Anti-ADDL antibodies differentially block oligomer binding to hippocampal neurons.

Abeta-derived diffusible ligands (ADDLs) are abundant in AD brain, bind to hippocampal neurons and induce deficits in rodent cognition. To further investigate ADDL binding to neurons and identify antibodies that block this association, a panel of anti-Abeta and anti-ADDL antibodies was characterized for their ability to immuno-detect neuronally bound ADDLs and attenuate the binding of ADDLs to neurons. The results showed that anti-Abeta and anti-ADDL antibodies were able to abate ADDLs binding to hippocampal neurons, but to different degrees. Quantitative assessment of binding showed that one antibody, ACU-954 was markedly more effective at blocking ADDL binding than other antibodies assessed. ACU-954 was also found to block ADDL binding to hippocampal slice cultures, attenuate the ADDL-induced loss of dendritic spines and detect "natural ADDLs" in human AD tissue. These results demonstrated that antibodies that bind to and block ADDL binding to neurons can be identified, although their efficacy is conformationally specific since it is not readily apparent or predictable based on the core linear epitope or affinity for monomeric Abeta.

Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels.

During ischemic stroke, neurons at risk are exposed to pathologically high levels of intracellular calcium (Ca++), initiating a fatal biochemical cascade. To protect these neurons, we have developed openers of large-conductance, Ca++-activated (maxi-K or BK) potassium channels, thereby augmenting an endogenous mechanism for regulating Ca++ entry and membrane potential. The novel fluoro-oxindoles BMS-204352 and racemic compound 1 are potent, effective and uniquely Ca++-sensitive openers of maxi-K channels. In rat models of permanent large-vessel stroke, BMS-204352 provided significant levels of cortical neuroprotection when administered two hours after the onset of occlusion, but had no effects on blood pressure or cerebral blood flow. This novel approach may restrict Ca++ entry in neurons at risk while having minimal side effects.

Differential effects of coadministration of fluoxetine and WAY-100635 on serotonergic neurotransmission in vivo: sensitivity to sequence of injections.

Serotonin 5-HT(1A) receptor antagonists potentiate the effects of serotonin reuptake inhibitors on extracellular serotonin levels in a variety of brain regions. These effects are quite variable, however, with reports indicating potentiations of anywhere from 100-1900%. One factor that might impact the magnitude of such potentiations is the timing of administration of the two agents; reports in which the reuptake inhibitor is given prior to the serotonin receptor antagonist consistently report larger potentiations than reports in which the antagonist is given first. To test this relationship directly, microdialysis and electrophysiology studies were performed to assess the magnitude of increase in extracellular serotonin and changes in cellular activity produced by the serotonin reuptake inhibitor fluoxetine and the 5-HT(1A) receptor antagonist WAY-100635 under various dosing regimens. In microdialysis studies, when WAY-100635 (0.5 mg/kg s.c.) was administered 80 min after fluoxetine (10 mg/kg i.p.) the increase in serotonin was more than twice that observed when the compounds were coadministered. In electrophysiology studies in vivo, WAY-100635 reversed the depression of cell firing produced by fluoxetine when administered 30 min after fluoxetine, but when the two compounds were coadministered, a depression in firing rate was observed comparable to that produced by fluoxetine alone. In contrast, slice recording studies showed that WAY-100635 blocked the effects of fluoxetine regardless of the order of administration. These results indicate that fluoxetine and WAY-100635 can interact in a fashion not predicted by the currently accepted model. It is likely that neuronal circuitry outside of the raphe nuclei underlies this relationship.

An instrumental method for long-term continuous REM sleep deprivation of neonatal rats.

STUDY OBJECTIVES: The present study describes a new method for instrumental REM sleep deprivation (RSD) of neonatal rats. DESIGN: In the new method, an experimental neonatal rat and a yoked control neonatal rat were singly housed in a small plexiglass chamber which was divided into two separate units by a vertical wall. The floor of the housing chamber was attached to the platform of a standard laboratory test tube shaker. EEG and EMG electrodes were implanted by the soft head plug method which permitted continuous, long-term polysomnography. EEG and EMG signals were sent to a computer that was programmed to turn on the shaker for 5 seconds whenever the experimental rat entered REM sleep. SETTING: NA PATIENTS: NA INTERVENTIONS: NA RESULTS: The shaking of the chamber usually terminated REM sleep by entry to slow-wave sleep or wake. Amount of RSD depended on the shaker's oscillation speed. At higher speed the method reduced REM sleep by more than 80%. CONCLUSIONS: Thus, the new instrumental method of RSD can be used to study developmental functions of neonatal REM sleep. In particular, the instrumental method can test the hypothesis that in rats neonatal RSD produces the adult depressogenic effect of neonatally administered clomipramine.

Ontogeny of REM sleep in rats: possible implications for endogenous depression.

Nine neonatal Long-Evans rats had continuous (24 h/day) polysomnography for 2 weeks, from age 14 days through age 27 days. A new finding was that six more or less independent measures of REM sleep occurrence decreased in parallel from age 14 days to age 27 days. The measures included parallel decreases of four measures of 24-h REM duration (tonic REM sleep, phasic REM sleep, mean REM period duration, and number of REM periods) along with parallel increases of two measures of REM delay (REM latency and percent of nonsleep onset REM periods). A parsimonious interpretation of the correlated changes is that a common developmental REM sleep inhibitory process accounts for the six parallel changes over time. This hypothesis can be tested empirically by studying inhibitory processes that operate on the pedunculopontine tegmental/latero-dorsal tegmental nuclei, the generators of REM sleep. The study also noted that compared with (same species) normal adults, endogenous depressives had the same distinctive REM sleep characteristics as neonatal rats. The similarity suggests that an underdeveloped, relatively weak REM sleep inhibitory process may account for the REM sleep peculiarities of endogenous depression. This hypothesis can be tested in adult rats made "depressed" by neonatal treatment with antidepressant drugs. Thus, the ontogeny of REM sleep suggests a developmental process that may be altered in humans predisposed to endogenous depression, and may account for the (life-long) REM sleep abnormalities of the disorder.

The augmentation hypothesis for improvement of antidepressant therapy: is pindolol a suitable candidate for testing the ability of 5HT1A receptor antagonists to enhance SSRI efficacy and onset latency?

The development of selective serotonin reuptake inhibitors (SSRIs) provided a major advancement in the treatment of depression. However, these drugs suffer from a variety of drawbacks, most notably a delay in the onset of efficacy. One hypothesis suggests that this delay in efficacy is due to a paradoxical decrease in serotonergic (5-HT) neuronal impulse flow and release, following activation of inhibitory presynaptic 5-HT1A autoreceptors, following acute administration of SSRIs. According to the hypothesis, efficacy is seen only when this impulse flow is restored following desensitization of 5-HT1A autoreceptors and coincident increases in postsynaptic 5-HT levels are achieved. Clinical proof of this principal has been suggested in studies that found a significant augmenting effect when the beta-adrenergic/5-HT1A receptor antagonist, pindolol, was coadministered with SSRI treatment. In this article, we review preclinical electrophysiological and microdialysis studies that have examined this desensitization hypothesis. We further discuss clinical studies that utilized pindolol as a test of this hypothesis in depressed patients and examine preclinical studies that challenge the notion that the beneficial effect of pindolol is due to functional antagonism of the 5-HT1A autoreceptors.

Cognition-enhancing drugs increase stimulated hippocampal theta rhythm amplitude in the urethane-anesthetized rat.

Synchronous hippocampal electroencephalographic activity occurring in a frequency range of 3 to12 Hz (i.e., hippocampal theta rhythm) has been associated with mnemonic processes in vivo. However, this link is tenuous and theta rhythm may be secondary to processes that underlie mnemonic function. If theta rhythm is associated with mnemonic or cognitive function, cognition-enhancing drugs should enhance theta rhythm regardless of their primary biological target. In the current study, we evaluated several drugs that were shown to have cognition-enhancing properties in preclinical behavioral models and that vary with respect to their primary biological target: 1) the nootropic piracetam (250 and 500 mg/kg); 2) the small-conductance calcium-activated potassium-channel blocker apamin (0.1 and 0.4 mg/kg); and 3) the acetylcholinesterase inhibitor donepezil (0.1-10.0 mg/kg). All of the cognition-enhancing drugs produced dose-dependent increases in hippocampal theta rhythm amplitude elicited by stimulation of the brainstem reticular formation at doses that did not affect peak theta frequency in the urethane-anesthetized rat. These increases were reversed by the muscarinic receptor antagonist scopolamine, suggesting a common final cholinergic action of these compounds. The use-dependent N-methyl-D-aspartate antagonist dizocilipine maleate and scopolamine reduced theta amplitude (both) and frequency (dizocilipine maleate only). These data demonstrate that hippocampal theta rhythm is sensitive to cognition-modulating compounds, suggesting that theta rhythm may be closely associated with cognitive function.

Rat strain differences in the ability to disrupt sensorimotor gating are limited to the dopaminergic system, specific to prepulse inhibition, and unrelated to changes in startle amplitude or nucleus accumbens dopamine receptor sensitivity.

Previous studies indicate that a variety of pharmacological agents interfere with the prepulse inhibition of the acoustic startle (PPI) response including phencyclidine (PCP), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), amphetamine, and apomorphine. Strain differences have been observed in the ability of apomorphine to disrupt PPI, although the degree to which these strain differences occur after administration of nondopaminergic drugs or the degree to which differences can be observed in other models of dopamine (DA) receptor activation has not been elucidated. The present study tested the effects of apomorphine, amphetamine, 8-OH-DPAT, and PCP on PPI in the Sprague Dawley and Wistar rat strains. Because apomorphine disrupts PPI via activation of DA receptors in the nucleus accumbens, apomorphine-induced hyperlocomotion, also a behavioral model of nucleus accumbens DA receptor activation, was measured in both rat strains. Administration of PCP or 8-OH-DPAT attenuated PPI in both strains, whereas apomorphine and amphetamine only attenuated PPI in Wistar rats. The ability of apomorphine to increase motor activity in the absence of a startle-eliciting stimulus was similar in the two strains, as was apomorphine-induced hyperlocomotion. A time course analysis of the effects of apomorphine on startle response in Sprague Dawley rats found that changes in the magnitude of PPI followed changes in basic startle amplitude. Similarly, no apomorphine-induced attenuation of PPI was observed in Sprague Dawley rats after 6-OHDA-induced DA receptor supersensitivity in the nucleus accumbens. These data suggest a dissociation between the effects of DA receptor agonists in PPI and other behavioral models of DA receptor activation.

Brainstem carbachol injections in the urethane anesthetized rat produce hippocampal theta rhythm and cortical desynchronization: a comparison of pedunculopontine tegmental versus nucleus pontis oralis injections.

Previous research has demonstrated that brainstem injections of acetylcholine agonists (e.g., carbachol) produced electrophysiological indicators of rapid-eye-movement (REM) sleep in the cat. Recent reports now indicate that this phenomenon may hold true for rats as well. Relatively few reports, however, have examined the effect of these injections on REM indicators in the anesthetized rat, a preparation useful for elucidating underlying neurobiological mechanisms controlling REM sleep processes. The present study compared the effect of injections of carbachol (5 micrograms in 250 nl) into the pedunculopontine tegmental nucleus (PPTg) or the nucleus pontis oralis (NPO) on two tonic indicators of REM sleep in the urethane-anesthetized rat. Namely, changes in the hippocampal EEG and in the cortical EEG. Carbachol injections into either site produced a change in both the hippocampal EEG and cortical EEG to a REM-like state at short latencies. The length of these changes (duration of effect), however, was site-dependent. Thus, PPTg carbachol injections induced significantly longer lasting effects in both the hippocampal and cortical EEG than did NPO injections. The results that brainstem carbachol injections in rats, as in cats, may provide a useful model for investigating tonic REM sleep processes.

Antidepressant-like effects of 5-hydroxytryptamine1A receptor agonists on operant responding under a response duration differentiation schedule.

A response duration differentiation schedule, where rats depress a lever for between 1.0 and 1.3 s to obtain a food reward, provides a useful measure for detecting antidepressant activity. It is known that 5-hydroxytryptamine1A (5-HT1A) receptor agonists exhibit antidepressant-like activity in multiple animal models of depression, however, compounds selective for this receptor have not been tested in this model to date. Thus, the present study sought to determine the effect of the full 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the partial 5-HT1A agonist, buspirone, on responding in the response duration differentiation task. The effects of these drugs were compared to the effects of the non-specific serotonergic agonist, lysergic acid diethylamide (LSD); the phenothiazine, chlorpromazine; the atypical antidepressant, trazodone; and the non-selective 5-HT1A antagonists, propranolol and alprenolol. It was found that propranolol, trazodone, and both the full (8-OH-DPAT) and partial (buspirone) 5-HT1A agonists produced increases in the mean response duration, which is typical of antidepressant activity. By contrast, with the exception of propranolol, compounds lacking antidepressant efficacy (e.g. chlorpromazine, LSD and alprenolol), failed to produce increases in mean response durations. Further, the effects of 8-OH-DPAT were inhibited by pretreatment with the 5-HT1A antagonist, (-)-alprenolol (3.0 and 30.0 mg/kg i.p.). The results of this study provide further support for the suggestion that 5-HT1A agonists may be useful for the treatment of clinical depression and that these effects are specifically mediated by 5-HT1A receptors.

Decreased dorsal raphe nucleus neuronal activity in adult chloral hydrate anesthetized rats following neonatal clomipramine treatment: implications for endogenous depression.

Although the biological cause of endogenous depression is unknown, one commonly held hypothesis proposes that depression results, in part, from decreased central serotonin (5-HT) neurotransmission. Previous research found that clomipramine (CLI) treatment of neonatal rats produced, in adult rats, a variety of behavioral and physiological dysfunctions resembling those found in human endogenous depression. It was later reported that adult CLI-treated rats exhibited a decreased discharge of 5-HT neurons in the dorsal raphe nucleus (DRN) compared with control rats. This finding, however, was not replicated in subsequent studies that detected differences in DRN receptor function. Several factors were identified that may have contributed to the inability of the latter studies to detect CLI vs. control differences in DRN firing rates and interspike interval histograms (ISIH). Among these were the anesthetic used, the age at which the adult rats were tested, and the location of the recording electrode. The present study controlled these variables by using chloral hydrate anesthesia, testing 'depressed' rats at both 2 and 3 months of age, and verifying electrode location using standard histological techniques. We found that DRN unit firing in 'depressed' rats (0.417 +/- 0.071 spikes/s) was less than half that of 'non-depressed' control rats (i.e. neonatal saline treatment 0.968 +/- 0.12 spikes/s). Additionally, ISIH's indicated that, in addition to the lower firing rate of 5-HT DRN neurons, adult CLI rats had an altered temporal discharge pattern of these neurons. Thus, the ISIH of 5-HT DRN neurons recorded from CLI rats was characterized by a flat distribution suggesting random temporal firing patterns. These results confirm previous findings of decreased DRN firing rates and flat ISIH's in 'depressed' rats and extend previous findings to younger rats of a different strain. The results thereby lend support to the hypothesis of a role for decreased central 5-HT as a substrate for the behavioral deficiencies observed in endogenous depression and suggest that these deficiencies may also result, in part, from a random, rather than orderly, temporal pattern of discharge in these neurons.

Medial septal unit firing characteristics following injections of 8-OH-DPAT into the median raphe nucleus.

Extracellular single-unit recording techniques were used to examine the firing characteristics of neurons in the medial septum/diagnol band of Broca complex (MS/DB) following injections of the 5-HT1A agonist, 8-OH-DPAT, into the median raphe nucleus (MRN) of urethane-anesthetized rats. It had previously been shown that MRN injections of 8-OH-DPAT produce hippocampal theta rhythm. Injections of 8-OH-DPAT into the MRN produced a change in firing characteristics of MS/DB neurons from an irregular discharge to a pattern of rhythmical bursting in synchrony with hippocampal theta rhythm. Cross-correlational and coherence analyses demonstrated that the rhythmical firing pattern of MS/DB neurons strongly correlated with rhythmical fluctuations in the hippocampal EEG during periods of hippocampal theta produced by 8-OH-DPAT injections, but not during baseline conditions (i.e. hippocampal desynchronization). The results suggest that MRN control of the hippocampal EEG is modulated by the MS/DB. Serotonergic projections from the MRN to the MS/DB may normally act to inhibit the rhythmical bursting of MS/DB neurons, thereby producing hippocampal desynchronization. Suppression of MRN 5-HT neurons by MRN injections of 8-OH-DPAT would disinhibit MS/DB neurons, allowing them to burst rhythmically and thereby produce hippocampal theta rhythm.

sigma2 Site-mediated inhibition of electrically evoked guinea pig ileum longitudinal muscle/myenteric plexus contractions.

Functional and binding studies were performed in order to characterize the relative efficacy and affinity of a number of compounds that bind to sigma sites. The ability of sigma site ligands to inhibit electrically evoked contraction of the guinea pig ileum longitudinal muscle/myenteric plexus preparation was compared to the affinities of these compounds for sigma1 sites (assessed by displacement of [3H](+)-pentazocine) and sigma2 sites (assessed by displacement of [3H]1,3-di-o-tolylguanidine (DTG) in the presence of 5 microM dextromethorphan). It was shown that the rank order of potencies for suppression of electrically evoked contractions of guinea pig ileum perfectly matched the rank order of affinities of these compounds for the sigma2 binding site, while correlating poorly with the sigma1 binding site. In addition, no significant correlations were found between the efficacy of the tested compounds to inhibit contraction of the guinea pig ileum preparation and previously reported affinities for muscarinic, dopamine D2 or MK-801 binding sites. Thus, the present study represents the first functional bioassay selectively sensitive to agents interacting with the sigma2 receptor subtype binding site, and provides a means with which to further elucidate the functional role of sigma2 sites.

Peripheral nicotine administration increases rubral firing rates in the urethane-anesthetized rat.

The presence of cholinergic input to the red nucleus (RN) in the cat is demonstrated by choline acetyltransferase (ChAT) staining; however, it is unclear what effect this cholinergic input has on neurons of the RN. Further, the presence of cholinergic neurons in the rat RN has been the subject of controversy. The present study examined the effects of intravenous injections of S(-)-nicotine tartrate (62.5-250 micrograms/kg) on the firing rate of rubral neurons. Dose-dependent increases in firing rates were observed which were blocked by pre-treatment with the nicotinic antagonist, mecamylamine hydrochloride. Smaller consistent increases were found after pretreatment with 62.5 micrograms/kg or 125 micrograms/kg doses of nicotine than were observed following the initial administration, suggesting a desensitizing response typical of nicotinic receptors.

Injections of muscimol into the median raphe nucleus produce hippocampal theta rhythm in the urethane anesthetized rat.

It has previously been shown that serotonergic [5-hydroxytryptamine (5-HT)] neurons of the median raphe nucleus (MR) are critically involved in the control of the hippocampal electroencephalogram (EEG). Activation of MR 5-HT neurons desynchronizes the hippocampal EEG, whereas inhibition of MR 5-HT activity produces hippocampal theta rhythm. The MR contains an intrinsic population of gamma-aminobutyric acid (GABA) containing neurons that synapse on 5-HT cells of the MR. The present study examined the effects on the hippocampal EEG of injections of the GABAA agonist muscimol hydrobromide into the MR. Low doses of muscimol (0.5 microgram) produced hippocampal theta rhythm at a mean latency of 6.81 min and for a mean duration of 23.6 min. Higher doses (1.0 microgram and 3.0 micrograms, respectively) produced theta at mean latencies of 2.24 min and 3.2 min and for mean durations of 31.84 min and 24.88 min. Injections of muscimol into regions adjacent to the MR generated theta at significantly longer latencies or were without effect. The present results indicate that MR injections of muscimol produce theta by inhibiting the activity of MR 5-HT neurons. It is concluded that MR GABAergic systems, via their influence on MR 5-HT cells, serve an important role in the control of the hippocampal EEG.

The supramammillary nucleus: is it necessary for the mediation of hippocampal theta rhythm?

Recent evidence suggests that the supramammillary nucleus of the posterior hypothalamus serves as an important relay in a brainstem to septum/hippocampus pathway involved in the generation of hippocampal theta rhythm. In order to examine the role of the supramammillary nucleus as a possible relay/mediator of hippocampal theta rhythm, electrolytic lesions and procaine injections were administered to the supramammillary nucleus of freely moving and urethane-anesthetized rats, respectively. In the urethane-anesthetized rat, it was found that procaine injections attenuated both the frequency and amplitude of theta rhythm elicited by stimulation of the pontine reticular formation. These data suggest that the pontine reticular elicitation of hippocampal theta rhythm is mediated through connections with the supramammillary nucleus. However, it was found that lesions of the supramammillary nucleus failed to produce significant changes in the hippocampal electroencephalogram of freely moving animals. Several explanations concerning this apparent discrepancy are discussed. The most compelling is that multiple brainstem to septum/hippocampus pathways may serve to generate or facilitate the generation of theta rhythm in the freely moving animal. The present report demonstrates that the supramammillary nucleus plays a questionable role in the mediation of hippocampal electroencephalogram signals which are thought to be important for mnemonic processes.

Separation of hippocampal theta dipoles by partial coherence analysis in the rat.

In order to separate the effect of different theta generators in the hippocampus and to characterize the pattern of relationships between them, in this study, we calculated the coherence that remains between EEG signals, recorded (1) in the stratum oriens of the CA1 region and (2) close to the hippocampal fissure in the dentate gyrus of the right or left hippocampus, after the variations, common also for a third recording site is eliminated (partialization). We found that in both anesthetized and freely moving rats, there is a selective high correlation (coherence) between theta rhythmic activities of contralateral homonymous sites of the hippocampus. The coherence between field potentials recorded in ipsilateral superficial and deep layers was eliminated when allowance was made for any of the contralateral hippocampal recordings. On the other hand, coherence between contralateral homonymous theta dipoles did not decrease when partialized by a heteronymous hippocampal EEG signal. The present results support earlier findings on multiple hippocampal theta dipoles and indicate that they can be separated using partial coherence analysis. The left and right superficial and deep dipoles oscillate as if they formed two separate systems one extending over the superficial CA1 layers on both sides and the other consisting of the left and right deep hippocampal theta dipoles. The results also suggest an important role of the commissural projections in interhemispheric theta synchronization.

Injections of excitatory amino acid antagonists into the median raphe nucleus produce hippocampal theta rhythm in the urethane-anesthetized rat.

The median raphe nucleus (MR) exerts a pronounced desynchronizing influence on the hippocampal EEG. MR stimulation disrupts theta, while MR lesions produce constant uninterrupted theta. The MR receives pronounced excitatory amino acid (EAA)-containing afferents that have been implicated in several MR-mediated behaviors. The present study examined the effects on the hippocampal EEG of MR injections of the following EAA antagonists in the urethane-anesthetized rat: 2-amino-7-phosphonoheptanoate (AP-7), dizocilpine maleate (MK-801), and gamma-glutamyl-aminomethylsulfonic acid (GAMS). MR injections of the competitive (AP-7) and non-competitive (MK-801) N-methyl-D-aspartic acid (NMDA) receptor antagonists produced theta at short latencies (2.86 min; 4.02 min, respectively) and for long durations (116.1 min; 66.8 min, respectively). It was further shown that the theta-eliciting effects of AP-7 injections could be reliably and temporarily reversed with MR injections of NMDA. MR injections of the kainate/quisqualate receptor antagonist (GAMS) also produced theta at relatively short latencies (6.5 min) and for long durations (60.5 min) indicating that EAA effects on the MR are not NMDA receptor specific. Injections of each of the foregoing EAA antagonists into regions of the brainstem adjacent to the MR including the dorsal raphe nucleus and the medullary or pontine reticular formation generated theta at very long latencies or were without effect. The present findings indicate EAA afferents to the MR normally exert an excitatory influence on the MR in its desynchronization of the hippocampal EEG, whereas the removal of EAA inputs to MR produces the opposite: a reduction of MR activity and hence the elicitation of theta.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological suppression of the median raphe nucleus with serotonin1A agonists, 8-OH-DPAT and buspirone, produces hippocampal theta rhythm in the rat.

The effects on the hippocampal electroencephalogram of microinjections of procaine hydrochloride and the serotonin1A agonists, 8-OH-DPAT and buspirone, into the median raphe nucleus were examined in the urethane anesthetized rat. Injections of procaine, 8-OH-DPAT or buspirone into the median raphe nucleus produced a change in the hippocampal electroencephalogram from a spontaneous desynchronized pattern to a synchronized pattern (theta rhythm) within short latencies and for long durations post-injection. Procaine was shown to elicit theta at a mean latency of 52 s and for a mean duration of 21.75 min; buspirone at a mean latency of 2 min and for a mean duration of 34.5 min. A dose dependent relationship was observed between 8-OH-DPAT injections and latencies but not durations. Small doses (0.5 micrograms) of 8-OH-DPAT produced theta at a mean latency of 1.33 min and large doses (3.0 micrograms) at a mean latency of 1.17 min. 8-OH-DPAT injections generated theta for a mean duration of 62 min. Injections of each of these substances into structures dorsal, lateral or rostrocaudal to the median raphe (dorsal raphe nucleus, pontine reticular formation, caudal linear nucleus or raphe pontis, respectively) failed to generate theta or in a few cases produced theta at very long latencies (> 24 min). Saline injections in the median raphe nucleus or control structures were without effect. The demonstration that agents injected into the median raphe nucleus that inhibit its activity (procaine and serotonin1A agonists) produce theta indicate that serotonin-containing median raphe neurons normally suppress theta or are involved in the control of hippocampal desynchronization. The present findings are consistent with previous work showing that median raphe nucleus stimulation desynchronizes the hippocampal electroencephalogram and that median raphe nucleus lesions produce constant theta, but are at odds with the proposal that serotonergic mechanisms may play a role in the generation of the theta rhythm.

Effects of reinforcement history on responding under progressive-ratio schedules of reinforcement.

The effects of experimental history on responding under a progressive-ratio schedule of reinforcement were examined. Sixteen pigeons were divided into four equal groups. Groups 1 to 3 were trained to peck a key for food under a fixed-ratio, variable-ratio, or differential-reinforcement-of-low-rate schedule of reinforcement. After training, these pigeons were shifted to a progressive-ratio schedule, later were shifted back to their original schedule (with decreased rates of reinforcement), and finally were returned to the progressive-ratio schedule. Pigeons in Group 4 (control) were maintained on the progressive-ratio schedule for the entire experiment. To test for potential "latent history" effects, pigeons responding under the progressive-ratio schedule were injected with d-amphetamine and given behavioral-momentum tests of prefeeding and extinction. Experimental histories affected responding in the immediate transition to the progressive-ratio schedule; response rates of pigeons with variable-ratio and fixed-ratio histories were higher than rates of pigeons with differential-reinforcement-of-low-rate and progressive-ratio-only histories. Pigeons with differential-reinforcement-of-low-rate histories, and to a lesser degree pigeons with variable-ratio and fixed-ratio histories, also had shorter postreinforcement pauses than pigeons with only a progressive-ratio history. No consistent long-term effects of prior contingencies on responding under the progressive-ratio schedule were evident. d-Amphetamine and resistance-to-change tests failed to reveal consistent latent history effects. The data suggest that history effects are sometimes transitory and not susceptible to latent influences.