Morphine-naloxone interactions: a role for nonspecific morphine excitatory effects in withdrawal.

The opiate antagonist naloxone precipitates withdrawal when given either 15 minutes after or 1 minute before a single injection of morphine in drug-naïve mice. We propose that withdrawal signs arise from a synergistic mixture of excitatory influences that are direct (agonistic action on nonspecific opiate receptors) and indirect (sensory and affective disorders, stress, hormonal and neurotransmitter dysfunction, and so forth). The predominant effects during precipitated withdrawal are assumed to be direct, whereas during abstinence in tolerant animals they are indirect.

Evidence against a role of acetaldehyde in electroencephalographic signs of ethanol-induced intoxication.

Acetaldehyde, the proximate metabolite of ethanol, when injected intravenously in rats produced electroencephalogram (EEG) changes similar to those observed after ethanol administration; that is, low doses activated the cortical EEG and higher doses caused activation followed by synchronization. However, when acetaldehyde was administered as a continuous infusion to simulate production of ethanol-derived acetaldehyde, only synchronization occurred, and then only at the higher doses. At low infusion dosage when the EEG was unaffected, concentrations of acetaldehyde in the blood were equal to or greater than those which occur during intoxication. Thus, acetaldehyde by itself cannot account for ethanol-induced EEG synchronization.

Drug effects on active immobility responses: what they tell us about neurotransmitter systems and motor functions.

The literature reviewed indicates that active immobility can be promoted by systemic injections of various neurotransmitter systems, as follows: (1) Dopaminergic blockade of both D1 and D2 receptor subtypes. (2) Cholinergic agonism of both muscarinic and nicotinic receptors. (3) Noradrenergic agonism of both alpha-1 and alpha-2 receptors (but these agonists may interfere with haloperidol- and reserpine-induced catalepsy). (4) GABA agonism. (5) Histamine agonism, particularly at the H1 receptor. (6) Opiate agonism, including action of many endogenous opiate peptides, particularly those affecting mu and delta receptors. (7) Agonism by certain other peptides (neurotensin, cholecystokinin). Among the major interactions of neurotransmitter systems that regulate immobility, are the following: (1) Cholinergic-dopaminergic (cholinolytics disrupt catalepsy of dopaminergic blockade and dopaminergic agonists tend to disrupt cholinomimetic catalepsy). (2) Opiate-induced catalepsy is antagonized by the dopamine agonist, apomorphine, but is enhanced by amphetamine. It is also antagonized by certain alpha-2 adrenergic agonists, while it does not seem to be antagonized by anticholinergics. (3) Numerous other interactions have been reported, involving opiates and MSH, serotonin and dopamine mimetics, serotonin and ketamine, GABA and neuroleptics, neurotensin and anticholinergics and histamine. The significance of the multiple neurotransmitter systems is unknown. One possible explanation is that the various neurotransmitter systems participate in mediating the sensory inputs that are involved in triggering immobility and regulate the higher-order limbic and basal ganglia processing reactions that engage a final motor output pathway from the brainstem. The brain is assumed to contain two sets of systems, each with its own, or possibly overlapping, set of neurotransmitter systems, that promote either active immobility or locomotion. The systems reciprocally inhibit each other. Another view, not mutually exclusive, is that output from the locomotor-promoting system provides a negative feedback, via the active immobility pathways, to act as a "brake" on movement, while at the same time maintaining the muscular tonus that is characteristic of active immobility.

Behavioral arrest: in search of the neural control system.

Scientists have spent hundreds of years trying to understand how the brain controls movement. Why has there been so little interest in knowing how the brain STOPS movement? This review calls attention to behavioral phenomena in which an animal or human undergoes temporary total-body arrest of movement, that is, behavioral arrest (BA). These states can be actively induced by visual stimuli, by body and limb manipulations, and by drugs. Historically, these states have been considered as unrelated, and their literature does not cross-connect. What is known about the causal mechanisms is scant, limited mostly to implication of the brainstem in manipulation-induced BA and dopaminergic blockade in the striatum in the case of drug-induced BA. The possibility has not been experimentally tested that all of these states share with each other not only an active global immobility in which awkward postures are maintained, but also underlying neural mechanisms. This review identifies key brainstem, diencephalic, and basal forebrain areas that seem to be involved in causing BA. We review the evidence that suggest a possible role in BA for the following brain structures: entopeduncular nucleus, medullary and pontine reticular zones, parabrachial region, pedunculopontine nucleus and nearby areas, substantia nigra, subthalamic nucleus, ventromedial thalamic nucleus, and zona incerta. Such areas may operate as a BA control system. Confirmation of which brain areas operate collectively in BA would require testing of several kinds of BA in the same animals with the same kinds of experimental tests. Areas and mechanisms might be elucidated through a strategic combination of the following research approaches: imaging (fMRI, c-fos), lesions (of areas, of afferent and efferent pathways), chemical microstimulation, and electrical recording (of multiple units and field potentials, with an emphasis on testing coherence among areas). We suggest the working hypothesis that BA is created and sustained by coherent, perhaps oscillatory, activity among a group of basal forebrain and brainstem areas that collectively disrupt the normal spinal and supraspinal sequencing controls of reciprocal actions on the extensors and flexors that otherwise produce movement.

Oscillatory electrographic activity in the hippocampus: a mathematical model.

This model of hippocampal function describes the bilaterally symmetrical interactions of the various intrahippocampal populations of neurons that are functionally homogeneous (septal and entorhinal sources of input, granule cells, CA field pyramids cells, and basket cells). Activity of each homogeneous population is described as a first order nonlinear differential equation. Parameters are simulated, with activity defined in relative units ranging from 0 to 1.0. The first 26 equations (13 identified pools in each hemisphere) were solved simultaneously by computer to produce plots of the time course of activity changes in each of the populations. The simulations performed thus far show that the model parallels certain known properties of the system: (1) there is the expected reciprocal relationship between pyramidal cells and basket cells; (2) activity can be made to oscillate or achieve steady-state, simulating EEG "theta" rhythm or low voltage, fast activity; (3) oscillation occurs where it is known to occur (CA pyramidal cells and the dentate region), where it is presumed to occur (in basket cells), and does not occur where it is known not to occur (CA pyramidal cells); (4) there is a narrow range of frequency, and attempts to increase frequency readily terminate oscillation to cause steady-state activity; (5) oscillation requires excitatory drive from the medial septum, whereas entorhinal input is relatively less important; and (6) increases in medial septal activity can increase oscillation frequency. The results also predict certain undiscovered phenomena: (1) there is a major influence of variations in decay rate of activity in various neuronal pools; (2) there is probably an ultra-slow oscillation in the CA area; and (3) the CA projection ot the entorhinal cortex seems to be important in modulating frequency and amplitude of theta rhythm.

Do neurons process information by relative intervals in spike trains?

We suggest the possibility that neurons process information in terms of the relative duration of clusters of adjacent and successive inter-action potential intervals ("bytes" of intervals). If this concept is plausible, as is supported by research from several laboratories which have specifically addressed this possibility, one should be able to see evidence for such patterning in the published illustrations from studies in which this concept was not considered. We present some of this evidence here, along with some illustrations from the original publications. Byte patterns are evident in these examples, even though they went unrecognized by authors and readers alike. It is true that interval patterns are not obvious in all published illustrations of spike trains, and we suggest that this can be explained by one or more of the following: (1) some neurons may operate with an interval-pattern code while others do not, (2) a given neuron may use an interval-pattern code only under certain conditions, and (3) even when such a code exists, it may be difficult to detect for identifiable technical reasons. Therefore, we believe that the relative-internal-pattern concept is a valid scientific hypothesis which merits specific testing of its validity and range of applicability.

Plasma levels of 5alpha-androstane-3alpha,17beta-diol in boys during adolescent growth.

A radioimmunoassay using as antibody against testosterone-3-carboxymethyloxime-BSA is described for the measurement of androstanediol (5alpha-androstane-3alpha,17beta-diol) in human plasma. Sephadex LH 20-column chromatography was used to separate other steroids croos-reaching with the antibody from androstanediol. The sensitivity of the assay was 7 pg and the recovery of labelled androstanediol was 65.1%. The intra-assay coefficient of variation was 9.9%. The existence of 5alpha-androstane-3alpha,17beta-diol in the androstanediol fraction could be demonstrated by gas chromatography and mass spectrometry (GC-MS). Plasma concentration of this substance was measured in 53 normally developing pre-pubertal and pubertal boys and in 13 adult men. The mean concentrations significantly rose from puberty stage 1 to 2, and stage 2 to 3. Although there was no significant difference between the plasma concentrations at stages 3 and 4, an increment from stage 4 and 5 was highly significant. Levels in adult males were significantly higher than those in the stage 5 of normal puberty.

Differences among humans in steady-state evoked potentials: evaluation of alpha activity, attentiveness and cognitive awareness of perceptual effectiveness.

We examined some of the variables that were possible sources of the wide variability among and within human subjects in their steady-state visual evoked potentials (VEP) in response to continuously counter-phased visual stimuli (vertical bars). We found that within a given subject the magnitude of VEP was reasonably consistent during replicate trials under comparable conditions. However, across subjects there were enormous differences (as much as 17-fold) in the VEP magnitude (i.e. in the spectral power developed at the stimulus reversal frequency). These differences could not be explained by differences among subjects in arousal (alpha activity before or during stimulation), attentiveness (as indicated by reaction times to random cueing), or by a person's subjective impression of his responsiveness to stimulation.

Cholinergic-dopaminergic interactions in experimental catalepsy.

The 'pinch-induced' model of catalepsy in the mouse was disrupted by atropine sulfate (4 mg/kg IP), confirming an earlier finding, and also by the antinicotinic mecamylamine (4 mg/kg). Either anticholinergic, when given concurrently with haloperidol (5 mg/kg), interfered with the typical haloperidol-induced enhancement of catalepsy. In mice pretreated with a peripheral cholinergic blocker, the cholinomimetic pilocarpine (10 mg/kg) enhanced catalepsy. The dopamine (DA) agonist apomorphine (5 mg/kg) reversed the enhancement that was normally caused by pilocarpine. Apomorphine did not stimulate open field locomotion in mice that were pretreated with pilocarpine. This lack of correlation between catalepsy and open field activity indicates that catalepsy in a unique state that involves more than mere absence of movement. The DA mechanisms, thus, appear to be specifically antagonistic to catalepsy or, conversely, cholinergic mediation of catalepsy involves reduced influence of DA systems.

Experimental catalepsy is both enhanced and disrupted by apomorphine.

In mice that were scored for the length of time they remained immobile in awkward postures (cataleptic) on an inclined wire grid, a large IP dose of pilocarpine (80 mg/kg) caused a clear catalepsy, which was prevented by both dopamine agonists that were tested, apomorphine (4 or 8 mg/kg, IP) and bromocriptine (8 mg/kg, IP). In other experiments, haloperidol (2.5 mg/kg) caused mild catalepsy. As expected, neither 4 nor 8 mg/kg apomorphine caused much effect when given alone, but both doses produced profound and long-lasting catalepsy in the haloperidol-treated animals. Bromocriptine also had little effect when given alone, and neither 4 nor 8 mg/kg enhanced the haloperidol catalepsy. Apomorphine alone produced catalepsy at low doses. Repeated testing after a low (0.3 mg/kg) dose of apomorphine showed that catalepsy was most profound at 5 min postinjection, with progressive decline thereafter. Apomorphine, but not bromocriptine, thus can produce catalepsy under certain conditions of DA receptor blockade or in low dose. Catalepsy, and perhaps other forms of hypomotility, appear to be differentially mediated by a subclass of dopaminergic receptors.

Evidence for a cholinergic role in haloperidol-induced catalepsy.

Experiments in mice tested previous evidence that activation of cholinergic systems promotes catalepsy and that cholinergic mechanisms need to be intact for full expression of neuroleptic-induced catalepsy. Large doses of the cholinomimetic, pilocarpine, could induce catalepsy when peripheral cholinergic receptors were blocked. Low doses of pilocarpine caused a pronounced enhancement of the catalepsy that was induced by the dopaminergic blocker, haloperidol. A muscarinic receptor blocker, atropine, disrupted haloperidol-induced catalepsy. Intracranial injection of an acetylcholine-synthesis inhibitor, hemicholinium, prevented the catalepsy that is usually induced by haloperidol. These findings suggest the hypothesis that the catalepsy that is produced by neuroleptics such as haloperidol is actually mediated by intrinsic central cholinergic systems. Alternatively, activation of central cholinergic systems could promote catalepsy by suppression of dopaminergic systems.

Morphine-induced regional and dose-response differences on unit impulse activity in decerebrate rats.

Previous studies have indicated that morphine alters nerve impulse activity differently in various brain areas of intact animals. Because morphine has profound effects on visceral organs and on the spinal cord, cervically transected preparations, in which hypothermia was prevented, were used for recording spontaneous impulse activity before and for 30 min after morphine simultaneously from six regions of the brain: caudate (Cau), midbrain reticular formation (MBRF), central grey (CG), cingulate cortex (CC), hippocampus (Hip), and substantia nigra (SN). Morphine (5 and 15 mg/kg, i.p.) caused a naloxone-preventable depression of impulse activity in most brain areas. The depression was, however, especially pronounced in the CG, more so with the lower than the higher dose; naloxone completely blocked the low-dose effect. The MBRF responded with increased impulse activity after 5 mg/kg, but with depression after 15 mg/kg; naloxone blocked both responses. Activity in both the Hip and CC was depressed by the low dose of morphine, but not by the high dose; naloxone blocked the depression. Both doses of morphine generally depressed the variance in impulse activity, with a clear preferential depression of CG variance; naloxone blocked the CG variance effect, but not that of other brain areas.

Nonspecific excitatory effects of morphine: reverse-order precipitated withdrawal and dose-dose interactions.

We recently reported that, in naive mice pretreated with naloxone, morphine can cause withdrawal-like signs that seemingly are not mediated by "opiate" receptors. Such results were confirmed and extended here with another mouse strain. Repetitive vertical jumping could occur respective of injection sequence and depended on dose and dose ratio of the two drugs.

Differential effects of low doses of ethanol on the impulse activity in various regions of the limbic system.

This study was a follow-up to our earlier data which indicated that the hippocampus was one of the brain areas in which ethanol had a preferential action. Rabbits were chronically implanted with electrodes in 9 brain areas associated with the hippocampus. The EEG and multiple-unit activity were recorded simultaneously in each area before and for 15 min after i.p. injection of ethanol at dosages of 0, 150, 300, or 600 mg/kg, given in random order. Subjective evaluation of EEG tracings from all brain areas did not disclose any regional differences. The incidence of hippocampal theta rhythm was depressed transiently at the 2 lower doses and was increased in some rabbits at later post-injection times after the largest dose. Quantitative analysis of the unit activity revealed several major effects of ethanol. Individual rabbits varied significantly in their degree of response. The effects of ethanol included phasic decreases and increases, which varied with the brain area and the dose. A predominant depression of MUA occurred in the septum, fimbria/fornix, entorhinal cortex, and CA1 zone of the hippocampus. Large transient increases in MUA were noted in the CA1, hippocampal commissure, and entorhinal cortex. Overall, regional differences in unit activity consisted of a relatively greater effect in the septum, CA1, and the entorhinal cortex. Conspicuously smaller effects were evident in the CA3 and dentate zones of the hippocampus.

Ethanol-induced regional and dose-response differences in multiple-unit activity in rabbits.

Multiple-unit activity (MUA), recorded simultaneously from many brain areas, was used to detect the existence ahd location of "target sites" for ethanol action in rabbits with chronically implanted electrodes in 14 areas. Each of 12 rabbits received intraperitoneal injection of 300, 600, 900, and 1200 mg/kg of 20% ETOH and a saline control injection given in random order with at least a 4-day interval between injections. Large amounts of MUA data, recorded continuously for a 2-min pre-injection control period and a 15-min post-injection period, were quantified by a sensitive and unique technique. MUA changes did not correlate with alcohol-induced changes in the corresponding EEG for the same locus. Whereas visual inspection of the EEG did not disclose any regional differences in response to ethanol, both temporal and topographical differences in ethanol effect on MUA were observed. There were 14 histologically verified brain areas with adequate sample size for statistical evaluation of MUA response. At high doses, all brain areas were affected. Included among the brain areas which were least affected by low doseas were the caudate nucleus, septum, fornix, and medial forebrain bundle. Those areas that met the criteria for target sites of responding quickly (less than 5 min) to low doses (300 mg/kg) were: cerebellar cortex, cerebral cortex, hippocampus, lateral and medial geniculate nuclei, midbrain reticular formation, and pyriform cortex. In conjunction with the preliminary study [Brain Res. 70, 361 (1974], the data indicate that the most ethanolsensitive tissue is found in the various kinds of cortex, cerebellar and cerebral (both paleocortex and neocortex).

What is the meaningful measure of neuronal spike train activity?

Neuronal spike train activity is conventionally viewed in terms of certain measures of central tendency (mean or median of intervals between discrete events or mean rate of such events) and their associated measures of variability (S.D., skew, etc.). Less commonly, investigators will compute the probabilities of occurrence in an Information Theory context. Another rarely considered measure of spike trains is serial ordering. Seldom is more than one of these approaches applied to the same spike train, and we are unaware of any case where all 3 have been applied to the same train. In order to test the inter-relationships among these approaches, we examined the same spike trains with all 3 analytic methods. Measures of central tendency were taken from the original absolute interval values, whereas entropy and serial order (Markov order) were computed from the sequences of patterns of adjacent intervals, expressed in the same non-parametric format. We found that entropy (measure of uncertainty) did not correlate well with the degree of serial ordering (Markov order). Entropy also did not correlate well with measures of central tendency (median or mean interval, or impulses/s) nor with the variability of such measures. An inverse correlation was seen between Markov order and several measures of central tendency (mean interval and rate) as well as with several measures of variability. The implications of these analyses extend beyond the analysis of spike trains to most all biological and physical time series. For neurophysiologists, these analyses may challenge our common assumptions about the most appropriate way to describe and interpret neuronal spike train activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopaminergic mediation of reward: evidence gained using a natural reinforcer in a behavioral contrast paradigm.

Previous studies suggest a dopaminergic basis for the apparent reward properties of self-stimulation of certain brain areas with electrical current. The data of this present study indicate that there may be a dopaminergic role in the perceived hedonic quality of natural reinforcers. Using a classical behavioral contrast paradigm, we observed in rats that the perceived reward of a saccharin solution was decreased by haloperidol and increased by apomorphine, in doses that did not cause non-specific performance effects.

Membrane glycoconjugates as potential mediators of alcohol effects.

1. Membrane glycoconjugates include glycoproteins and glycolipids that have many important functions in a wide variety of tissues, especially brain. 2. Alcohol's ability to fluidize and swell plasma membranes could be expected to alter the orientation and conformation of the embedded glycoconjugates. 3. Both kinds of glycoconjugates can contain terminal moieties of sialic acid, which has been shown to be decreased by single doses of alcohol. Chronic exposure to alcohol may have no effect on sialic acid, except in very young animals. 4. Glycolipids containing sialic acid (gangliosides) are also decreased by acute doses of alcohol, but chronic alcohol has little effect. Thus, gangliosides may have a role in the development and expression of tolerance. 5. Glycoproteins containing sialic acid may also be involved in alcohol action, but there has been less research in this area. 6. Alcohol-induced disruptions in membrane glycoconjugates could affect the important cellular functions that glycoconjugates have, and thus research on alcohol effects on glycoconjugates could lead to important discoveries of diagnostic and therapeutic value for alcohol abuse and alcoholism.

Effects of chronic alcohol consumption in weanling rats on brain gangliosides.

Chronic ingestion of ethyl alcohol in pre-weanling rats can decrease whole-brain levels of sialic acid (SA), an acidic sugar that serves as terminal groups on glycolipids (gangliosides) and glycoproteins. Because SA occurs in both classes of membrane-bound chemicals, the alcohol effect could be on either or both parent compounds. We examined the effects of alcohol on gangliosides by measuring levels of six specific ganglioside species in post-weanling rats that were fed liquid alcohol diet for 35 days. We found no major effect on any of the ganglioside species in the alcohol-fed rats compared with their pair-fed littermates. These data suggest that alcohol may have acute effects on membrane gangliosides, but during chronic exposure in more mature animals, the membrane may adapt and maintain near-normal ganglioside composition. Thus, gangliosides may reflect mechanisms of membrane tolerance; they could also be involved in mediating metabolic dependencies in neuronal membranes, a possibility that needs testing.

Unit activity indicators of a catecholamine role in expression of morphine effects.

1. We tested the hypothesis that morphine effect on unit activity in certain limbic system areas is primarily dependent on morphine's action on noradrenergic function. Unit activity (UA) was recorded in two limbic areas rich in noradrenergic projections and in a control area (caudate). We compared the influence of morphine on the UA of these areas in intact rats and in rats that were lesioned with intraventricular 6-OH dopamine to destroy adrenergic input. 2. The results showed that: a) morphine alone depressed UA in the caudate, while causing a mild increase in the hippocampus and cingulate gyrus, b) lesioning of animals with 6-OH dopamine resulted in suppressed morphine response in the noradrenergically innervated limbic areas, and c) the caudate was depressed similarly by morphine whether or not there was 6-OH dopamine lesioning. 3. Thus we conclude that the full expression of morphine effects in these two limbic areas seems to require intact noradrenergic input.