Quantitation of a mass action of dopaminergic neurones regulating temporal damping of linear electrocortical waves

We have previously proposed that electrocortical waves are linear waves, subject to regulation by mesotelencephalic dopaminergic neurones. As a further means to test this theory, selective unilateral lesions of varying extent were made in the nucleii of origin of the dopaminergic mesotelencephalic tract. Changes in the electrocortical power spectrum were assessed by a repeated measure, between hemispheres comparison of ratio changes in power. With increasing unilateral dopamine cell damage, the animals showed increasing contralateral sensorimotor neglect. Curve fitting the ratio changes in power attributable to lesion, showed that estimates of the power of driving signals and the temporal damping moved in reverse directions with increasing extent of lesion, as expected from the theory. A further test was undertaken, to determine whether equal estimates for a transformation of surface signals were obtained from each side. Equality would not be expected if the equation for relative power were invalid. Left and right equality was found for three grades of unilateral lesion.     

Amplitude and phase relations of electrocortical waves regulated by transhypothalamic dopaminergic neurones: A test for a linear theory

We have previously proposed that electrocortical activity (EEG) arises as a manifestation of linear waves generated by resonance among telencephalic neurones, and that this activity is controlled in part by ascending neurones from the brain-steim, which regulate the damping of each resonance. The presentexperiments focus on a specific class of ascending neurones, the mesotelencephalic dopaminergic cells, because these cells are thought to mediate important psychological effects, and are conveniently subject to selective lesion. A critical test of the theory is undertaken, by performing selective unilateral lesion, assessing the changes in the power spectrum of the EEG attributable to lesion, and determining whether the changes in phase of the EEG correspond to that predicted from the changes in power. Results support the theory, although the model order applicable in these experiments is inadequate. The consequences of these findings for automata theory, linear network theory and their application to mammalian brains are briefly discussed.     

A test for constant natural frequencies in electrocortical activity under lateral hypothalamic control

An initial test for a theory of lateral hypothalamic regulation of electrocortical activity is undertaken. The theory supposes lateral hypothalamic input directly or indirectly damps telencephalic resonances involving linear wave phenomena, enabling this pathway to act as parametric control of information processing in cortical neural networks. Relative changes in left and right electrocortical power spectra are used to test for the presence of resonant modes with constant natural frequencies in conditions of asymmetrical damping, following unilateral lesion of the lateral hypothalamus. Natural frequency values for the modes clustered about center frequencies in the EEG band are obtained. This method has the advantage of minimising the effects of time-variation and the recorded signal's distortion from the electrocortical local spatial average, but limits consideration to five dominant modes of resonance. The uncertainty of true model order, and errors in curve-fitting impose limitations on the test.     

Direct determination of homovanillic acid release from the human brain, an indicator of central dopaminergic activity

The plasma concentration of the dopamine (DA) metabolite, homovanillic acid (HVA), is used as an indicator of central nervous system dopaminergic activity. Using percutaneously inserted catheters we were able to obtain blood samples simultaneously from the right and left internal jugular veins. Veno-arterial HVA plasma concentration differences combined with adjusted organ plasma flows were used, according to the Fick Principle, to determine the HVA overflow from the brain. The HVA overflow from the liver was also measured. HVA overflow from the brain represented 12% of the total body HVA production. A similar amount was released from the liver, illustrating the limited validity of peripheral plasma HVA measurements as an indicator of central dopaminergic activity. HVA release from the human brain displayed a degree of asymmetry, the overflow into the left internal jugular vein being 36% greater than that into the right. Cerebral venous blood flow scans indicated that cortical cerebral regions drained preferentially into the right internal jugular; by inference the higher HVA overflow on the left originated from dopamine-rich subcortical brain areas. Since HVA in plasma may arise from the metabolism of DA existing either as a neurotransmitter or a norepinephrine (NE) precursor we measured the internal jugular vein plasma concentrations of NE, and its metabolite dihydroxyphenylglycol (DHPG), to determine whether they displayed a similar pattern of release to HVA. The overflow of both NE and DHPG into the right internal jugular vein was approximately double that on the left. Since the overflow of HVA did not parallel that of NE and DHPG it may be inferred that the origin of much of the subcortically produced HVA is from dopaminergic neurons and not from the metabolism of precursor DA in noradrenergic neurones or cerebrovascular sympathetic nerves.     

Changes in striatal specific 3-H-atropine binding after unilateral 6-hydroxydopamine lesions of nigrostriatal dopaminergic neurones.

Specific binding of ³H-atropine to crude synaptosomal membrane fractions of the rat striatum was measured at different times after unilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic neurones. In a group of rats killed between 4 to 15 days after lesioning the right side, specific ³H-atropine binding was reduced by 20 percent compared to the right side of unlesioned rats. There was a concomitant increase (20 percent) of specific ³H-atropine binding in the contralateral side compared to control animals. These changes in muscarinic receptor binding depended on the time after which the lesions were made : maximum effects occured about 8 days after lesioning but almost completely disappeared 13 days later. Dissociation constants for ³H-atropine in the right and left striata of control and lesioned rats were not significantly different. The decrease in muscarinic receptor binding in the ipsilateral striatum of lesioned animals may result from an activation of cholinergic neurones produced by removal of the inhibitory dopaminergic terminals.     

Dissociate destruction of noradrenaline and dopamine descending projections in the thoracic spinal cord of the rat

Intracisternal administration of 6-hydroxydopamine to male Wistar rats produced a near complete depletion of noradrenaline levels, as measured by a radioenzymatic assay in micropunches sampled from the dorsal, lateral and ventral horns of the thoracic spinal cord. This drastic effect was reversed by pretreatment with desipramine, a pharmacological inhibitor of noradrenergic neuron uptake. Surprisingly, dopamine content was not significantly reduced. The question as to whether such a lack of concomitant dopamine decrease might be inherent to the dopamine assay itself could be answered by the results obtained with both pharmacological (reserpine) treatments and interference determinations in the dopamine assay. The relative potency of 6-hydroxydopamine to destroy noradrenergic and dopaminergic neurons might account for their differential behavior. Conversely, a large midbrain section performed by knife cut could decrease both dopamine and DOPAC (one of its major acid metabolites) in the thoracic lateral horn and partly in the ventral one. The noradrenaline content was not reduced. Results are discussed in light of recently reported data on dopaminergic descending projections to the spinal cord. The lesion procedures presented here seem to provide valuable tools to dissociate noradrenergic from dopaminergic spinal projections, which is necessary for further anatomical and functional studies on these systems.     

Effect of microelectrophoretically applied acetylcholine, noradrenaline, dopamine and serotonin on the discharge of paraventricular oxytocinergic neurones in the rat

The effects of microelectrophoretic applications of neurotransmitter substances and their antagonists on the activity of paraventricular oxytocinergic neurones were studied in urethane anesthetized lactating rats. Oxytocinergic neurones were identified by their antidromic response to the stimulation of the neurohypophysis and by their characteristic high frequency discharge of action potentials approximately 15-20s before reflex milk ejection. Acetylcholine (ACh) excited the majority (75%) of paraventricular oxytocinergic neurones, and none of the cells was inhibited in its activity by ACh. In about half of the oxytocinergic cells, atropine and hexamethonium reduced the number of action potentials during the burst discharge preceding reflex milk ejection. Noradrenaline (NE), dopamine (DA) and serotonin (5-HT) reduced the activity of most (75-100%) of oxytocinergic neurones, and none of the cells was excited by these catecholamines. These results suggest that paraventricular oxytocinergic neurones receive excitatory cholinergic inputs and inhibitory noradrenergic, dopaminergic and serotonergic inputs.     

DSP 4, a neurotoxic agent that destroys noradrenergic endings, selectively increases "expectancy" in the cat

Cats were treated with DSP 4, a neurotoxic agent known to destroy central noradrenergic endings. A significant increase was subsequently noticed in the amount of time spent by the treated animals in an attitude of "expectancy", i.e. of motionless waiting for an "event to occur". They even developed this attitude when no such real situation existed. Concomitantly, an increase was noticed in the power of the 14 Hz electrocortical rhythms recorded over the somatic sensory cortex. These patterns, designated as "mu" rhythms, had previously been shown to characterize this particular type of attentive state. The present data tends to confirm our previous hypothesis, that immobile expectancy and its accompanying electrocortical pattern are under a noradrenergic inhibitory control.     

Catechol-O-Methyltransferase (COMT) Protein Expression and Activity after Dopaminergic and Noradrenergic Lesions of the Rat Brain

The occurrence of catechol-O-methyltransferase (COMT) in presynaptic neurons remains controversial. This study utilized dopaminergic and noradrenergic toxins to assess the presence of COMT in the presynaptic neurons originating from the substantia nigra, ventral tegmental area or locus coeruleus. Destruction of dopaminergic and noradrenergic neurons was assessed by measuring the dopamine and noradrenaline content in the projection areas of these neurons. Additionally, COMT protein expression and activity were examined in several projection areas to determine whether there are any changes in COMT values. Colocalization studies were done to identify COMT-containing postsynaptic neurons. Despite successful lesioning of dopaminergic and noradrenergic neurons, no changes in COMT protein expression or activity could be noted. These results strongly suggest that COMT is not present in presynaptic dopaminergic and noradrenergic neurons. There was a high colocalization of COMT with the GABAergic marker of short neurons both in the striatum and cortex but only a weak, if any, with the cholinergic marker in the cortex.     

Serious-mindedness and the effect of self-induced respiratory changes upon parietal EEG

The role of serious-mindedness (so-called telic dominance) in regulation of parietal cortex EEG was investigated. Ten telic (serious-minded) and 10 paratelic (playful state-dominant) individuals were selected on the basis of their responses to the Telic Dominance Scale. They all performed instructed breathholding (hypopnea) and excessive breathing (hyperpnea) in counterbalanced order. The paratelic individuals yielded relatively high scores of integral EEG power; theta power was markedly increased in the left hemisphere during hyperpnea, and reduced in the right hemisphere during hypopnea. Both hyperpnea and hypopnea were reported to be more aversive to the paratelic than to the telic subjects, but no group difference in respiratory activity was found. The electrocortical and hedonic tone differences between the groups are discussed in relation to the distinction between the prefrontal (dopamine) activation pathway and frontoparietal (noradrenalin) arousal pathway, as well as in relation to changes in cortical blood flow and proprioceptive feedback.     

Frontal Cortical and Left Temporal Glutamatergic Dysfunction in Schizophrenia

Glutamatergic mechanisms have been investigated in postmortem brain samples from schizophrenics and controls. D-[3H]Aspartate binding to glutamate uptake sites was used as a marker for glutamatergic neurones, and [3H]kainate binding for a subclass of postsynaptic glutamate receptors. There were highly significant increases in the binding of both ligands to membranes from orbital frontal cortex on both the left and right sides of schizophrenic brains. The changes are unlikely to be due to antemortem neuroleptic drug treatment, because no similar changes were recorded in other areas. A predicted left-sided reduction in D-[3H]aspartate binding was refuted at 5% probability, but not at 10%. Previously reported high concentrations of dopamine in left amygdala were strongly associated with low concentrations of D-[3H]aspartate binding in left polar temporal cortex in the schizophrenics. The findings are compatible with an overabundant glutamatergic innervation of orbital frontal cortex in schizophrenia. The results also suggest that schizophrenia may involve left-sided abnormalities in the relationship between temporal glutamatergic and dopaminergic projections to amygdala.     

Effects of weak electromagnetic fields on global electrocortical activity

Effects of weak electromagnetic fields are considered on recently proposed covariant and generalized coupling models of global electrocortical activity. A method to calculate the ratio of components of signal velocities is given. First-order shift in frequencies is obtained in the presence of a weak, time-varying magnetic field.     

Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats

In Parkinson's disease, nigral dopaminergic neurones degenerate, whereas post-synaptic striatal target neurones are spared. In some atypical parkinsonian syndromes, both nigral and striatal neurones degenerate. Reduced activity of complex I of the mitochondrial respiratory chain has been implicated in both conditions, but it remains unclear if this affects the whole organism or only the degenerating brain structures. We therefore investigated the differential vulnerability of various brain structures to generalized complex I inhibition. Male Lewis rats infused with rotenone, a lipophilic complex I inhibitor [2.5 mg/kg/day intraveneously (i.v.) for 28 days], were compared with vehicle-infused controls. They showed reduced locomotor activity and loss of striatal dopaminergic fibres (54%), nigral dopaminergic neurones (28.5%), striatal serotoninergic fibres (34%), striatal DARPP-32-positive projection neurones (26.5%), striatal cholinergic interneurones (22.1%), cholinergic neurones in the pedunculopontine tegmental nucleus (23.7%) and noradrenergic neurones in the locus ceruleus (26.4%). Silver impregnation revealed pronounced degeneration in basal ganglia and brain stem nuclei, whereas the hippocampus, cerebellum and cerebral cortex were less affected. These data suggest that a generalized mitochondrial failure may be implicated in atypical parkinsonian syndromes but do not support the hypothesis that a generalized complex I inhibition results in the rather selective nigral lesion observed in Parkinson's disease.     

Inference of a stable dispersion relation for electrocortical activity controlled by the lateral hypothalamus

A second test is undertaken for a theory of linear wave motion in electrocortical waves, under lateral hypothalamic control via regulation of damping. This test invokes a general property of linear systems, namely that wave motion with characteristic natural frequencies implies fixed phase velocities associated with each wavelength, independent of the changes in hypothalamic input. A means of testing the invariance of this dispersion relation at the point of recording is derived from a simplified biophysical model for waves in a dipole layer. The method avoids some problems implicit in direct spatio-temporal wave analysis. Results confirm that the model under test is internally consistent, and is also consistent with other findings concerning the origin and spatial nature of the EEG.     

The effects of tectal lesion on the survival of isthmic neurones in Xenopus

The isthmic nucleus (IN) is a visual relay centre of the frog brain. It receives afferent projection from the optic tectum of the same side and projects bilaterally to both tecta. In young postmetamorphic Xenopus frogs, the survival of neurones in the IN on both sides was studied following the complete removal of the right tectum. In 6- to 8-week-old frogs, the right tectum was surgically removed and the operated animals allowed to survive for 1 to 13 weeks after operation. In selected animals, 3 days before the intended sacrifice, the postoptic commissure was transected and the cut isthmotectal fibres filled with horseradish peroxidase (HRP). In serial paraffin sections of the midbrain, the numbers of surviving and dying (pyknotic) neurones in the left and right IN were counted. The soma size of viable isthmic neurones and the volume of both IN were measured. Pyknotic neurones were seen between 1 and 6 weeks after operation in both the left and right IN, although the rate of cell loss was much greater in the latter. Virtually all the neurones of the right IN degenerated by 6 weeks after tectal ablation. In contrast, approximately 60% of neurones of the left IN survived. HRP histochemistry showed labelled isthmic neurones both in the left and right IN up to 3 weeks after operation. Thereafter, HRP-labelled neurones appeared only in the left IN. These observations indicate that the removal of the natural target of isthmic neurones brings about severe neurone death.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of Dopaminergic Neurons in Denervation-Induced α1-Adrenergic Up-Regulation in the Rat Cerebral Cortex

The density of [3H]prazosin binding to alpha 1-adrenoceptors in the rat cortex was measured after selective and mixed noradrenergic or dopaminergic lesions. DSP-4 produced a selective noradrenergic lesion and increased the density of alpha 1-adrenoceptors. 6-Hydroxydopamine produced a selective dopaminergic lesion (after desipramine protection of noradrenergic neurons) and a mixed noradrenergic and dopaminergic lesion that did not change the cortical alpha 1-adrenoceptor binding. On the basis of the results obtained, a hypothesis is put forward that the central dopaminergic system controls the denervation-induced cortical alpha 1-adrenoceptor up-regulation.     

Long-term administration of cocaine or serotonin reuptake inhibitors results in anatomical and neurochemical changes in noradrenergic, dopaminergic, and serotonin pathways

The catechol and indole pathways are important components underlying plasticity in the frontal cortex and basal ganglia. This study demonstrates that administering rats either cocaine or a selective serotonin (or 5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) for 16 weeks results in reduced density of dopaminergic and noradrenergic terminals in the striatum and olfactory bulb, respectively, reflecting pruning of the terminal arbor of ventral midbrain dopaminergic and locus coeruleus noradrenergic neurones. In the striatum of cocaine-treated animals, basal dopamine levels, as well as cocaine-induced dopamine release, is diminished compared with controls. In contrast, serotonergic fibers, projecting from the raphe, sprout and have increased terminal density in the lateral septal nucleus and frontal cortex, following long-term cocaine or SSRI treatment. This is associated with elevated basal 5-HT and enhanced cocaine-induced 5-HT release in the frontal cortex. The anatomical and neurochemical changes in serotonergic fibers following cocaine or SSRI treatment may be explained by attenuated 5-HT_1A autoreceptor function in the raphe. This study demonstrates extensive plasticity in the morphology and neurochemistry of the catechol and indole pathways that contribute to drug-induced plasticity of the corticostriatal (and other) projections. Moreover, our data suggest that drug-induced plastic adaptation is anatomically widespread and consequently, likely to have multiple and complex consequences.     

Effects of Chronic and Subchronic Nicotine on Tyrosine Hydroxylase Activity in Noradrenergic and Dopaminergic Neurones in the Rat Brain

Chronic nicotine (0.8 mg/kg by daily subcutaneous injection) over a 7 to 28-day period was found to increase the activity of tyrosine hydroxylase in predominantly noradrenergically innervated regions but not in dopaminergic projection areas. Increases in tyrosine hydroxylase activity were observed in dopaminergic cell body regions only after nicotine treatment for 3 to 5 days. The increase in tyrosine hydroxylase activity in noradrenergic neurones was evident first in the cell bodies in the locus coeruleus from 3 to 7 days, reaching 223% of control activities, and was followed by increases of up to 205% in the terminals up to 3 weeks later. It was then established that nicotine for 7 days was sufficient to increase the activity of the enzyme to the same extent in the terminals at 21 days even without further nicotine administration. This is consistent with axonal transport preceded by induction of the enzyme in noradrenergic cell bodies, whereas "delayed activation" might account for the transient effect seen in dopaminergic cell body regions. The response in the locus coeruleus to nicotine for 7 days was completely blocked by daily preinjection with mecamylamine but not with hexamethonium, which is consistent with the effect of nicotine on tyrosine hydroxylase being mediated by central nicotinic receptors.     

Chronic guanethidine treatment of female rats including effects on the fetus.

Adult virgin female rats were injected daily with low doses (5 or 10 mg/kg) or a high dose (30 mg/kg) of guanethidine for 12 or 18 weeks respectively. 'Short' and 'long' noradrenergic neurones were unaffected by low doeses. This contrasts markedly to earlier findings in male rats in which long-term damage of 'short' noradrenergic neurones occurred, and indicates a basic difference between 'short' noradrenergic neurones in male and female rats. Widespread degeneration of both types of neurones followed treatment with high doses and little reinnervation was observed 8 weeks after cessation of treatment. Fertility, pregnancy and litter size were apparently unaffected. Some teratogenic effects were observed in the offspring of female rats treated with guanethidine (10 or 25 mg/kg/day) before and throughout pregnancy. However, these effects had largely disappeared by the time the offspring were 10 weeks old. Since noradrenergic neurones of newborn rats are particularly sensitive to damage by guanethidine it would appear that either very little guanethidine crosses the placental barrier or that noradrenergic neurones are not susceptible during prenatal development to the cytotoxic effects of guanethidine.