charge ratios for these multiple peaks arising from charge state shifting give MW measurements of individual ions with an average accuracy of 0.2%. The MW distribution was obtained by measurements for a number of individual ions from the same sample [plasmid DNA: pGEM-5S MW(cal) = 1.946 MDa], yielding a MW(obs) of 1.95 +/- 0.07 MDa for ions clustered in the vicinity of the expected MW.

Cyclotrons↗
PubMed1996

Screening derivatized peptide libraries for tight binding inhibitors to carbonic anhydrase II by electrospray ionization-mass spectrometry.

This paper describes the use of electrospray ionization-mass spectrometry (ESI-MS) to screen two libraries of soluble compounds to search for tight binding inhibitors for carbonic anhydrase II (EC 4.2.1.1). The two libraries, H2NO2SC6H4C(O)NH-AA1-AA2-C(O)NHCH2CH2CO2H where AA1 and AA2 are L-amino acids (library size: 289 compounds) or D-amino acids (256 compounds), were constructed by attaching tripeptides to the carboxyl group of 4-carboxybenzenesulfonamide. Screening of both libraries yielded, as the tightest binding inhibitor, compound 1 (AA1 = AA2 = L-Leu; binding constant Kb = 1.4 x 10(8) M-1). The ability of ESI-MS to estimate simultaneously the relative binding affinities of a protein to soluble ligands in a library, if general, should be useful in drug development.

Amino Acid Sequence↗
PubMed1996

Phosphorylation of brain sodium channels in the I--II linker modulates channel function in Xenopus oocytes.

Voltage-gated sodium channels, which initiate action potentials in mammalian brain neurons, are modulated functionally by cAMP-dependent protein kinase A (PKA), resulting in reduced sodium current amplitude. Comparing brain and muscle sodium channels, we show that only the brain channel is modulated by PKA. The brain sodium channel I-II linker is both necessary and sufficient for PKA modulation, as shown by exchanging the I-II linker regions of the two channels. PKA consensus sites in the brain channel I-II linker were eliminated by deletion and site-specific mutagenesis. The mutant channels demonstrated decreased levels of phosphorylation when metabolically labeled in oocytes with [gamma-32P]-ATP, and they did not respond with a reduction in current magnitude after PKA induction. Modulation of the brain channel by PKA phosphorylation was mimicked by adding fixed negative charges at the PKA consensus sites, suggesting that the decrease in current was a direct result of the negative charge at one or more of the PKA sites in the I-II linker.

Alanine↗
PubMed1996

"Colored" noise waveforms and quadrupole excitation for the dynamic range expansion of Fourier transform ion cyclotron resonance mass spectrometry.

Fourier transform ion cyclotron resonance (FTICR) mass spectrometry offers unparalleled analytical performance in most regards but has a dynamic range of typically no better than 10(2)-10(3). This limitation reportedly arises from two opposing constraints, involving the maximum number of ions that can be effectively trapped (10(6)-10(7)) and the minimum number of ions required to produce a detectable signal (10(2)-10(3)). A potential solution to this dynamic range limitation is presented, based on the application of selected-ion accumulation using quadrupole excitation. We show that lower concentration species can be effectively accumulated in the FTICR trapped ion cell, while the more abundant species are continually removed by the application of quadrupolar excitation in the form of band-limited or "colored" noise waveforms. The result is that "room" is made in the cell for lower abundance species, even during extended accumulation periods. This approach was demonstrated with mixtures of the bovine proteins, insulin, ubiquitin, and cytochrome c. For normal accumulation, the dynamic range was approximately 100. The application of selected-ion accumulation in the form of colored noise allowed the extension by 2 orders of magnitude and the detection of species of 1 x 10(-8) M concentration from a solution also containing another component at 9 x 10(-5) M. With this method, a putative new low abundance variant of bovine insulin was observed, and selected-ion accumulation and subsequent collisionally activated dissociation were used for its identification. Dipolar magnetron excitation was also explored to enhance selected-ion accumulation and was found to reduce the amount of buffer gas required for complete removal of the undesired species by a factor of 5. Further possible improvements are discussed, as are the complications due to the required balance between magnetron and cyclotron damping rates.

Amino Acid Sequence↗
PubMed1996

Cholinergic improvement of a naturally-occurring memory deficit in the young rat.

In a single-trial, passive-avoidance response (PAR) paradigm, young rats at post-natal day (PND) 16 were found to exhibit a performance deficit that diminished progressively with age. When administered prior to training, single peripheral injections of cholinomimetic drugs, either a muscarinic agonist (arecoline, pilocarpine or oxotremorine), an acetylcholinesterase inhibitor (tacrine or E2020), or nicotine, increased the response latencies for young rats to that of adult levels in a dose-dependent manner (overall dose range = 0.003 microgram/kg-10 mg/kg). Neither the cholinergic antagonists scopolamine, atropine or mecamylamine, nor a series of non-cholinergic drugs, diazepam, haloperidol, phenobarbital, pargyline, D-amphetamine, imipramine, piracetam or N-methyl-D-aspartate (NMDA) increased PAR latencies. When 0.1 mg/kg scopolamine was given to young rats prior to arecoline, the dose-effect curve for enhanced latency times was shifted to the right. Higher doses of scopolamine completely blocked the effects of arecoline. Scopolamine (0.001-1.0 mg/kg) administered subsequent to, rather than before PAR training, blocked the usual arecoline-induced enhancement of response latencies. Alternatively, consolidation could be facilitated with different doses of tacrine (0.0003-10 mg/kg). These results demonstrate that young rats fail to remember the PAR but that retention for this task can be specifically enhanced with cholinomimetic drugs.

Animals↗