Laterality and 3H-imipramine binding: studies in the frontal cortex of normal controls and suicide victims.

Serotonin [5-hydroxytryptamine (5-HT)]-sensitive imipramine binding (IB) was determined in the left and right hemisphere of frontal cortex of suicide victims and nonpsychiatric controls who died due to myocardial infarction or accident. The Kd (an inverse measure of affinity of 3H-imipramine to its binding sites) was significantly higher in left hemisphere than right hemisphere in normal controls. There were no differences in Bmax and Kd or Bmax between left hemisphere and right hemisphere in normals and suicides, respectively. These results do not support the finding of hemispheric asymmetry of 5-HT uptake as measured by IB (Bmax) in postmortem tissue from controls and suicide victims.     

Responding for brain stimulation: Stress and desmethylimipramine

1. Stressors influence the activity of biogenic amines and provoke a variety of behavioral disturbances which have been considered as models of human depression.

2. To evaluate the effects of Stressors on reward processes, responding for electrical brain stimulation was assessed after acute or chronic shock, and the modification of performance by desmethylimipramine was determined.

3. While escapable shock did not affect performance, inescapable shock reduced responding from the nucleus accumbens and medial forebrain bundle, but not from the substantia nigra. These deficits were were antagonized by repeated Stressor application or by desmethylimipramine.

4. Uncontrollable Stressors may influence motivational processes subserved by some brain regions, and may thus influence affective state. Chronic stress or desmethylimipramine may Induce adaptive neurochemical changes, thereby preventing the behavioral disturbances otherwise produced by Stressors.     

Behavioral and neurochemical effects of (-)- and (±)-cathinone: Dose-response and time-course

1. The purpose of the present study was to compare (-)-cathinone and its analogue (+)cathinone using behavioral and neurochemical measures.

2. Rats were trained to discriminate between 0.6 mg/kg (-)- or (+)-cathinone and saline in a food-motivated, two-lever operant task. In addition, concentrations of dopamine, norepinephrine, 5-hydroxytryptamine and their major metabolites were analyzed in the nuclei accumbens and septi lateralis.

3. The results suggest that (-)- and (+)-cathinone have similar effects on behavior and neurochemistry with (-)-cathinone being more potent.     

(Re-)organization of the developing human brain following periventricular white matter lesions

Unilateral periventricular brain lesions served as a model for the investigation of (re-)organization following insults to the developing human brain. In both the motor and the language systems (re-)organization was observed in the contra-lesional hemisphere. In the motor system, the contra-lesional hemisphere can develop (or maintain) ipsilateral cortico-spinal projections to the paretic hand; in the language system, left-sided lesions can induce (re-)organization of speech production in the right hemisphere. This interhemispheric (re-)organization can achieve normal language functions, whereas the hand contra-lateral to the lesion always remains markedly impaired. Despite these functional differences, the two systems share common principles concerning their reorganizational mechanisms:

(1) Interhemispheric (re-)organization always occurred in areas homotopic to the “original” areas in the affected hemisphere, (2) the degree of interhemispheric (re-)organization correlated with structural damage to hand or facial motor tracts, and (3) afferent functions (the somatosensory hand representation, the perception of speech) did not follow their efferent counterparts (the motor hand representation, and the production of speech), but remained in the affected hemisphere.     

Nonlinear pharmacokinetics of chlorimipramine after infusion and oral administration in patients

1. In this study the pharmacokinetics of 75 mg and 150 mg chlorimipramine after infusion and tablets was followed for four weeks in chronically treated patients.

2. The clearence was found to be dose dependent.

3. From the time course of the metabolite desmethylchlorimipramine in plasma it can be concluded, that chlorimipramine tablets are resorbed totally.

4. No correlation between pharmacokinetic and improvement parameters could be found.

5. Doubling of the dosage leads to 3 fold chlorimipramine and 4 fold desmethylchlorimipramine concentrations.

6. The estimated half lives are higher than known hitherto.

7. Especially for chronic treatment with 150 mg chlorimipramine, plasma concentration monitoring is recommended, because 20% of the patients did not reach steady state for chlorimipramine and 60% for desmethylchlorimipramine, in these 4 weeks.     

Acute low-level formaldehyde behavioural and neurochemical toxicity in the rat

1. The purpose of the present study was to determine the effects of low-level formaldehyde exposure upon behavior and neurochemistry in the male rat.

2. Rats were exposed to either air or formaldehyde vapor (5, 10 or 20 parts per million) for 3 hours on 2 consecutive days during which behavioral observations were made. Following the second exposure session the rats were sacrificed and their brains analyzed for norepinephrine, dopamine, 5-hydroxytryptamine and their major metabolites.

3. Formaldehyde exposure resulted in decreased motor activity and neurochemical changes in dopamine and 5-hydroxytryptamine neurons.     

Changes in retention of a visual discrimination task following unilateral and bilateral transections of temporo-entorhinal connections in rats

In a previous study, it was shown that the lateral entorhinal cortex (LEC) in the left hemisphere contains higher concentration of glutamate than in the right hemisphere. The purpose of the present study was to examine potential relationship between this neurochemical asymmetry and behavior. Rats with either left, right, or bilateral transections of the fiber connections between the temporal cortex and LEC were tested for postoperative retention of a visual discrimination task. Because histological verification of lesions was crucial in this study, analyses of neurochemistry had to be omitted. The results showed that both left and bilateral lesions resulted in impaired retention, but the bilateral group was even more impaired than the left group. The rats with lesions in the right hemisphere, however, used fewer trials to reach the learning criterion than the control group, but they did not make fewer errors than the controls. The results are discussed in terms of lateralization of mnemonic processes.     

Increasing membrane polyunsaturated fatty-acid content augments cyclic AMP formation and prostaglandin production in NIE-115 neuroblastoma

1. Addition of linoleic acid (50 μM) to culture medium significantly increases levels of polyunsaturated fatty acids (PUFA) in membrane phospholipids of NIE-115 neuroblastoma.

2. Basal levels of cyclic AMP are elevated significantly in supplemented ceils.

3. Exogenous prostaglandins (PG) PGE₁ and PGD₂ stimulate cAMP formation in NIE-115 neuroblastoma.

4. Supplemented cells produce higher levels of PGE and PGD than do control cultures.

5. Inclusion of cyclooxygenase inhibitors in culture medium does not block elevation of cyclic nucleotide in supplemented cells.

6. Endogenous PG production and receptor activation cannot account for increased cAMP in EFA-supplemented neuroblastoma.     

Effects of lithium, nortriptyline and dexamethasone on insulin sensitivity

1. The effects of lithium, dexamethasone, nortriptyline and their combinations on insulin sensitivity, expressed as a drop of plasma glucose in response to insulin challenge, were investigated in healthy volunteers.

2. Short-term (three weeks) lithium treatment did not appear to exert any influence on the insulin sensitivity.

3. Dexamethasone administered alone (2 mg given 57 hours prior to the test) had no effect on the insulin sensitivity of drug-free healthy subjects. However, after three weeks of lithium treatment the dexamethasone premedication resulted in slight flattening of glucose response to insulin in the same persons.

4. Nortriptyline administered for three weeks to healthy volunteers, pretreated with dexamethasone, increased insulin sensitivity.

5. These findings may have clinical implications regarding the treatment of depressed diabetic patients, and may provide information about the regulation of insulin sensitivity.     

Investigations of melatonin secretion in man

1. Overnight melatonin secretion shows substantial and significant intraindividual stability and large interindividual variation.

2. Melatonin concentrations obtained between 1 and 5 a.m. significantly correlate with overall melatonin secretion (expressed as the area under the curve) while a single determination of serum melatonin does not adequately reflect the entire night secretion.

3. Secretion correlates positively with “neuroendocrine responsiveness” (rating responses in other neuroendocrine challenge tests) and there is trend for negative correlation with age.

4. In volunteers the administration of the usual therapeutic dose of lithium did not alter the overnight melatonin secretion. However, there was an elevation of isolated secretory values at the early morning timepoints.

5. In comparison with volunteers, lithium administration tended to reduce the overnight melatonin secretion in bipolar patients, however, the difference did not reach statistical significance.     

Circadian rhythm of plasma melatonin in endogenous depression

1. The circadian rhythm of plasma melatonin was investigated in normal men 18–30 years (N=5), normal men 50–70 years (N=5) and in six patients with endogenous depression.

2. The environmental photoperiod was 11 hours.

3. The subjects and patients were indoors with lights on from 07:00 until 23:00 hours.

4. Blood samples were obtained every 4 hours over a 24 hour period, with additional sampling at 22:00 and 02:00 hours.

5. Plasma melatonin was estimated by radioimmunoassay compared to both groups of controls.

6. In the depressed patients, the levels of melatonin were low throughout the 24 hour period.

7. The depressives had a delayed onset of the dark phase of the rhythm.

8. The patients also showed peak melatonin levels occurring earlier than in the controls.

9. Circadian rhythm of melatonin and therefore of its pacemaker may be altered in endogenous depression.     

D-baclofen: Is it an antagonist at baclofen receptors?

1. Following intrathecal administration Into the spinal subarachnoid space, baclofen produced dose related increases in tail flick latency. L-Baclofen was twice as potent as the DL-racemate and 100 times more potent than D-baclofeu.

2. When D-baclofen was injected intrathecally 15 min prior to L-baclofen, the subsequent effect of L-baclofen was markedly reduced. This reduction was dose-related for D-baclofen in doses at least 20 times the L-baclofen dose. D-baclofen administered concomitantly with L-baclofen only slightly increased the effect of L-baclofen.

3. Pretreatment with D-baclofen (up to 10 times the dose of L-baclofen) did not inhibit the effect of L-baclofen when drugs were injected intraperitoneally.

4. These results indicate that D-baclofen can antagonize the antinociceptive effect of L-baclofen following intrathecal administration. D-Baclofen should prove to be a useful tool for investigation of the role of stereoselectlve baclofen receptors in a variety of pharmacological processes.     

Factors associated with a good response to lithium in aggressive mentally handicapped subjects

1. Twenty-five (25) mentally handicapped in-patient adults with persistent aggressive behaviour took part in a double-blind crossover trial lasting 5 months comparing the effects of lithium with placebo on aspects of aggressive behaviour.

2. All patients were receiving neuroleptic and/or anticonvulsant drugs which were continued during the trial.

3. Seventeen (17) of the patients showed greater improvement during the lithium phase compared to placebo.

4. Multiple regression analysis was carried out to determine which of 17 background variables were related to outcome.

5. The following factors were associated with a good response to lithium: less than one aggressive episode per week before starting treatment, overactivity, Stereotypic behaviour, female sex and epilepsy.

6. No patient became toxic during the investigation although lithium levels were maintained within the therapeutic range (0.5–0.8 mmol/l).     

Novelty seeking and harm avoidance in Parkinson's disease: effects of asymmetric dopamine deficiency

OBJECTIVES: Although changes in novelty seeking and harm avoidance have been reported among patients with Parkinson's disease (PD), the findings regarding the neurochemical correlates of such changes are inconsistent. This study was designed to examine the hypothesis that different patterns of motor and neurochemical asymmetry in PD may have contributed to the conflicting results. METHODS: Forty PD patients (divided into two groups according to initial asymmetry in dopamine deficit: left hemisphere, n = 22; right hemisphere, n = 18) and 17 age matched healthy controls completed the Tridimensional Personality Questionnaire (Cloninger, 1987). RESULTS: Only patients with greater dopamine loss in the left hemisphere showed reduced novelty seeking, whereas only patients with reduced dopamine in the right hemisphere reported higher harm avoidance than matched healthy controls. Novelty seeking was not associated with disease duration, current motor symptoms, or medication, whereas harm avoidance was significantly correlated only with the severity of bradykinesia and depression. CONCLUSIONS: Approach and avoidance reflect different patterns of dopaminergic asymmetry. Whereas reduced novelty seeking reflects deficit in the mesolimbic branch of ascending dopamine transmission in the left hemisphere, increased harm avoidance is associated with greater dopamine loss in the right striatum.     

Platelet H imipramine binding: A possible predictor of response to antidepressant treatment

1. No significant difference in the density (Bmax) of platelet ³H imipramine recognition sites were found between the group of 20 unmedicated depressed patients and 10 healthy volunteers. The mean K_D value was significantly higher in the population of depressives than in controls.

2. Non-responders (after 2 weeks of treatment with antidepressants) had significantly lower initial Bmax values than responders or control subjects. Density of platelet ³H imipramine site may thus be a predictor of early response to antidepressant therapy.

3. No significant sex differences were found in K_D or Bmax values in the depressed group or in control subjects. There was, however, a seasonal variation in Bmax but not in K_D values of platelet ³H imipramine binding.     

Cell cultures as models for studying neural functions

1. Two cell culture systems were used for studies of neural functions in vitro. A neuronal hybrid cell line (neuroblastoma x glioma hybrid cells) and primary glial-rich cultures of newborn murine brain.

2. The level of cyclic AMP in both systems is regulated by two groups of hormones, those that stimulate and those that inhibit formation of cyclic AMP.

3. Among the inhibitory hormones active on the hybrid cells are opioids. Therefore the cells are being used in the elucidation of action of opioids.

4. The list of stimulating and inhibitory hormones regulating the primary glial-rich cultures includes several peptide hormones such as the gastro- intestinal peptides secretin and vasoactive intestinal peptide, the calcaemic hormones parathyrin and calcitonin, adrenocorticotropin and melanotropins, and somatostatin.

5. Noradrenaline (via - and (β-adrenergic receptors) and adenosine (via A₁) and A₂ receptors) inhibit and stimulate cyclic AMP synthesis in the primary glial-rich cultures.

6. Bradykinin slowly hyperpolarizes the hybrid cells and elicits formation of cyclic GMP. Both responses desensitize rapidly.

7. Substance P increases the permeability of hybrid cells for Na⁺, as measured by using ¹⁴C-guanidinium as substitute for Na⁺.

8. Hybrid cells actively accumulate taurine, an amino acid that appears to fulfill important functions in the nervous system.

9. The transport of taurine across the plasma membrane is highly specific for and strictly dependent on Na⁺.

10. The pumped power station hypothesis of taurine action in the nervous system views taurine gradient plus taurine carrier as a transport system for the elimination of sodium from neurons during phases of high neuronal activity.     

Alterations in receptor number, affinity and laminar distribution in cat visual cortex during the critical period

1. The number, affinity, and laminar distributions of various receptors in cat visual cortex were examined during postnatal development using homogenate and autoradiographic techniques.

2. For all receptor populations examined, the total number of receptors (B_max) increased from relatively low early values to peak values during the first three months of postnatal life followed by a drop or plateau in the number of receptors. This peak in B_max occured during the physiologically-defined period for cortical plasticity.

3. For most receptors examined, the affinity (K_D) was also altered during postnatal development.

4. Many of the receptor populations examined exhibited changes in their initial laminar distributions during the first three months of postnatal development, although other did not.

5. The results show a more complex picture of receptor ontogenesis than previously reported, and suggest that the observed receptor modifications affect the synaptic efficacy and the basic chemical circuitry of the visual cortex during the critical period.     

The effects of caerulein on nocturnal, sleep

1. Caerulein, a decapeptide chemically related to cholecystokinin octapeptide, was examined polysoninographically for its effect on nocturnal sleep in healthy volunteers.

2. The subjects were 6 males (20–24 years of age). Either a placebo (saline) or caerulein 0.6 μg/kg was administered intramuscularly to volunteers at 23:00.

3. Polysomnograms were then recorded from 23:00 till 06:30.

4. Little variation in sleep period time, total sleep time, sleep efficiency index, sleep latency, or REM sleep latency in the drug night were found as compared to the control night values.

5. The percentage of REM stage sleep increased significantly (P < 0.01) on the drug administered night, whereas the change in the percentages of each of the other stages was not significant.

6. The REM density of the vertical eye movements tended to increase on the drug night, but the density of the horizontal eye movements showed no change.

7. There were no changes in the spontaneous GSRs in either vola or dorsum manus.

8. As caerulein shows alpha-1 adrenergic receptor blocker activity, it is suggested that caerulein may increase REM sleep by affecting the central noradrenergic neurons.     

Effects of unilateral microinjections of sulpiride into the medial prefrontal cortex on circling behavior of rats

1. Bilateral 6-OHDA lesions of rats' medial prefrontal cortex increased locomotor activity after 7–10 days suggesting that cortical DA may normally inhibit motor behaviour. However, hyperactivity may have resulted from enhanced subcortical DA function.

2. Acute manipulation of frontal cortical DA neurotransmission in the present experiment avoided lesion-induced subcortical changes.

3. Sulpiride (0, 6, 12, 24 ug in 1 ul) was Injected unilaterallv into the medial prefrontal cortex of rats pretreated with (+)-amphetamine (1.5 mg/kg i.p.).

4. Circling behavior was scored during four 5-min intervals of a 60-min test session which began with injections and placement in a flat, circular arena.

5. SUL resulted in ipslversive circling whereas its vehicle did not. These results were consistent with those seen with other DA drugs and suggest an excitatory influence of frontal cortical DA on locomotor activity.     

The response of the pineal melatonin miosynthesis to the selective MAO-A inhibitor, clorgyline, in young and middle-aged rats

1. Clorgyline increased pineal melatonin and N-acetylserotonin (NAS) and decreased 5-hydroxyindoleacetic add (5-HIAA) content in 3 and 12 months of age male Sprague-Dawley rats kept under 12:12 h light: dark schedule. Exposure to light for 24 h before Clorgyline administration resulted in additonal elevation of NAS and melatonin.NAS and melatonin levels after clorgyline injections were significantly higher while 5-HIAA levels were significantly lower in young than in middle-aged rats.

2.The 5-HIAA/5-HT ratio (index of monoamine oxidase activity) was higher in middle-aged than in young rats suggesting the lesser degree of clorgyline-induced inhibition of MAO-A in old than in young rats.

3. It is suggested that melatonin response to a single dose of the selective MAO-A inhibitor might be used for the assessment of the aging changes of the rat (and human) pineals.