Dwight C. German

Electrophysiological evidence for excitation of rat ventral tegmental area dopamine neurons by morphine.

A considerable body of evidence indicates that opiates have an important influence on midbrain dopaminergic neurons. However, little data exist concerning the effects of opiates on the activity of single dopaminergic neurons, particularly the dopaminergic neurons of the ventral tegmental area. Firing rates of mesencephalic dopaminergic neurons were recorded extracellularly, and the effects of morphine, administered systemically or applied locally onto dopaminergic cells, were tested in paralyzed, unanesthetized or chloral hydrate anesthetized rats. In general, dopaminergic neurons were excited by both systemically and locally applied morphine. When mesencephalic dopaminergic neurons were subdivided into substantia nigra zona compacta (A9) and ventral tegmental area (A10) neurons, A10 neurons were excited 2-3 times more than A9 neurons by systemic morphine. Systemic administration of the specific opiate antagonist, naloxone, in large part reversed the effects of morphine. Microiontophoretic or micropressure ejection of morphine caused an apparent depolarization-induced excitation of both A10 and A9 dopaminergic neurons. These results provide direct evidence that morphine increases impulse flow of A10 dopaminergic neurons, which are known to be involved in locomotor stimulant and positive reinforcement effects of opiates.

Catecholamine systems as the neural substrate for intracranial self-stimulation: a hypothesis.

Abstract The hypothesis was investigated that activation of central catecholamine (CA) systems is essential for intracranial self-stimulation (ICSS). Brain sites that support ICSS in the rat were found to be highly correlated with electrodes in 3 major CA systems: the mesolimbic and nigrostriatal dopaminergic systems and the dorsal noradrenergic system. Stimulation at ICSS loci in the brain stem causes release of catecholamines at terminals in ascending CA systems. Lesion studies show suppression of ICSS proportional to the degree of damage to the stimulated CA system. Drugs influence ICSS in accordance with their effects on transmission at dopaminergic and noradrenergic synapses. Enhancement of nicotinic-cholinergic mechanisms facilitates ICSS, but the effect requires that CA mechanisms be intact. Neurophysiological experiments suggest that two systems characterized by different axonal refractory periods are involved in ICSS. The data are insufficient to determine whether these correspond to the dopamine and norepinephrine systems. Norepinephrine has an inhibitory effect at many postsynaptic receptor sites, and ICSS is often accompanied by reduction or cessation of cellular discharges in NE terminal areas. Food ingestion has also been demonstrated to produce an inhibitory effect on cells in a noradrenergic terminal area. ICSS has been demonstrated in numerous species, including man, in brain areas that overlap considerably with loci whose stimulation supports ICSS in the rat. Stimulation of ICSS loci in man is commonly associated with verbal reports of intense pleasurable sensations.

Activity of mesencephalic dopamine and non-dopamine neurons across stages of sleep and waking in the rat

Single unit activity of dopamine and non-dopamine neurons in the substantia nigra and ventral tegmental area was recorded across stages of sleep and waking in the rat. These stages consisted of slow wave sleep (SWS), rapid eye movement (REM) sleep, awake-quiet (AQ) and awake-moving (AM). The dopamine neurons showed no change in mean firing rate across the stages of sleep or waking. During REM sleep, however, the dopamine cells fired with a more variable interspike interval than during SWS. In contrast, non-dopamine neurons in the substantia nigra and ventral tegmental area showed large increases in firing rate in REM compared to SWS, and in AM compared to AQ, without showing changes in interspike interval variability. In conclusion, whereas other monoaminergic neurons and various cortical and subcortical neurons exhibit marked changes in firing rate across the stages of sleep and waking, the dopamine neurons are unique in their lack of change in firing rate across stages.

Axonal and transneuronal transport in the transmission of neurological disease: Potential role in system degenerations, including alzheimer's disease

Neurons depend upon the processes of axonal and transneuronal transport for intra- and intercellular communication and trophic support. Experimental studies in the last decade have elucidated the mechanisms underlying these processes, and provided evidence for their role in the spread of viral and toxic diseases through the nervous system. Recent advances in neuroanatomy, and in the pathological study of certain degenerative conditions, such as Alzheimers disease, suggest that the same principles may underlie the anatomical specificity of cell loss in a variety of system degenerations. In Alzheimers disease, as well as in olivo-ponto-cerebellar atrophy, progressive supranuclear palsy, amyotrophic lateral sclerosis, primary autonomic failure of the Shy-Drager type, and other system degenerations, the main feature that marks the affected populations of neurons is their anatomical interconnectivity. We consider here the possibility that, in these conditions, the processes of axonal and transneuronal transport may subserve the transmission from neuron to neuron of a toxic or infectious agent, or alternatively that the diseases may result from the failure of normal transport of a trophic agent. This hypothesis not only provides a unifying framework in which to view a variety of seemingly disparate conditions, but also suggests certain approaches to identifying the causative agents.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian syndrome in Macaca fascicularis: which midbrain dopaminergic neurons are lost?

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces, in both human and non-human primates, a syndrome very similar to idiopathic Parkinsons disease. The syndrome is associated with degeneration of the dopamine-containing neurons in the substantia nigra, many of which project to the neostriatum. The purpose of the present study was to quantify the regional distribution of midbrain dopamine neurons remaining after MPTP administration to the monkey (Macaca fascicularis) and to develop alternative procedures for maintaining the normal nutrition in MPTP-treated animals. Three monkeys were treated with MPTP and three served as controls. Representative sections were examined from rostral to caudal through the midbrain dopamine cell nuclei and the location of every tyrosine hydroxylase-containing cell was entered into a computer. Midbrain dopamine neuronal cell loss ranged from 36-78%, being most extensive in the two monkeys which exhibited the most severe parkinsonian syndrome. The greatest cell loss (46-93%) occurred in the substantia nigra pars compacta, or nucleus A9, and the loss was primarily in the ventral portion of the nucleus. Contrary to most previous reports, however, there was also a loss of cells in the ventral tegmental area (28-57%) and ventral reticular formation (33-87%), corresponding to nuclei A10 and A8, respectively. Since neuroanatomical tracing studies have shown that the dorsal and lateral portions of the striatum (areas showing the greatest dopamine depletion after MPTP) receive input from cells in the ventral A9 and from cells in the A8 and A10 areas, the present data suggest that MPTP preferentially destroys dopamine cells that project to the striatum (i.e. the mesostriatal cells).

Alzheimer's disease: neurofibrillary tangles in nuclei that project to the cerebral cortex.

We have used an antibody to the paired helical filament protein to immunohistochemically identify the regional distribution of subcortical nuclei containing neurofibrillary tangles in brains from Alzheimers disease patients. Sections were examined from the cerebral cortex, diencephalon, midbrain and pons in seven Alzheimers and three age-matched normal brains. The antibody sensitively stained the many tangles, and senile plaques, in the cerebral cortex of the Alzheimers brains and the few tangles and senile plaques in the aged normal cortex. Ten subcortical nuclei contained many tangles in the Alzheimers brains. The tangles were found not only within the locus coeruleus and dorsal raphe nucleus, which often have been shown to be involved in Alzheimers neuropathology, but also within several other nuclei not previously related to this disease. For example, tangles were found in the nucleus paranigralis, peripeduncular nucleus, medial parabrachial nucleus and several midline thalamic nuclei. All of the nuclei which contained tangles have been shown, in neuroanatomical tracing studies, to project to the cerebral cortex. These data indicate that Alzheimers disease is a disease of the cerebral cortex and the numerous subcortical nuclei which diffusely innervate it, and are consistent with the hypothesis that the cerebral cortex is the primary target of the disease and the interconnected subcortical nuclei are secondarily affected due to retrograde transport of a cortical pathogen or failure of normal transport of a trophic agent.

Effects of chronic desipramine treatment on rat brain noradrenergic responses to α-adrenergic drugs☆

It has been previously reported that long-term tricyclic antidepressant treatment in the rat causes a subsensitivity of central beta-receptor-stimulated adenylate cyclase along with alterations of brain norepinephrine (NE) content and metabolism. We have confirmed earlier findings that after one week of desipramine treatment (5.0 mg/kg b.i.d.) brain NE levels decline while NE metabolism is similar to control animals, but is above control after 12 days of treatment. Single cell recordings from noradrenergic neurons of the locus coeruleus (LC) show that after one week of desipramine treatment, neuronal firing rate is lower than in control rats but greater than that seen in response to acutely administered drug. Furthermore, desipramine injection in a dose which profoundly altered LC impulse flow in control rats produced little or no effect on impulse flow in chronically treated rats. Of 25 or 250 microgram/kg doses of clonidine, which are equieffective for decreasing brain NE metabolism in control animals, only the larger dose decreased NE metabolism in 12 day desipramine-treated rats. The postsynaptic alpha-antagonist prazosin (5.0 mg/kg) increased NE metabolism in both groups. These results suggest that presynaptic (alpha 2) adrenoreceptors become subsensitive during long-term desipramine treatment, thus allowing recovery of noradrenergic impulse flow in the presence of NE uptake inhibition.

Neuronal pathology in the nucleus basalis and associated cell groups in senile dementia of the Alzheimer's type Possible role in cell loss

The loss of cortical cholinergic innervation in senile dementia of the Alzheimers type (SD AT) is associated with cell loss in the nucleus basalis and related cell groups (magnocellular basal nucleus, MBN). We examined MBN in Nissl-, acetylcholinesterase- and thioflavin S-stained sections in two cases of SDAT and in four control brains. Using these sensitive methods, senile plaques were easily demonstrated in MBN, and most MBN neurons showed neurofibrillary degeneration as an early change. Cell loss appeared to be due to maturation of neurofibrillary tangles, displacing normal cellular contents. In contrast to theories that the cell loss in MBN represents retrograde degeneration due to axonal injury in the cerebral cortex, MBN neuronal perikarya may be involved by the same primary processes as cortical neurons.

Mesencephalic dopaminergic unit activity in the behaviorally conditioned rat.

Abstract The activity of single dopamine (DA)-containing cells in the medial substantia nigra and ventral tegmental area was recorded in awake behaving rats. These rats were trained, using either instrumental or classical conditioning techniques, to respond for chocolate milk reinforcement. More than 50% of the cells tested showed changes in firing pattern associated with some aspect of the conditioned response. Furthermore, the incidence of active DA cells and their firing rates were increased in animals given the DA receptor blocker, haloperidol. Our results indicate that some DA cells change their firing pattern following behaviorally relevant stimuli, and that the incidence of spontaneously active DA neurons is low in the awake rat.

Primate neostriatal neurons containing tyrosine hydroxylase: Immunohistochemical evidence

We have detected, in monkey caudate nucleus and putamen, neuronal cell bodies containing tyrosine hydroxylase-like immunoreactivity, as revealed by peroxidase-antiperoxidase immunohistochemistry. Many of these cells are distributed in an outer rim of 1-2 mm throughout the anterior-posterior extent of the neostriatum near its borders with the corona radiata; others are embedded in the adjacent white matter, especially near the ventral putamen and nucleus accumbens. Light and electron microscopy indicate that they are small (8-12 micron), bipolar cells with large nuclei. Such neostriatal neurons, containing tyrosine hydroxylase-like immunoreactivity, number in the tens of thousands.