Choline chloride fails to improve cognition of Alzheimer's disease.

Seven mildly to moderately demented patients with Alzheimer's disease were treated with either placebo or choline chloride (50, 100 and 200 mg/kg/24 hrs) in a double blind, crossover study. Detailed psychometric analysis was carried out at the end of each two-week period of drug or placebo administration. No subjects showed significant overall improvement at any dose level despite more than a doubling of the baseline plasma choline level.

Excretion of amines and their metabolites by two patients in hepatic coma treated with L-dopa.

Two patients in hepatic coma were treated with L-dopa. The first patient showed clear clinical improvement, but the second patient did not. Analyses of urinary metabolites indicated that L-dopa was not absorbed by the second patient. There was evidence that L-dopa had the following beneficial effects in the first patient: (1) increased production of urine, which could have been accompanied by increased excretion of toxins; (2) displacement of tyramine from transmitter sites (because increased excretion of p-hydroxyphenylacetic acid, a major metabolite of tyramine, occurred during L-dopa treatment in patient 1); (3) replenishment of dopamine, and to a much lesser extent, norepinephrine, at central or peripheral neuroeffector junctions; and (4) scavenging of methyl groups by L-dopa, because ratio of methylated amines to catecholamines was higher than normal in both comatose patients before L-dopa treatment, and this ratio decreased during L-dopa treatment in patient 1.

Ventricular fluid homovanillic acid and 5-hydroxyindoleacetic acid concentrations in patients with movement disorders.

Ventricular fluid concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), the respective metabolites of dopamine and serotonin, were measured in 57 patients undergoing thalamotomy for relief of movement disorders. The diseases included were Parkinson disease, dystonia, cerebral palsy, multiple sclerosis, and posttraumatic or posthypoxic encephalopathy. Untreated parkinsonian patients had the lowest mean HVA level (119 ng per milliliter). Patients with multiple sclerosis or with posttraumatic or posthypoxic encephalopathy with both intellectual impairment and bilateral motor involvement had lower mean HVA levels (197 and 177 ng per milliliter, respectively) than cerebral palsy patients with bilateral motor disease (233 ng per milliliter), dystonia patients (246 ng per milliliter), or multiple sclerosis patients with normal intellect (376 ng per milliliter). The data suggest that diffuse cerebral disease may lead to diminished dopaminergic activity. Ventricular fluid 5-HIAA levels were similar in all groups of patients. Chronic cerebellar stimulation markedly increased ventricular fluid HVA and 5-HIAA levels, indicating that cerebellar stimulation affected cerebral dopaminergic and serotonergic systems.

Diminished ventricular fluid dopamine metabolites in adult-onset dystonia.

Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), the respective metabolites of dopamine and serotonin, were measured in ventricular fluid obtained from 20 patients with torsion dystonia at the time of ventriculography prior to thalamic surgery. The patients could be divided into two distinct types of dystonia--childhood-onset and adult-onset--which were identifiable on clinical and biochemical grounds. In the 14 patients with childhood-onset dystonia, the first symptom appeared in one limb in early childhood and the disease usually progressed rapidly. In the six patients with adult-onset dystonia, the first symptom usually appeared in axial muscles after adolescence and the disease progressed slowly. Ventricular fluid HVA levels were significantly lower in the patients with adult-onset dystonia than in those with childhood-onset dystonia. The differences suggest diminished dopaminergic activity, possibly secondary to nigrostriatal dysfunction, in adult-onset dystonia.

Ventricular fluid somatostatin concentration decreases in childhood-onset dystonia.

Somatostatin was measured in CSF from individuals with a variety of neurologic diseases. In ventricular CSF, somatostatin concentration was significantly lower in individuals with childhood-onset dystonia than in individuals with other forms of dystonia or with other disorders. Severity of childhood dystonia correlated with somatostatin concentration, suggesting a progressive dysfunction of somatostatin-containing neurons with increasing disease severity. There were no significant differences in somatostatin concentration in lumbar CSF. Multiple forms of immunoreactive somatostatin were found in a pool of lumbar CSF from normal individuals. Labeled somatostatin administered intra-arterially to rats failed to cross the blood-brain barrier.

Decreased ventricular fluid norepinephrine metabolite in childhood-onset dystonia.

3-methoxy-4-hydroxyphenylglycol (MHPG), the primary brain metabolite of norepinephrine (NE), was measured in ventricular fluid from 51 patients with dystonia, other movement disorders, or hydrocephalus. The dystonic patients were divided into three categories: childhood-onset form with early limb dystonia and rapid progression to generalized symptoms, more localized and benign adult-onset dystonia, and symptomatic dystonia. Patients with the childhood form had significantly lower ventricular fluid MHPG levels (8.7 +/- 0.6 ng per milliliter) than other dystonic patients (11.4 +/- 1 ng per milliliter), age-matched controls with neurologic disease (11.7 +/- 1.1 ng per milliliter), or other movement disorders (11.8 +/- 0.7 ng per milliliter). Decreased ventricular fluid MHPG levels suggest a possible abnormality of brain NE function in childhood dystonia.

Striatal met-enkephalin concentration increases following nigrostriatal denervation.

Following specific lesion of the nigrostriatal dopaminergic pathways in rat brain, striatal met-enkephalin on the lesioned side increased to 245% of that on the non-lesioned side. This increase was evident only after a lag period of 7 days and the increase was maintained for at least 2 months after lesion. By contrast, there was no change in striatal somatostatin or vasoactive intestinal polypeptide concentration, indicating that the effect was not a generalised one. Levels of all three of these neuropeptides were unchanged in frontal cortex. These findings support the concept of a dopaminergic-enkephalinergic functional interrelationship in the striatum. In addition, the findings provide evidence that, following destruction of nigrostriatal dopaminergic neurons, not only is there a gradually developing postsynaptic dopamine receptor supersensitivity but also a compensatory alteration in the enkephalinergic system.

Patterns of dystonia ("I-D-I" and "D-I-D-") in response to l-dopa therapy for Parkinson's disease.

The clinical, biochemical, and pharmacologic responses to L-dopa were studied in 87 patients with Parkinson's disease. Eleven of the 87 patients had a long-duration response, 39 had a short-duration response, and 37 had a combination of both. Thirty-four of the 39 patients with short-duration response to L-dopa experienced a consistent and reproducible sequence of clinical and biochemical events after each dose, characterized by improvement of parkinsonism and a single phase of dystonia occurring during or shortly after the peak of dopa concentration in plasma and during maximal clinical improvement. We have called this the I-D-I- response, for Parkinsonism-Improvement-Dystonia-Improvement-Parkinsonism. The remaining five patients all had the onset of the disease at an unusually young age and showed a distinctly different response pattern consisting of a first phase of dystonia, before there was any improvement, followed by a phase of improvement without dystonia and then by a second phase of dystonia before the abrupt return of parkinsonism. We have called this the D-I-D response, for Parkinsonism-Dystonia-Improvement-Dystonia-Parkinsonsim. Dystonia occurs in the D-I-D- response when the concentration of dopa in plasma passes through a critical but relatively low level, whereas it remains absent as long as the concentration of dopa remains above that level. In the I-D-I- response, dystonia is avoided by keeping the plasma concentration of dopa low, in the D-I-D- response by keeping it high. It is postulated that in the D-I-D response postsynaptic depolarization blockade due to supramaximal stimulation of the neuronal system mediating dystonia occurs, whereas in the I-D-I response the postsynaptic members of the same neuronal population respond with excitation but not with depolarization blockade.

Vasoactive intestinal peptide in cerebrospinal fluid.

Immunoreactive vasoactive intestinal peptide (VIP) was measured in lumbar and ventricular cerebrospinal fluid (CSF) from patients with various neurological disorders and in 2 hour aliquots of cisternal fluid removed continuously from rhesus monkeys. Although most of the VIP in concentrated pools of human ventricular fluid and of monkey cisternal fluid co-eluted with synthetic porcine VIP28 on a column of Sephadex G-25 superfine, there was evidence that smaller immunoreactive fragments were also present. A circadian pattern of CSF VIP concentration was observed in 2 of the 3 monkeys studied, with highest levels occurring at night and lowest during the day. Ventricular fluid VIP levels were highest in hydrocephalic children and lowest in patients with multiple sclerosis or epilepsy, while VIP was not detectable in ventricular fluid from patients in coma following a severe head injury. There were no significant differences in VIP concentrations in CSF from patients with dystonia. Parkinson's disease, or Alzheimer's disease, suggesting that VIP containing neurons are not affected in these disorders. Lumbar fluid VIP levels were low in patients undergoing aneurysm surgery. Since VIP is a potent vasodilator, these findings may have important implications in relation to the development of vasospasm following subarachnoid hemorrhage.

Kindling in developing rats: variability of afterdischarge thresholds with age.

In the kindling model, the occurrence of afterdischarges is necessary for the development of seizures. In this study, the afterdischarge thresholds of the amygdala were determined in rats of 4 different age groups, beginning with 15-day-old suckling rats. Afterdischarges were triggered in 75% of the suckling rats and in all of the rats in the older age groups. The afterdischarge thresholds varied with age, being highest in the suckling group, lowest in the 35-day-old group and intermediate in the older groups. This variability of the thresholds did not correlate with the alterations in the catecholamine levels in the amygdala that occur during maturation. The failure of 25% of suckling rats to develop afterdischarges may explain why some suckling rats do not kindle.

Dopamine receptor sensitivity following nigrostriatal lesion in the aged rat.

This investigation sought to determine whether the ability to regulate dopamine receptor sensitivity following removal of dopaminergic innervation is altered during aging. Aged (24-26 months old) Fisher 344 rats compared with young (6 months old) rats had lower levels of dopamine and dopamine receptor binding ([3H]ADTN), but no change of dopamine-stimulated adenylate cyclase activity. Unilateral lesion of the nigrostriatal pathway produced equivalent dopaminergic denervation in rats of both age groups. The denervated striata of young rats had greatly enhanced dopaminergic sensitivity as evidenced by apomorphine induced rotational behavior and increased dopamine stimulated adenylate cyclase activity and [3H]ADTN binding. Old rats responded similarly with a very high degree of increased dopaminergic sensitivity in both the behavioral and biochemical parameters, demonstrating that the ability to regulate dopamine receptors remains basically intact. However, deficits of supersensitivity occurred in apomorphine induced rotational behavior and [3H]ADTN binding and there was a large deficit in the guanine nucleotide sensitive subcomponent of [3H]-ADTN binding. Supersensitivity of dopamine stimulated adenylate cyclase was not altered. The diminished ability to develop supersensitivity to [3H]ADTN binding could contribute to decreased [3H]ADTN binding in unlesioned rats.

Unilateral peri-substantia nigra catecholaminergic lesion and amygdala kindling.

Recent evidence suggests that the substantia nigra (SN) may be involved in the modulation of kindled seizures in adult rats. In this report we investigated the role of the dopaminergic nigrostriatal pathway in mediating the SN effect on seizures by lesioning this pathway with unilateral infusions of 6-hydroxydopamine (6-OHDA) in the vicinity of the right SN with or without desmethylimipramine pretreatment. Our data suggest that the facilitation of amygdala kindling observed following 6-OHDA lesion in the vicinity of the ipsilateral SN is due to norepinephrine depletion of the ipsilateral forebrain. Selective destruction of the nigrostriatal dopaminergic neurons neither facilitates nor inhibits the development of amygdala-kindled convulsions in adult rats.

Age-related changes in striatal dopamine activity following nigral muscimol infusions.

Microinfusions of muscimol into the substantia nigra pars reticulata produced marked increases in striatal dopamine (DA) utilization without affecting striatal DA concentration in adult rats. In contrast, muscimol increased striatal DA concentration and decreased DA utilization in 16-day-old rat pups. The striatal norepinephrine concentration was not altered in either group. Since previous studies have shown that similar infusions of muscimol are anticonvulsant in adults and proconvulsant in rat pups, our results suggest that the nigrostriatal pathway may play an important role in mediating the nigral effects on seizures.

Free and conjugated dopamine in human ventricular fluid.

Free dopamine and an acid hydrolyzable conjugate of dopamine were measured in human ventricular fluid specimens with a radioenzymatic assay and by high performance liquid chromatography (HPLC) with electrochemical detection. Only trace amounts of free norepinephrine and dopamine were detected in ventricular fluid from patients with movement disorders. When the ventricular fluid was hydrolyzed by heating in HClO4 by lyophilization in dilute HClO4, however, a substantial amount of free dopamine was released. Values for free plus conjugated dopamine in ventricular fluid from patients who had never taken L-DOPA ranged from 139 to 340 pg/ml when determined by HPLC and from 223 to 428 pg/ml when measured radioenzymatically. The correlation coefficient for values obtained by the two methods in the same sample of CSF was 0.94 (P less than 0.001). Patients who had been treated with L-DOPA had higher levels of conjugated dopamine in their ventricular CSF which correlated inversely with the time between the last dose of L-DOPA and withdrawal of the ventricular fluid. Additionally, one patient with acute cerebral trauma had elevated levels of free norepinephrine and both free and conjugated dopamine in his ventricular fluid. Conjugation may be an important inactivation pathway for released dopamine in man.

The effects of delta 9-tetrahydrocannabinol on potassium-evoked release of dopamine in the rat caudate nucleus: an in vivo electrochemical and in vivo microdialysis study.

The effect of systemically administered delta 9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, on the potassium-evoked release of dopamine (DA) was examined in the neostriatum of the chloral hydrate anesthetized rat. Both in vivo electrochemical and in vivo microdialysis techniques were employed. A low dose of THC (0.5 mg/kg, i.p.) increased the time course of potassium-evoked in vivo electrochemical signals corresponding to released extracellular DA. In vivo microdialysis showed an increase in potassium-evoked DA release following 0.5 and 2.0 mg/kg doses of THC. Potassium-evoked electrochemical signals corresponding to released extracellular DA were augmented in time course following i.p. administration (5.0 mg/kg) of nomifensine, a recognized and potent catecholaminergic reuptake blocker. In addition, in vivo brain microdialysis studies of nomifensine (5.0 mg/kg i.p.) on neostriatal potassium-evoked DA release showed that DA levels were augmented in magnitude over the time course of the microdialysis. Taken together, these studies indicate that THC has a potent presynaptic augmenting effect on at least the neostriatal portions of the mesotelencephalic DA system in the rat, although the possibility that this effect could be mediated transsynaptically cannot be ruled out. Given the previous extensive evidence for an involvement of portions of the mesotelencephalic DA system in mediating the reinforcing and euphorigenic properties of many classes of abused drugs, and in mediating direct electrical brain stimulation reward, we suggest that the presently demonstrated effects of THC on forebrain dopamine function may be related to marijuana's euphorigenic properties and, thus, to its abuse potential.

Evidence for selective loss of brain dopamine- and histamine-stimulated adenylate cyclase activities in rabbits with aging.

Dopamine-stimulated adenylate cyclase activity in striatum and both dopamine- and histamine-stimulated adenylate cyclase activity in hypothalamus, frontal cortex and anterior limbic cortex declined by about 50% as rabbits aged from 5.5 months to 5.5 years of age. These changes were primarily in maximal response to amine although an additional component involving decreased affinity in the case of dopamine may also be present. In contrast, dopamine-stimulated adenylate cyclase of retina and both basal and guanyl-5'-yl-imidodiphosphate (Gpp(NH)p)-stimulated activity in these regions were not altered with age. There was no measurable decrease in the old animals in either dopamine or norepinephrine concentration in striatum, anterior limbic cortex or retina, or in choline acetylase activity or [3H]quinuclidinylbenzilate binding in striatum, anterior limbic cortex or frontal cortex. It is proposed that selective age-dependent decreases in transmitter receptors coupled to adenylate cyclases occur in the absence of or independent from neuronal cell loss, as evidenced by the retention of the other biochemical markers.

Acute and chronic effects of oral physostigmine and lecithin in Alzheimer's disease.

Alzheimer patients were treated with lecithin and gradually increasing doses of oral physostigmine during a drug trial to determine if these compounds would improve memory. Memory was measured using a selective reminding task. Of 16 patients, 10 showed improvement in total recall, retrieval from long-term storage and a decrease in intrusions. The optimal dose was 2.0 mg or 2.5 mg of physostigmine per dose for most patients. During a replication study, all 10 patients again responded. During long-term (4 to 20 months) treatment of five patients, most demonstrated continued drug response initially but then lost responsiveness to physostigmine and their dementia progressed. Physostigmine treatment appeared to improve memory with or without concomitant lecithin therapy. However, progressive dementia ensued despite physostigmine therapy. The degree of memory improvement correlated with increasing cerebrospinal fluid cholinesterase inhibition suggesting that memory improvement is associated with entry of physostigmine into the brain.

Classical conditioning, decay and extinction of cocaine-induced hyperactivity and stereotypy.

Following 10 daily pairings of multiple conditioned stimuli with injection of cocaine (15 mg/kg), the presentation of the stimuli alone elicited behaviors in rats similar to those induced by cocaine. The behaviors included increased duration or frequency of rearing, sniffing, head bobbing, and horizontal locomotor activity (crossing). The level of the conditioned response for several of these behaviors approximated that induced by the drug itself. The conditioned drug effect showed decay over 15 days but little extinction during 4 daily trials. Brain concentrations of the dopamine metabolites, homovanillic acid and dihydroxyphenylacetic acid, were similar in the conditioned and pseudoconditioned control groups in both the caudate and mesolimbic areas. The behavioral results demonstrate that, in a classical conditioning paradigm, previously neutral stimuli can elicit behaviors similar to those induced by cocaine and that certain conditioned responses show time related decline. This agrees with the reported conditioning of amphetamine's behavioral effects but differs in terms of the action on brain dopamine turnover.

Intranigral GABAergic drug effects on striatal dopamine activity.

Concentrations of striatal dopamine (DA), serotonin (5-HT) and their metabolites were measured following infusions of the GABAA receptor agonist, muscimol, or GABAA receptor antagonist, bicuculline, into the substantia nigra (SN) or areas dorsal to the SN in adult rats and 16-day-old rat pups. Results indicated that intranigral infusions of muscimol produced site-specific increases in the concentrations of striatal DA metabolites in adults, while in pups, intranigral muscimol infusions produced site-specific increases in the concentrations of striatal DA. Intranigral infusions of bicuculline had no effect on striatal DA or its metabolites in either age group. Neither GABAergic drug had any effect on striatal 5-HT or its metabolite. The data suggest that the effect of nigral GABAA agonist infusions on the activity of the nigrostriatal pathway is age-specific. The lack of opposing effects following the nigral infusion of a GABAA receptor antagonist indicates that the influences of GABAA agonists may be mediated by different mechanisms as a function of age.