The effects of centrally acting drugs on the EEG correlates of meditation

The present study investigated the effects of three centrally acting drugs on the significant increase in the intermediate alpha frequency of the electroencephalogram (EEG) that accompanied meditation in a male volunteer. When compared to the EEG recorded before each of the three drugs was administered, naloxone tended to enhance the increase in the power of the intermediate alpha EEG (9.4–10.4 Hz), while diazepam tended to spread the increase to the slow (7.4–9.4 Hz) alpha EEG, and flumazenil was without much effect on the overall EEG pattern. However, these EEG changes when compared to similar changes obtained with saline administration were not significantly different from the latter. Thus, it is unlikely that the EEG correlates of meditation are causally related to the rise or fall of endogenous opioid peptides or benzodiazepinelike substances in the brain.This research was supported by a grant from the Singapore Turf Club (STC 4837). The authors would like to thank the subject for volunteering as a subject in this study; and Ms. Chua Mui Eng for her technical assistance.     

Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists

The brain and the peripheral (hormonal) angiotensin II systems are stimulated during stress. Activation of brain angiotensin II AT(1) receptors is required for the stress-induced hormone secretion, including CRH, ACTH, corticoids and vasopressin, and for stimulation of the central sympathetic activity. Long-term peripheral administration of the angiotensin II AT(1) antagonist candesartan blocks not only peripheral but also brain AT(1) receptors, prevents the hormonal and sympathoadrenal response to isolation stress and prevents the formation of stress-induced gastric ulcers. The mechanisms responsible for the prevention of stress-induced ulcers by the AT(1) receptor antagonist include protection from the stress-induced ischemia and inflammation (neutrophil infiltration and increase in ICAM-1 and TNF-alpha) in the gastric mucosa and a partial blockade of the stress-induced sympathoadrenal stimulation, while the protective effect of the glucocorticoid release during stress is maintained. AT(1) receptor antagonism prevents the stress-induced decrease in cortical CRH(1) and benzodiazepine binding and is anxiolytic. Blockade of brain angiotensin II AT(1) receptors offers a novel therapeutic opportunity for the treatment of anxiety and other stress-related disorders.     

Interleukin-6 is a centrally acting endogenous pyrogen in the rat.

Intracerebroventricular (i.c.v.) injection of human recombinant interleukin-6 (IL-6; 20-100 ng) caused significant increases in colonic temperature and resting oxygen consumption (VO2) in conscious rats. These effects were prevented by pretreatment with a cyclooxygenase inhibitor (flurbiprofen, 1 mg/kg, i.p.) or a corticotrophin-releasing factor antagonist (alpha-helical CRF9-41, 25 micrograms, i.c.v.). Higher doses of IL-6 (i.c.v.) caused only small changes in VO2 and temperature, and very high doses given intravenously (i.v.) (4 micrograms/kg) were required to stimulate these parameters. Central injection of anti-rat IL-6 antibody inhibited the effects of interleukin-1 beta (i.c.v.) or endotoxin injection (i.p.) on colonic temperature and VO2 in conscious rats. These data indicate that IL-6 is an important endogenous pyrogen that acts within the central nervous system.     

The effect of various centrally active drugs on adenosine uptake by the central nervous system

1. Adenosine and its analogs depress the firing of neurons in various brain regions. The primary mode of action of adenosine in exerting this effect appears to be the depression of transmitter release from presynaptic nerve terminals. This is a result of reduced calcium mobilization. 2. Adenosine uptake inhibitors and deaminase inhibitors depress the firing of central neurons. Adenosine antagonists, caffeine and theophylline, excite central neurons. Adenosine is therefore likely to be released in sufficient quantities to exert an ongoing modulation of synaptic transmission in the intact brain. 3. A number of groups of centrally active drugs inhibit adenosine uptake by brain synaptosomal preparations. These include the benzodiazepines, phenothiazines, various other sedatives and hypnotics, tricyclic antidepressants, non-steroidal anti-inflammatory analgesics, some steroids, diphenylhydantoin, puromycin and toyocamycin. 4. It is proposed that many agents with anxiolytic, sedative, analgesic or anti-convulsant actions may achieve their effects by inhibiting adenosine uptake and thus potentiating extracellular adenosine levels. 5. Morphine also elevates extracellular adenosine levels but achieves this by enhancing adenosine release.     

EEG correlates of social creativity

EEG correlates of social creativity defined as ability to originally and flexibly interpret social significant situations were studied. It was found that the alpha2 and gamma2 rhythms are specific bands which make it possible to tell the difference between social creativity and control task. Solving socially significant problems in experimental conditions is accompanied by an increase in the power of the delta and gamma2 bands and desynchronization in the alpha2 band less pronounced in divergent tasks than during the interpretation of convergent visual stimuli.     

New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases

We describe here the synthesis and activity of a new series of oxime reactivators of cholinesterases (ChEs) that contain tertiary amine or imidazole protonatable functional groups. Equilibration between the neutral and protonated species at physiological pH enables the reactivators to cross the blood-brain barrier and distribute in the CNS aqueous space as dictated by interstitial and cellular pH values. Our structure-activity analysis of 134 novel compounds considers primarily imidazole aldoximes and N-substituted 2-hydroxyiminoacetamides. Reactivation capacities of novel oximes are rank ordered by their relative reactivation rate constants at 0.67 mm compared with 2-pyridinealdoxime methiodide for reactivation of four organophosphate (sarin, cyclosarin, VX, and paraoxon) conjugates of human acetylcholinesterase (hAChE). Rank order of the rates differs for reactivation of human butyrylcholinesterase (hBChE) conjugates. The 10 best reactivating oximes, predominantly hydroxyimino acetamide derivatives (for hAChE) and imidazole-containing aldoximes (for hBChE) also exhibited reasonable activity in the reactivation of tabun conjugates. Reactivation kinetics of the lead hydroxyimino acetamide reactivator of hAChE, when analyzed in terms of apparent affinity (1/K(ox)) and maximum reactivation rate (k(2)), is superior to the reference uncharged reactivators monoisonitrosoacetone and 2,3-butanedione monoxime and shows potential for further refinement. The disparate pH dependences for reactivation of ChE and the general base-catalyzed oximolysis of acetylthiocholine reveal that distinct reactivator ionization states are involved in the reactivation of ChE conjugates and in conferring nucleophilic reactivity of the oxime group.     

Pre-clinical toxicity of IDPH-791: a new centrally acting muscle relaxant in rats.

IDPH-791, a novel centrally acting muscle relaxant, in doses up to 500 mg/kg (po) for 14 days did not result in any appreciable adverse effect on body weight gain, food or water consumption including biochemical and haematologica parameters in rats. Variations observed in the biochemistry and haematology were either comparable to controls or were within normal limits.     

Effects of morphine and other centrally acting drugs on 3,4-dihydroxyphenylethylene glycol sulfate (DOPEG-SO4) in rat brain

Brain concentrations of DOPEG-SO₄ were measured fluorometrically 0, 0.5, 1, 2, 4 and 8 hr after i.p. injections of morphine sulfate (20 mg/kg), d-amphetamine sulfate (5 mg/kg), desmethylimipramine HCl (25 mg/kg), or reserpine (5 mg/kg) in order to observe the effects of these drugs on intraneuronal norepinephrine degradation. No change in brain levels of DOPEG-SO₄ was found until 8 hr after morphine, at which time the metabolite was significantly (p<.01) decreased. d-Amphetamine and desmethylimipramine significantly (p<.01) decreased the metabolite at all observed timepoints after 0 hr. Brain DOPEG-SO₄ after reserpine was significantly (p<.01) increased at 0.5 and 1 hr, and significantly (p<.01) decreased at 4 and 8 hr. DOPEG-SO₄ remained unchanged 0–8 hr after saline injections. These results, together with previous measurements of brain 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MOPEG-SO₄), indicate that the mechanism of morphine action on noradrenergic neurons differs from those of the other drugs examined and that morphine may cause central norepinephrine release.     

Hemodynamic effects of centrally administered, norcocaine in the rat.

Norcocaine is the N-demethylated metabolite of cocaine. It is present in the CNS and is reported to be pharmacologically active. The present study was designed to evaluate the cardiovascular actions of norcocaine following central administration. Wistar Kyoto (WKY) rats were anesthetized with pentobarbital and instrumented for measurement of blood pressure and renal and hindlimb blood flow (via Doppler flowprobes). A cerebroventricular cannula was placed in the lateral ventricle for drug administration. Cocaine or norcocaine was administered centrally in a dose range of 0.025 to 4.0 mg/kg. Under the above experimental conditions, 4.0 mg/kg of norcocaine decreased blood pressure without a significant change in either hind limb or renal blood flow. Central administration of cocaine also produced a similar depressor response. In conscious, unrestrained rats, cocaine produced a pressor response while norcocaine did not significantly alter blood pressure. The depressor response to both cocaine and norcocaine in the anesthetized animal is speculated to be due to the local anesthetic properties of the drugs.     

Refinement of structural leads for centrally acting oxime reactivators of phosphylated cholinesterases

We present a systematic structural optimization of uncharged but ionizable N-substituted 2-hydroxyiminoacetamido alkylamine reactivators of phosphylated human acetylcholinesterase (hAChE) intended to catalyze the hydrolysis of organophosphate (OP)-inhibited hAChE in the CNS. Starting with the initial lead oxime RS41A identified in our earlier study and extending to the azepine analog RS194B, reactivation rates for OP-hAChE conjugates formed by sarin, cyclosarin, VX, paraoxon, and tabun are enhanced severalfold in vitro. To analyze the mechanism of intrinsic reactivation of the OP-AChE conjugate and penetration of the blood-brain barrier, the pH dependence of the oxime and amine ionizing groups of the compounds and their nucleophilic potential were examined by UV-visible spectroscopy, (1)H NMR, and oximolysis rates for acetylthiocholine and phosphoester hydrolysis. Oximolysis rates were compared in solution and on AChE conjugates and analyzed in terms of the ionization states for reactivation of the OP-conjugated AChE. In addition, toxicity and pharmacokinetic studies in mice show significantly improved CNS penetration and retention for RS194B when compared with RS41A. The enhanced intrinsic reactivity against the OP-AChE target combined with favorable pharmacokinetic properties resulted in great improvement of antidotal properties of RS194B compared with RS41A and the standard peripherally active oxime, 2-pyridinealdoxime methiodide. Improvement was particularly noticeable when pretreatment of mice with RS194B before OP exposure was combined with RS194B reactivation therapy after the OP insult.     

The physiological correlates of Kundalini Yoga meditation: a study of a yoga master

This study explores the physiological correlates of a highly practiced Kundalini Yoga meditator. Thoracic and abdominal breathing patterns, heart rate (HR), occipital parietal electroencephalograph (EEG), skin conductance level (SCL), and blood volume pulse (BVP) were monitored during prebaseline, meditation, and postbaseline periods. Visual analyses of the data showed a decrease in respiration rate during the meditation from a mean of 11 breaths/min for the pre- and 13 breaths/min for the postbaseline to a mean of 5 breaths/min during the meditation, with a predominance of abdominal/diaphragmatic breathing. There was also more alpha EEG activity during the meditation (M = 1.71 V) compared to the pre- (M = .47 V) and postbaseline (M = .78 V) periods, and an increase in theta EEG activity immediately following the meditation (M = .62 V) compared to the pre-baseline and meditative periods (each with M = .26 V). These findings suggest that a shift in breathing patterns may contribute to the development of alpha EEG, and those patterns need to be investigated further.     

The effect of transcendental meditation on iconic memory.

Three experiments investigated the effects of transcendental meditation (TM) on iconic memory. The task involved reporting of digits shown tachistoscopically, using Sperling's partial-report technique. Experiment 1 was a pilot study involving a meditation group and a nonmeditation gropu. All subjects were run in a pretest/treatment/posttest design. During the treatment phase the meditation group practiced TM for a 20-minute period and the nonmeditation group relaxed with eyes closed. The results showed that the treatment increased performance in meditators, but not in nonmeditators. In this experiment important controls such as individual administration of the task, extrinsic rewards, subject pacing, and adequate practice were lacking. Experiment 2 was a replication of the first, with these controls added. The results no longer showed a superiority for the meditation treatment. In fact, the meditation group performed worse on each day of running. Experiment 3 was a replication of Experiment 1, to assess whether the meditation effect of Experiment 1 was due to (a) differential increased attention of the meditators (minimized in subject-paced Experiment 2), (b) a gain early in learning for the meditators that was eliminated due to practice in Experiment 2, or (c) a lack of proper control procedures in Experiment 1. The performance of the meditators was, again, significantly lower. This research illustrates the importance of careful control when investigating the effects of meditation on behavior. It also suggests that the effects of meditation may depend on which hemisphere is dominant in performing the task.