A high level of strain variation within the Mycoplasma ovipneumoniae population of the UK has implications for disease diagnosis and management.

Mycoplasma ovipneumoniae is one of only two mycoplasma species associated with small ruminant disease in Britain and has been associated with an increasing number of disease outbreaks since 2002. This investigation used well-defined techniques to assess the variability of UK M. ovipneumoniae isolates, in an attempt to identify strain clusters within the population. Strains received for routine diagnosis between 2002 and 2004 were analysed using random amplified polymorphic DNA (RAPD) and pulsed field gel electrophoresis (PFGE). Of the 43 samples screened 40 RAPD Hum-1, 41 RAPD Hum-4 and 40 PFGE profiles were observed. Composite data analysis divided strains into 10 similarity clusters with SDS-PAGE and Western blotting indicating that this DNA variability is translated into a pattern of variable protein expression. In order to assess the strains isolated within flocks two sets of samples, from diverse locations, were included in this test panel. The presence of variable isolates existing on the same farm may reflect animal movement and the introduction of asymptomatic, carrier, animals where M. ovipneumoniae is already established within a flock. These findings have significant implications regarding disease diagnosis and management.

Purkinje cell degeneration and control mice: responses of single units in the dorsal cochlear nucleus and the acoustic startle response.

The cartwheel cell is the most numerous inhibitory interneuron of the dorsal cochlear nucleus (DCN). It is expected to be an important determinant of DCN function. To assess the contribution of the cartwheel cell, we examined the discharge characteristics of DCN neurons and behavioral measures in the Purkinje cell degeneration (pcd) mice, which lack cartwheel cells, and compared them to those of the control mice. Distortion product otoacoustic emissions and auditory brainstem-evoked response thresholds were similar between the two groups. Extracellularly recorded DCN single units in ketamine/xylazine-anesthetized mice were classified according to post-stimulus time histogram (PSTH) and excitatory-inhibitory response area (EI-area) schemes. PSTHs recorded in mouse DCN included chopper, pauser/buildup, onset, inhibited and nondescript types. EI-areas recorded included Types I, II, III, I/III, IV and V. There were no significant differences in the proportions of various unit types between the pcd and control mice. The pcd units had slightly lower thresholds to characteristic frequency tones; however, they had spontaneous rates, thresholds to noise, and maximum driven rates to noise that were similar to those of the control units. Pcd mice had smaller startle amplitudes, but startle latency, prepulse inhibition/augmentation and facilitation by a background tone were comparable between the two groups. From these results, we conclude that DCN function in response to relatively simple acoustic stimuli is minimally affected by the absence of the cartwheel cells. Future studies employing more complex and/or multimodal stimuli should help assess the role of the cartwheel cells.

Distortion product otoacoustic emissions in the CBA/J mouse model of presbycusis.

CBA mice do not exhibit age-related loss of auditory sensitivity or cochlear pathology until relatively late in life. Therefore, this strain is believed to be an excellent animal model for the examination of the effects of age on the cochlea. To evaluate the effects of age on outer hair cell function, 2f1-f2 distortion product otoacoustic emissions (DPOAEs) were measured for f2 between 8 and 16 kHz in CBA/J mice between 1 and 25 months of age. CBA mice exhibited mild age-related changes in DPOAE level and detection threshold at 17 months of age, and changes of 20-40 dB by 25 months of age. The DPOAE level decreased and detection threshold increased with age in a frequency-dependent manner, starting at high frequencies and eventually extending to low frequencies. The range of frequencies in which notches were observed in the DPOAE input/output (I/O) functions extended toward lower frequencies by 17 months of age. Notches were absent in the I/O functions of 25-month-old mice. The present results for a frequency range of 8-16 kHz suggest that age has modest effects on outer hair cell function in CBA mice.

Spatial organization of the reciprocal connections between the cat dorsal and anteroventral cochlear nuclei.

We are studying the interconnections between the anteroventral cochlear nucleus (AVCN) and the dorsal cochlear nucleus (DCN). Biotinylated dextran was injected into the DCN, where the best frequency of responses was also recorded. Ventrotubercular neurons in AVCN were labeled, along with cochlear nerve fibers and the axons of cells in DCN. In AVCN, a central band of labeled cochlear nerve axons and large endbulbs was labeled. Bordering this band was a 'fringe' of smaller tuberculoventral axonal endings forming pericellular nests. Most AVCN neurons projecting to DCN were stellate, elongate, or giant cells, located in the posterior division of AVCN, regardless of the DCN injection site. About 75% of the labeled AVCN cells lay within the bands of labeled cochlear nerve fibers. Another 15% were in the outer fringes on either side of these bands, while 10% were outside the bands and the fringes. These findings suggest that most AVCN neurons projecting to the DCN conform to the tonotopic map. A significant portion of the ventrotubercular neurons occupy side-bands in AVCN. Reciprocally, the tuberculoventral tract forms a robust fringe of axonal endings flanking the central bands. The neuronal and axonal bands and side-bands may underlie excitatory and inhibitory signal transformations.

Responses of neurons to click-pairs as simulated echoes: auditory nerve to auditory cortex.

When two identical sounds are presented from different locations with a short interval between them, the perception is of a single sound source at the location of the leading sound. This "precedence effect" is an important behavioral phenomenon whose neural basis is being increasingly studied. For this report, neural responses were recorded to paired clicks with varying interstimulus intervals, from several structures of the ascending auditory system in unanesthetized animals. The structures tested were the auditory nerve, anteroventral cochlear nucleus, superior olivary complex, inferior colliculus, and primary auditory cortex. The main finding is a progressive increase in the duration of the suppressive effect of the leading sound (the conditioner) on the response to the lagging sound (the probe). The first major increase occurred between the lower brainstem and inferior colliculus, and the second between the inferior colliculus and auditory cortex. In neurons from the auditory nerve, cochlear nucleus, and superior olivary complex, 50% recovery of the response to the probe occurred, on average, for conditioner and probe intervals of approximately 2 ms. In the inferior colliculus, 50% recovery occurred at an average separation of approximately 7 ms, and in the auditory cortex at approximately 20 ms. Despite these increases in average recovery times, some neurons in every structure showed large responses to the probe within the time window for precedence (approximately 1-4 ms for clicks). This indicates that during the period of the precedence effect, some information about echoes is retained. At the other extreme, for some cortical neurons the conditioner suppressed the probe response for intervals of up to 300 ms. This is in accord with behavioral results that show dominance of the leading sound for an extended period beyond that of the precedence effect. Other transformations as information ascended included an increased variety in the shapes of the recovery functions in structures subsequent to the nerve, and neurons "tuned" to particular conditioner-probe intervals in the auditory cortex. These latter are reminiscent of neurons tuned to echo delay in bats, and may contribute to the perception of the size of the acoustic space.

Responses of anteroventral cochlear nucleus neurons of the unanesthetized decerebrate cat to click pairs as simulated echoes.

To elucidate the contribution of the anteroventral cochlear nucleus (AVCN) to 'echo' processing, this study documents the responses of AVCN neurons to simulated echoes and compares them to those of auditory nerve (AN) fibers. Single unit discharges were recorded from 121 units in the AVCN of 21 unanesthetized decerebrate cats in response to click pairs with inter-click intervals ranging from 1 to 32 ms between 45 and 105 dB SPL re 20 microPa. Units were classified according to the post-stimulus time histogram (PSTH) and excitatory-inhibitory response area (EI-area) schemes. Based on their spontaneous rates (SR), units were subdivided into low- ( < 20 spikes/s) and high- ( > 20 spikes/s) SR groups. A majority of the units exhibited second-click responses whose recovery time courses were similar to those of AN fibers. These units included primary-like, chopper and onset units in the PSTH scheme and Types I, I/III and III units in the EI-area scheme. A minority of the units exhibited responses that were distinct from those of AN fibers, in that they had second-click response recovery times that were either markedly reduced or prolonged. This group of units included those with primary-like, chopper and onset PSTHs and Type I/III and III EI-areas. No significant difference was found in the second-click response among various PSTH or EI-area types. High-SR AVCN units exhibited a decrease in the second-click response with increasing level. In contrast, low-SR AVCN units showed little level-dependent change in the second-click responses. This SR-based difference was similar to that previously found among AN fibers. The present results suggest that, although a majority of AVCN units exhibit similar time courses of second-click response recovery to those of AN fibers, there do exist mechanisms in the cochlear nucleus that can substantially alter this representation. Furthermore, the difference between the second-click response recovery functions of low- and high-SR AVCN units and the consistency of this finding between AVCN and AN suggest that SR represents an important dimension for signal representation in the AVCN neurons.

Distortion product otoacoustic emissions in the C57BL/6J mouse model of age-related hearing loss.

One of the earliest histopathological changes associated with age-related hearing loss appears to be the disruption of outer hair cells (OHCs). To evaluate age-related changes in OHC function, distortion product otoacoustic emissions (DPOAEs) were recorded in the young and aging C57BL/6J mouse. Starting in young adulthood, the C57 mouse displays age-related elevation of auditory brainstem response thresholds, beginning in the high frequencies and progressing toward lower frequencies. The 2f1-f2 DPOAEs of mice between 2 and 20 months of age were examined for f2s between 8 and 16 kHz. In this octave region, the features of 2f1-f2 DPOAEs in the 2-month-old C57 mouse were comparable to those described for non-murine rodents in the literature in terms of optimum f2/f1 ratio, optimum primary level difference, input/output (I/O) function features and microstructure. It was determined that f2/f1 = 1.2 and L1-L2 = 20 dB were optimal stimulus parameters for investigation of the effects of age on C57 DPOAEs. Age-related changes in DPOAE I/O functions consisted of a right shift (i.e. increased DPOAE detection thresholds), disappearance of 'notches' and shallowing of the slopes after 8 months of age. As DPOAE I/O functions continued to shift to the right and DPOAE levels decreased with age, the appearance of I/O functions became complex to include regions of steep or shallow slopes and plateaus. The present results suggest that the age-related elevation of auditory thresholds in the C57 mice is associated with substantial progressive changes in OHC function.

N-substituted phenyltropanes as in vivo binding ligands for rapid imaging studies of the dopamine transporter.

Variously substituted phenyltropanes are proven as superb binding ligands for the dopamine transporter (DAT). In this study, we examine four N-substituted phenyltropanes which are derivatives of RTI-55 as in vivo binding ligands in mice. In this series, the methyl group on the nitrogen was replaced by a propyl (RTI-310), an allyl (RTI-311), a butyl (RTI-312), or a fluoropropyl (RTI-313) group. The in vitro binding potencies of these compounds at rat striatal DAT varied somewhat but were about 1 nM. While these compounds did not display marked selectivity for the dopamine transporter, they were more selective than RTI-55. Injection of the radiolabeled compound into mice resulted in striatal-to-cerebellar ratios that varied from about 4.5-6.5. The ratios peaked most rapidly for RTI-311 and RTI-313, at about 20 min. Pharmacological inhibition studies indicated that these compounds were binding to DATs in the striatum, as expected. These findings suggest that some compounds of this type may be excellent in vivo binding ligands for rapid imaging studies of the DAT.

Responses of auditory nerve fibers of the unanesthetized decerebrate cat to click pairs as simulated echoes.

1. To elucidate the peripheral contribution to "echo" processing in the auditory system, we examined the characteristics of auditory nerve responses to click-pair stimuli in unanesthetized, decerebrate cats. We used equilevel click pairs at peak levels of 45, 65, and 85 dB SPL re 20 microPa. The interclick intervals ranged from 1 to 32 ms. This study reports results from 78 auditory nerve fibers in 7 cats. The fibers were divided into 2 groups: 33 low- and 45 high-spontaneous rate (SR), with SRs less than and > or = 20 spikes/s, respectively. A method was introduced to quantify the second-click response, and its recovery was examined as a function of the interclick interval. 2. In general, auditory nerve fibers showed a gradual recovery of the second-click response as interclick interval was increased. Noticeable differences in the second-click response recovery functions emerged among fiber populations that were related to the SR. Low-SR fibers showed little change in the recovery functions of the second-click response as the click level was increased from 45 to 85 dB SPL. In contrast, high-SR fibers showed slower recoveries with increasing click level from 45 to 85 dB SPL. At 45 and 65 dB SPL, the recovery functions of the two SR groups were similar. At 85 dB SPL, high-SR fibers exhibited slower recovery than low-SR fibers, regardless of fiber characteristic frequency. The interclick intervals at 50% second-click response ranged from 1 to 6 ms (mean, 1.4 ms) among low-SR fibers. The interclick intervals at 50% second-click response for high-SR fibers, whereas similar to those for the low-SR fibers at 45 and 65 dB SPL, ranged from 2 to 16 ms (mean, 3 ms) for high-SR fibers, at 85 dB SPL. 3. We also examined auditory nerve compound action potentials (CAPs) evoked by click-pair stimuli for various interclick intervals and click levels. With increasing interclick interval, the amplitude of the second-click CAP increased, and with increasing level, the second-click CAP showed slower recovery. At 45 dB SPL, the recovery functions of the second-click CAP were similar to those of the high- and low-SR fibers. At higher levels, the CAP exhibited lower second-click response values than both high- and low-SR fiber populations for interclick intervals < 4-8 ms. At 85 dB SPL, as interclick interval increased, between 8 and 16 ms, the CAP second-click response converged with that of the high-SR fibers, and by 32 ms, the second-click response values were similar for the CAP, high- and low-SR fibers. 4. The present results are consistent with those of forward masking studies at the level of the auditory nerve in that both demonstrate a short-term reduction of the neural responses. However, the two results differ in that we observed that high-SR fibers exhibited slower recovery than low-SR fibers in response to click-pair stimuli, opposite of the trend observed in the forward masking studies of responses to pure-tone bursts. 5. The present results on auditory nerve fiber responses to click-pair stimuli provide a reference for comparison with responses of central auditory neurons to similar stimuli. This information should serve to elucidate the peripheral contribution to the processing of echoes in the auditory system.

Synthesis and in vivo studies of a selective ligand for the dopamine transporter: 3 beta-(4-[125I]iodophenyl) tropan-2 beta-carboxylic acid isopropyl ester ([125I]RTI-121).

A selective ligand for the dopamine transporter 3 beta-(4-iodophenyl)tropan-2 beta-carboxylic acid isopropyl ester (RTI-121) has been labeled with iodine-125 by electrophilic radioiododestannylation. The [125I]RTI-121 was obtained in good yield (86 +/- 7%, n = 3) with high radiochemical purity (> 99%) and specific radioactivity (1210-1950 mCi/mumol). After i.v. administration of [125I]RTI-121 to mice, the rank order of regional brain tissue radioactivity (striatum > olfactory tubercles > > cortex, hippocampus, thalamus, hypothalamus, cerebellum) was consistent with dopamine transporter labeling. Specific in vivo binding in striatum and olfactory tubercles was saturable, and was blocked by the dopamine transporter ligands GBR 12,909 and (+/-)-nomifensine. By contrast, binding was not reduced by paroxetine, a serotonin transporter inhibitor, or desipramine, a norepinephrine transporter inhibitor. A variety of additional drugs having high affinities for recognition sites other than the neuronal dopamine transporter also had no effect. The [125I]RTI-121 binding in striatum and olfactory tubercles was inhibited by d-amphetamine in dose-dependent fashion. Nonmetabolized radioligand represents 85% of the signal observed in extracts of whole mouse brain. Thus, [125I]RTI-121 is readily prepared, and is a useful tracer for dopamine transporter studies in vivo.

Small neurons in the vestibular nerve root project to the marginal shell of the anteroventral cochlear nucleus in the cat.

We injected biotinylated dextran amine (BDA) into marginal shell regions of the anteroventral cochlear nucleus (AVCN) of the cat. These injections led to retrograde labeling of cells including small cells (median some area = 111 micron2, equivalent diameter = 11.9 microns) in the vestibular nerve root (VNR), just ventral to an anterior part of the AVCN. This is an unexpected new finding. The cells were scattered among BDA-labeled fibers and were oriented parallel to the course of the VNR fibers. We suggest that the small neurons of the VNR might serve as second-order vestibular neurons conveying information from vestibular end organs to the cochlear nucleus (CN) and/or act as interneurons between the olivocochlear fibers in the VNR and the CN.

Spontaneous and sound-evoked discharge characteristics of complex-spiking neurons in the dorsal cochlear nucleus of the unanesthetized decerebrate cat.

1. We examined the spontaneous and sound-evoked discharge characteristics of 20 complex-spiking units recorded in the dorsal cochlear nucleus (DCN) of 15 unanesthetized, decerebrate cats. 2. The extracellularly recorded complex spikes consisted of bursts of two to five action potentials whose size gradually decreased during the burst. Complex spikes were observed both in the spontaneous and sound-evoked activity of the units in our sample. 3. The spontaneous rates (SRs) of DCN complex-spiking units ranged from 0 to 30 spikes/s. Spontaneous activity consisted of complex and simple (i.e., the common single neuronal action potential) spikes. Comparison of the SR distributions of the DCN complex-spiking units with that of a total sample of 194 DCN units (from 9 cats) suggests that the complex-spiking units tended to be in the lower half of the DCN SR distribution. 4. Sound-evoked discharges could consist of both complex and simple spikes. On the basis of their sound-driven responses, we divided the DCN complex-spiking units into two groups. The majority (15 of 20, 75%) were weakly driven by pure tones and inhibited by broadband noise. They tended to have broad response areas. Their response latencies to pure tone and noise stimuli were relatively long (10-20 ms). The recording depths of these units tended to be superficial (i.e., 10 of 15 units were located within 400 microns of the dorsal surface of the DCN). A minority (5 of 20, 25%) of the complex-spiking units were strongly driven by pure tone and broadband noise stimuli. These units had more clearly defined excitatory regions of response areas than the weakly driven units. Their response latencies to pure tone and noise stimuli were short (< 10 ms). The recording depths of these units tended to be deeper (i.e., 4 of 5 units were located at 400-700 microns) than those of the weakly driven units. 5. Intracellular recording and labeling studies of in vitro DCN slice preparations have correlated complex spikes with the superficially located cartwheel cells. Given the complex spikes of the units, many of which were located superficially, we suggest that our sample, particularly the weakly driven group of neurons, corresponds to the cartwheel cells. 6. Cartwheel cells are putative inhibitory interneurons whose axons primarily contact on the main projection neurons of DCN, the fusiform cells. The present finding of sound-evoked discharges by the superficially located complex-spiking units suggests that cartwheel cells should play a role in modifying the sound-evoked responses of the fusiform cells.

Cocaine and 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid ester and amide analogues. New high-affinity and selective compounds for the dopamine transporter.

Several 2 beta-carboxylic acid ester and amide analogues of cocaine and of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acid were prepared. The binding affinities of these compounds, and of some previously prepared analogues, at the dopamine (DA), norepinephrine (NE), and serotonin (5-HT) transporters were determined. The phenyl esters of 3 beta-(4'-methylphenyl)- and 3 beta-(4'-chlorophenyl)tropane-2 beta-carboxylic acid are highly potent and highly selective for the DA transporter. The isopropyl esters of 3 beta-(4'-chlorophenyl)- and 3 beta-(4'-iodophenyl)tropane-2 beta-carboxylic acid also possess high DA affinity and show significant DA transporter selectivity. Similarly, the phenyl and isopropyl ester analogues of cocaine are much more selective for the DA transporter than cocaine. Tertiary amide analogues of cocaine and of 3 beta-(4'-substituted phenyl)tropane-2 beta-carboxylic acids are more potent inhibitors of radioligand binding at the DA transporter than the primary and secondary amide analogues. In particular, 3 beta-(4'-chlorophenyl)tropane-2 beta-N-morpholinocarboxamide as well as the 3 beta-(4'-chlorophenyl)- and 3 beta-(4'-iodophenyl)tropane-2 beta-N- pyrrolidinocarboxamides possess high affinity and selectivity for the DA transporter. The N,N-dimethylamide cocaine analogue is the most selective cocaine amide derivative for the DA transporter. High correlation between the inhibition of radioligand binding and inhibition of uptake at the DA, NE, and 5-HT transporter was found for a selected group of analogues. Within this group, one compound, the isopropyl ester of 3 beta-(4'-iodophenyl)-tropane-2 beta-carboxylic acid, was found to be more potent in the inhibition of radioligand binding than in the inhibition of DA uptake. Taken together with its high potency and selectivity at the DA transporter, this suggests that this compound may be a lead in the development of a cocaine antagonist.

A computational model with ionic conductances for the fusiform cell of the dorsal cochlear nucleus.

A computational model of a fusiform cell of the dorsal cochlear nucleus was developed. The results of model simulations are compared with the results of in vitro experimental observations obtained by other investigators. The structure of the present model is similar to that of Hodgkin-Huxley [J. Physiol. 117, 500-544 (1952)]. The model incorporates five nonlinear voltage-dependent conductances (three potassium and two sodium types) and their associated equilibrium-potential batteries, a leakage conductance, the membrane capacitance, and a current source. Model responses were obtained under both current- and voltage-clamp conditions. When a hyper- and depolarizing current sequence was applied [Manis, J. Neurosci. 10, 2338-2351 (1990)], the cell model was able to reproduce builduplike and pauserlike discharge patterns closely resembling Manis' observations. A transient "A"-type potassium conductance in the model played a major role in generating this phenomenon. The model predicts that blocking the "A" conductance should convert a builduplike or pauserlike pattern into a sustained regular pattern. A persistent sodium conductance in the model played the main role in reproducing: Spontaneous regular discharge; a discharge after a long latency under a long small (+0.025 nA) current; and nonlinear voltage-current characteristics with positive currents. Usefulness of the model can be seen as follows: (1) Several sets of experimental observations can be integrated into a common framework; (2) possible roles of different ionic conductances postulated to be present in the cell can be inferred by observing the model behavior with the conductances intact or blocked; and (3) time courses of ionic currents and conductance values obtained from the model under current- and voltage-clamp conditions can serve as predictions to be tested in future experimental studies.

Discharge suppression in the silent interval preceding the tone burst in pause-build units of the dorsal cochlear nucleus of the unanesthetized decerebrate cat.

A recent intracellular study of dorsal cochlear nucleus (DCN) neurons in vitro by Manis [P. B. Manis, J. Neurosci. 10, 2338-2351 (1990)] suggests that the expression of the pause-build discharge pattern is in large part dependent on hyperpolarization of their membrane potentials in a period just preceding a depolarizing stimulus ("hyperpolarization conditioning" hypothesis). Our examination of the activity of a sample of pause-build units (n = 72) revealed suppression of discharge activity during a time window of the silent interstimulus interval (SII) just preceding the tone burst relative to the spontaneous rate in 74% of all units. The discharge suppression of a subset of DCN pause-build units in the SII satisfies a requirement of the "hyperpolarization conditioning" hypothesis, and thus supports the hypothesis.

Enantiomeric N-substituted N-normetazocines: a comparative study of affinities at sigma, PCP, and mu opioid receptors.

The optical antipodes of N-allyl-N-normetazocine (2; SKF 10047, NANM) were the original compounds used for the classification of the sigma receptor as distinct from other receptors such as the PCP (NMDA), opioid, and dopamine receptors. Later studies showed that (+)-N-(dimethylallyl)-N-normetazocine [(+)-4, (+)-pentazocine] was more potent and selective for the sigma receptor. In order to gain additional structure-activity relationship information, several N-substituted N-normetazocine analogs were prepared and evaluated for their sigma-1 ([3H]-(+)-3-PPP or [3H]-(+)-pentazocine), PCP ([3H]TCP), and mu opioid ([3H]DAMGO) receptor binding affinities. (+)-N-Benzyl-N-normetazocine [(+)-10)] possessed subnanomolar affinities for the sigma site, Ki = 0.67. The analog (+)-10 showed greater than 14,000- and 2400-fold selectivity, respectively, for the sigma receptor relative to the PCP and mu opioid receptors. The N-substituted N-normetazocines were enantioselective for the sigma site. The (+)-N-benzyl analog, (+)-10, showed a 55-fold selectivity relative to (-)-10. Analysis of the data also revealed that (+)-normetazocine [(+)-1] [Ki = 30 nM] possessed the highest affinity for the PCP receptor. However, (+)-metazocine [(+)-5] (Ki = 41 nM) was the most selective compound for the PCP receptor relative to the sigma (51-fold) and mu opioid (greater than 200-fold) sites.

Analysis of temporal discharge characteristics of dorsal cochlear nucleus neurons of unanesthetized decerebrate cats.

1. We examined the mean and standard deviation (SD) of interspike intervals (ISI) and the coefficient of variation (CV, the ratio of SD of ISI to mean ISI) of ISIs versus time to study discharge regularity of units in the dorsal cochlear nucleus (DCN) of decerebrate unanesthetized cats. The units were characterized by the use of both poststimulus time histograms (PSTH) and excitatory-inhibitory area (EI-area) schemes. We present results of a systematic examination of all of 87 DCN pause-build units recorded in this study. In addition, we present examples of chopper subtypes of the DCN. 2. A major finding of this study is that a majority of the pause-build units in the present sample exhibited regular discharges in response to short (50 ms) tone bursts at characteristic frequency (CF), as revealed by CVs less than 0.5. A predominant portion of pause-build units (80% of 44 units with sufficient number of spikes for CV analysis) exhibited mean CVs less than 0.5 in the 20- to 39.9-ms time window in response to 50-ms tone burst at CF at 60 dB SPL re 20 microPa; 39% of the 44 units exhibited highly regular discharges (mean CV less than 0.35). During the onset (2-14.9 ms) time window, 77% (of 53 units with sufficient number of spikes for CV analysis) of the units had mean CVs less than 0.5, and 55% were less than 0.35. 3. In our sample of 87 DCN pause-build units, 59% had spontaneous rates (SR) greater than 15 spikes/s. The pause-build units of the present sample were distributed across four different EI-area types: III (51%), I/III (25%), II (15%), or IV (9%). In the 20- to 39.9-ms time window, the pause-build units with mean CVs less than 0.35 were exclusively of types III and I/III. All of the above EI-area types were represented in the lowest CV group for the 2- to 14.9-ms window. 4. The mean ISIs of DCN pause-build units typically showed a decrease during the first 20-25 ms of the response to 50-ms CF tone bursts, and stable mean ISIs in the latter half, when off-discharges were absent. In the presence of off-discharges, the mean ISIs decreased further in the last 5-10 ms of the response.(ABSTRACT TRUNCATED AT 400 WORDS)

Synthesis, ligand binding, QSAR, and CoMFA study of 3 beta-(p-substituted phenyl)tropane-2 beta-carboxylic acid methyl esters.

A series of 3 beta-(p-substituted phenyl)tropane-2 beta-carboxylic acid methyl esters (2) were synthesized and found to possess high affinity for the cocaine binding site in rat striatum. The p-chloro (2c) and p-iodo (2n) compounds, which were the most potent analogues prepared, were found to be 85 and 78 times more potent than (-)-cocaine. The p-bromo (2m) and p-methyl (2d) were also 56 and 60 times more potent than cocaine. QSAR and CoMFA studies were conducted to correlate binding affinity of the cocaine analogues with their structural features. Whereas the QSAR study gave relatively low correlations, the CoMFA study gave a correlation with high predictive value.