G. Frederick Wooten

Blood-brain barrier changes with kainic acid-induced limbic seizures

Rats were treated with kainic acid (KA) i.v. to produce increasingly severe limbic seizures that were monitored with a behavioral rating scale. At various times after the induction of seizures, the animals; blood-brain barriers (B-BB) were studied with alpha-[14C]aminoisobutyric acid ([14C]AIBA) autoradiography. Using optical density ratios, a coefficient was devised to assess the functional integrity of the B-BB in discrete anatomic regions and to quantitatively compare these measurements among different groups of experimental animals. In animals that exhibited only mild seizures, the B-BB was not different from controls. Animals with severe limbic seizures, however, showed alterations. For as long as 2 h after delivery of KA, the B-BB appeared normal; from 2 to 24 h, the permeability to [14C]AIBA was markedly increased throughout the brain, especially in limbic regions; from 24 h to 7 days the B-BB returned to normal except for a small residual change in limbic structures. These findings were confirmed with Evans blue dye studies of the B-BB. A correlation between focal accentuation of B-BB alterations and neuropathologic changes was found. These experiments indicted that recurrent limbic seizures may lead to a breakdown in the B-BB independent of systemic metabolic derangements. Marked focal metabolic and electrical changes, however, occurred in several limbic structures several hours before the blood-brain barrier was altered.

Depression is associated with impairment of ADL, not motor function in Parkinson disease

Depression was diagnosed in 15% of 100 consecutive patients with Parkinson disease (PD). Depression was associated with lower cognition, history of depression, and a higher Unified Parkinson’s Disease Rating Scale score. The latter was due to differences in the activities of daily living (ADL) subscale (17 ± 7 vs 12 ± 6; p = 0.004) rather than the motor subscale (30 ± 13 vs 26 ± 13; p = 0.27). These results suggest that ADL impairment may in part be due to depression. Patients with PD with poor function should be closely evaluated for depression.

Regulation of rat adrenal dopamine β-hydroxylase. II. Receptor interaction in the regulation of enzyme synthesis and degradation

Rat adrenal gland dopamine beta-hydroxylase is under neuronal regulation from the splanchnic nerve and hormonal control via adrenal cortical glucocorticoids. The regulatory systems act in different ways; neuronal stimuli induce dopamine beta-hydroxylase synthesis while hormonal stimulation inhibits enzyme degradation. Despite these mechanistic differences, both systems require a normally innervated cholinergic receptor to exert their effect. The enzyme response to either neural stimulation or ACTH administration is blocked by splanchnic denervation. Glucocorticoid stimulation of dopamine beta-hydroxylase, however, can occur after adrenal denervation, suggesting that ACTH acts on a receptor which requires splanchnic innervation, but glucocorticoids act distal to the receptor. Similar results were obtained when the effect of these manipulations were studied on phenylethanolamine N-methyltransferase, another enzyme in the catecholamine biosynthetic pathway. A model attempting to unify these and earlier findings is presented, in which the splanchnic nerve is involved in regulating both adrenal cortical glucocorticoidogenesis (by allowing ACTH to act on glucocorticoid synthesis) and adrenal medullary catecholamine biosynthesis (by induction of enzyme synthesis.).

A behavioral and 2-deoxyglucose autoradiographic study of the effects of cumulative morphine dose on naloxone precipitated withdrawal in the rat.

Abstract We have studied regional cerebral metabolism by 2-deoxyglucose autoradiography in 67 brain structures of morphine-dependent rats during fixed dose naloxone precipitated withdrawal. Behavioral indices of withdrawal were studied simultaneously in the same animals used in the cerebral metabolism studies. The effects of cumulative morphine dose (470, 1145 and 2345 mg/kg) with fixed dose (0.5 mg/kg) naloxone precipitated withdrawal upon behavioral and cerebral metabolic measures of the severity of withdrawal were compared. All morphine dependent groups studied exhibited the known behavioral sequelae of naloxone precipitated withdrawal. Qualitative withdrawal signs exhibited by all dependent groups included tachypnea, ptosis, penile erection, ejaculation, diarrhea, urination, salivation, lacrimation, rhinorrhea, and irritability. Quantitative signs of withdrawal for 470, 1145 and 2345 mg/kg cumulative morphine dose groupds were as follows (mean ± S.D.): wet shakes/50 min5.8 ± 1.0; 4.4 ± 0.8; 8.4 ± 1.4; acute weight loss (g)14.0 ± 5.6; 3.4 ± 1.0; 6.8 ± 3.2; ‘jumping’ attempts/50 min10.2 ± 5.7; 25.7 ± 5.9; 3.8 ± 1.2. None of the behavioral measures of morphine withdrawal showed cumulative morphine dose dependency. Metabolic mapping (using 2-deoxyglucose) of functional activity during naloxone precipitated withdrawal revealed several brain regions with cumulative morphine dose dependent increases in glucose utilization. The percentage increase in glucose utilization for several rat brain structures for the 3 cumulative morphine morphine dose treatment groups were as follows: diagonal band 51, 63, 87, medial preoptic area 36, 45, 74; lateral preoptic area 24, 47, 77; globus pallidus 19, 53, 62; paraventricular hypothalamus 56, 98, 118; lateral hypothalamus 65, 84, 112; nucleus accumbens 36, 51, 79; medial septum 49, 50, 88; lateral septum 66, 58, 119; central nucleus amygdala 36, 50, 55; medial mammillary nucleus 25, 87, 103; lateral mammilliary nucleus 27, 82, 97; anteroventral thalamus 63, 87, 107; nucleus centromedianus 34, 68, 78; lateral habenula 93, 119, 158; ventral tegmental area 23, 31, 79; interpeduncular nucleus 59, 94, 121; dorsal raphe 21, 48, 86; median raphe 37, 48, 84. Numerous gray structures additionally analyzed failed to show cumulative morphine dose dependent functional activity changes during fixed dose naloxone precipitated withdrawal. Examples of such unaffected structures, representative of several CNS systems, were the frontal motor and cingulate cortices, anterior hypothalamic area, medial and lateral entorhinal cortices, the dentate gyrus and perforant pathway, medial nucleus of the amygdala, medial geniculate nucleus, red nucleus, the pontine reticular formation, and cranial nerve nuclei III, VII, VIII. Thus, in several brain regions, there were clear cumulative morphine dose dependent increases in glucose utilization. Standard behavioral analyses of withdrawal in the same animals failed to demonstrate clear dose dependency. Metabolic mapping of brain regions showing time and dose effects of opiate drug treatments may facilitate the identification of CNS structures participating in opiate withdrawal phenomena. Once such structures are identified, brain regions of interest can be specifically studied with respect to potential molecular mechanisms of opiate dependence and withdrawal.

A highly sensitive radioenzymatic assay for simultaneous estimation of norepinephrine, dopamine, and epinephrine

We have developed a radioenzymatic assay for simultaneous estimation of norepinephrine (NE), dopamine (DA), and epinephrine (E) that was the result of the integration of several unique features of previously described assay procedures. Catecholamines in sera or tissue homogenates were enzymatically O-methylated in the presence of partially purified catechol-O-methyltransferase with S-[methyl-3H] adenosyl methionine serving as the methyl donor. The O-methylated products were then separated by thin-layer chromatography, eluted from the gel, and their tritium content determined. The assay allows measurement of catecholamines with a sensitivity in the ranges of 15-20 pg. In addition, the assay is highly specific, reproducible, relatively rapid and simple, and inexpensive.

Norepinephrine synthesis contributes to the accumulation of catecholamines after ligation of rat sciatic nerves

Norepinephrine (NE) accumulates proximal to lesions or constrictions in rat sciatic nerve 3. Current evidence suggests that the accumulating NE is contained in granular vesicles which are synthesized in cell bodies and rapidly transported along the axon to noradrenergic nerve terminals3, 5. In addition to NE these vesicles contain dopamine-fl-hydroxylase (DBH), the enzyme which catalyzes the conversion of dopamine to NE 5. As expected, the initial rates of accumulation of NE and DBH proximal to peripheral sympathetic nerve lesions are similar 1,3,7. However, there is an apparent discrepancy regarding the length of time that the accumulations of NE and DBH continue after peripheral nerve constriction. NE accumulation proximal to a ligation of rat sciatic nerve continues for up to 48 h3, 6, while DBH accumulation is linear for, at most, only 12 h 1,4,7. Development of a highly sensitive assay for NE 2 has afforded an opportunity to study quantitatively NE accumulation and to attempt to elucidate the mechanism of continued NE accumulation after that of DBH has ceased. Experiments were designed to test the hypothesis that the continued NE accumulation was due either to decreased breakdown or to synthesis of NE in situ. The sciatic nerves of ether anesthetized male Sprague-Dawley rats (250 g) were exposed and were ligated with 4-0 silk. Eight to 72 h later rats were killed by cervical dislocation and 1 cm segments proximal to the ligation and 1 cm segments from the corresponding portion of the unoperated contralateral control sciatic nerve were removed and assayed for NE or DBH. Segments (l cm) of sciatic nerve were homogenized in 750 #1 of 0.05 N HCI-1 m M MgC12. Aliquots of the supernatant fluid were analyzed for NE by the radioenzymatic method using [3H]S-adenosylmethionine as methyl donor as previously described 2. Results are expressed as either the ratio of NE content in the nerve segment proximal to the ligation to that of the contralateral control segment, or as ng of NE per 1 cm nerve segment. The time course of accumulation of NE proximal to a nerve ligation is shown in

Capgras Syndrome in Advanced Parkinson’s Disease

Psychosis is common in Parkinsons disease (PD), especially in advanced disease, and can lead to a number of psychotic symptoms, including delusions. One uncommon delusion is Capgras syndrome (CS). The authors report on three PD patients with a history of deep brain stimulation (DBS) who developed this delusion. The anatomic targets in these three patients were the subthalamic nuclei in two patients and the globus pallidus interna in one patient. The length of time between surgery and development of CS varied but was greater than 6 months. Additionally, all three patients showed evidence of impaired cognition prior to development of CS. Therefore, due to the length of time between DBS and CS in all three cases and the fact that one patient developed CS months after DBS explanation, DBS does not appear to be associated with CS. Given the distressing nature of this condition, patients with advanced PD who undergo DBS should be regularly screened for symptoms of psychosis with awareness of CS as a potential form.

MM1-Type Sporadic Creutzfeldt-Jakob Disease With Early Behavioral Changes and Prolonged Symptom Duration

To the Editor: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative prion disease, most commonly presenting with memory loss, aphasia, and frontal/executive dysfunction. Other presenting symptoms include cerebellar dysfunction, constitutional symptoms, or behavioral changes and psychiatric symptoms. Eighty-five percent of CJD cases are sporadic (sCJD), resulting from spontaneous transformation of the prion protein into a misfolded conformation. The duration of symptoms of sCJD is variable and is related, in part, to the different molecular subtypes of the prion protein. Parchi et al. classified six main subtypes of sCJD based on a methionine/valine polymorphism at codon 129 of the prion protein gene (PRNP) and the associated type of prion protein (1 or 2). Classification of sCJD based on genotype and molecular markers allows for characterization of the associated phenotypes, including symptoms at disease onset, age at onset, and duration of symptoms. We report a case of MM1-type sCJD with a symptom duration of at least 48 months.