James L. Hill

Clock Drawing in Alzheimer's Disease: A Novel Measure of Dementia Severity

We have tested a simple and reliable measure of visuospatial ability in Alzheimer patients — the Clock Drawing Test. To determine the usefulness of this measure, we asked 67 Alzheimer patients and 83 normal controls to draw the face of a clock reading the time of 2:45. Six independent observers blindly evaluated the results with ratings from 10 (best) to 1 (worst). The mean performance score of Alzheimer subjects was 4.9 ± 2.7 compared to 8.7 ± 1.1 for normal controls (P < .001). Inter‐rater reliability for the clocks drawn by Alzheimer patients was highly significant (r = 0.86; P < .001), and there was relatively little overlap between ratings for Alzheimer patients and normal controls. Furthermore, correlations were highly significant (P < .001) between the mean score of clock drawings and three independent global measures of dementia severity. Although the Clock Drawing Test is certainly not a definitive indicator of Alzheimers disease, the test is easy to administer and provides a useful measure of dementia severity for both research and office settings where sophisticated neuropsychological testing is not available.

Comparative anxiogenic, neuroendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers

The serotonin agonist m-chlorophenylpiperazine (m-CPP) had greater anxiogenic and other mood and cognitive effects when administered intravenously (0.1 mg/kg) rather than orally (0.5 mg/kg) to healthy subjects. Nonetheless, similar elevations in peak plasma cortisol and prolactin concentrations were obtained with the two dosage regimens, and temperature elevations were greater after oral m-CPP. Plateau phase plasma concentrations of m-CPP at the times of the maximum neuroendocrine responses to intravenous and oral m-CPP were similar. Since all rodent and nonhuman primate studies have used parenterally administered m-CPP, and previous clinical investigations using intravenous rather than oral m-CPP have yielded somewhat discrepant results, our normative data should be useful for comparing results, our normative data should be useful for comparing results across different human studies and across species.

Rat pup ultrasonic isolation calls: possible mediation by the benzodiazepine receptor complex

Rat pups, while separated from their littermates and placed in a novel environment, emit ultrasonic isolation calls. These ultrasonic calls decrease in number, power, and frequency following administration of the anxiolytic, diazepam (0.5 mg/kg). Pentylenetetrazol (20 mg/kg), which has been reported to be clinically anxiogenic, increases the number and the power of these calls. These changes following diazepam and pentylenetetrazol administration are dose dependent and do not appear to be secondary to nonspecific effects of these drugs on arousal or thermoregulation. The benzodiazepine receptor antagonist RO 15-1788, which has generally been reported to lack intrinsic activity at low doses, also decreases the number of rat pup isolation calls. These findings suggest that the benzodiazepine-GABA receptor-chloride channel complex may play a role in the physiologic mediation of the rat pup isolation call.

Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants.

Regional expression and antidepressant drug-induced regulation of mRNA encoding the serotonin (5-HT) transporter were studied in rat brain. While 5-HT transporter mRNA is abundantly expressed in the midbrain raphe complex, lower concentrations were also found in frontal cortex, hippocampus, and neostriatum using a combination of reverse transcriptase-polymerase chain reaction (RT-PCR), Southern hybridization, and sequence analysis. Long-term administration of antidepressants which inhibit 5-HT reuptake, but not monoamine oxidase inhibitors or 5-HT receptor agonists, decrease 5-HT transporter mRNA steady-state concentrations. Based on these observations, we conclude that (1) mRNA coding for the 5-HT transporter is present in several brain areas associated with ascending HT pathways, and (2) chronic treatment with reuptake inhibiting antidepressants may be associated with regulation of the 5-HT transporter at the level of gene expression which may contribute to the neuroadaptive mechanisms that likely underlie their therapeutic efficacy.

Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model

18 older normal volunteers (mean age = 66.5 +/- 7.9 years) and 46 younger volunteers (mean age = 27.0 +/- 6.1 years) were administered the anticholinergic drug scopolamine (0.5 mg i.v.) followed by a battery of cognitive tests evaluating attention, learning and memory. The older subjects were significantly more impaired than the younger by scopolamine on some tests of learning and memory. This increased sensitivity of the older group to scopolamine is consistent with studies in animals and humans showing decreased cholinergic system function with age. The findings also indicate that age is an important variable to consider in using the scopolamine model of memory impairment. The cognitive impairment caused by scopolamine in younger subjects in this and prior studies is similar to some, but not all aspects of the impairment which occurs in normal aging. Scopolamine also caused impairments on digit span and word fluency tasks, which are not consistent with normal aging changes. In the older group of subjects, scopolamine produced aspects of the cognitive impairment which occurs in AD on tests of episodic memory and learning, vigilance-attention, category retrieval, digit span, and number of intrusions. Other areas of cognition that are of relevance to aging and AD such as psychomotor speed, praxis, concept formation and remote memory were not evaluated in this study. Some of these are being evaluated in ongoing studies, along with additional and more specific tests of retrieval from knowledge memory, implicit memory and attention. The scopolamine model has provided a fruitful pharmacologic starting point for the study of a number of cognitive operations. The idea of dissecting apart aspects of memory systems pharmacologically depends on the availability of neurochemically specific drugs and on the specificity and sensitivity of neuropsychological tests for distinct cognitive operations or domains. Further studies using such tools will aid not only in the understanding of the impairments which occur in aging and in AD, but also of the conceptualization of memory and other cognitive operations and ultimately the physiological mechanisms involved in memory and learning.

Metergoline blocks the behavioral and neuroendocrine effects of orally administered m-chlorophenylpiperazine in patients with obsessive-compulsive disorder

The pharmacological probe, meta-chlorophenylpiperazine (m-CPP), administered orally to patients with obsessive-compulsive disorder (OCD) has been shown to induce an acute exacerbation in OCD symptoms as well as an exaggerated anxiogenic response in comparison with controls. The mechanism of m-CPPs behavioral effects in humans remains controversial. To further study m-CPPs actions in OCD patients, we completed a series of double-blind pharmacological challenges in 12 OCD patients. Six OCD patients received four separate challenges: placebo, metergoline, m-CPP, and metergoline plus m-CPP; the second group (n = 6) received metergoline and metergoline plus m-CPP in separate challenges. OCD patients receiving placebo or metergoline alone failed to show evidence of significant changes on any of the behavioral rating scales, in contrast to the patients who received m-CPP alone who exhibited significant increases in anxiety and OCD symptoms. However, the 12 OCD patients who received pretreatment with metergoline before m-CPP experienced no significant changes from baseline OCD symptoms or other behavioral changes. m-CPPs ability to elicit elevations in plasma prolactin was blocked by metergoline pretreatment. Metergolines ability to block m-CPPs effects on behavior and plasma prolactin lends further support to a serotonergic mediation of m-CPPs effects, including its elicitation of OCD symptoms.

A controlled comparison of adjuvant lithium carbonate or thyroid hormone in clomipramine-treated patients with obsessive-compulsive disorder

In this study, 16 patients with obsessive-compulsive disorder (OCD) who had partially improved during at least 6 months of treatment with clomipramine were sequentially treated with triiodothyronine and lithium carbonate in an 8-week double-blind crossover study. Both triiodothyronine and lithium carbonate have been reported to be efficacious in open trials as adjunctive agents when combined with tricyclics in the treatment of OCD and depressed patients. However, in our controlled study, OCD and depressive symptoms, as assessed by standardized rating scales in the patient group as a whole, did not significantly change after either adjuvant treatment. Further analysis on an individual patient basis revealed that neither adjuvant medication was associated with a clinically meaningful change (>25%) in OCD symptoms. However, lithium, but not triiodothyronine, adjuvant therapy was associated with a 25% or greater reduction in depression scores in 44% of the patients. This controlled study lends further support to the contention that OCD may represent a disorder with characteristics distinct from affective disorders.

A comparison of the behavioral effects of oral versus intravenous mCPP administration in OCD patients and the effect of metergoline prior to IV mCPP

In prior studies form three centers, an exacerbation of obsessive-compulsive disorder (OCD) symptoms was reported in some (55%-83%) patients with OCD receiving the serotonergic agonist m-chlorophenylpiperazine (m-CPP) orally, whereas intravenously administered mCPP produced anxiety but no OCD symptom exacerbation. In the present replication attempt, 27 OCD patients were given mCPP either orally (n = 17) or intravenously (n = 10) under double-blind conditions, using identical behavioral rating measures. OCD symptoms were significantly increased after intravenous mCPP (0.1 mg/kg), but not after oral mCPP (0.5 mg/kg). Anxiety and other ratings were markedly elevated after intravenous mCPP administration. After oral mCPP administration, anxiety and most other self-ratings were only slightly elevated in comparison to placebo administration, and behavioral rating increases were no different for the OCD patients compared to age-matched healthy controls. Pretreatment with the potent serotonin (5-HT) antagonist, metergoline, prior to intravenous mCPP was associated with essentially complete blockade of the exacerbation in OCD symptoms and the other behavioral responses in the OCD patients. These results suggest that the behavioral response of OCD patients to mCPP are variable and depend on the route and dose of mCPP. In addition, the ability of metergoline to antagonize the behavioral effects of intravenous mCPP suggests that these responses are mediated by 5-HT1/5-HT2 receptors.

Food intake, neuroendocrine and temperature effects of 8-OHDPAT in the rat

Administration of 8-hydroxy-2(di-n-propylamino)tetralin (8-OHDPAT) to rats produced dose-dependent decreases in food intake and hypothermia, increases in plasma prolactin and corticosterone, and a decrease in plasma growth hormone. 8-OHDPAT administration also induced the serotonin behavioral syndrome at all doses. Pretreatment with metergoline did not affect the 8-OHDPAT-induced behavioral syndrome or decrease in food intake but attenuated the prolactin increase and, furthermore, potentiated 8-OHDPAT-induced hypothermia. Pretreatment with ritanserin or naloxone did not modify 8-OHDPAT-induced changes in food intake, temperature or prolactin. Similarly, pretreatment with phenoxybenzamine, propranolol, clonidine, haloperidol and methiothepin also did not attenuate 8-OHDPAT-induced decreases in food intake. Administration of pindolol alone produced hyperthermia, decreased food intake and enhanced prolactin secretion. Pindolol thus appears to act as a partial 5-HT agonist in addition to being an antagonist at central 5-HT receptors.

Cognitive and Behavioral Effects of Cholinergic, Dopaminergic, and Serotonergic Blockade in Humans

The purpose of this study was to investigate the cognitive and behavioral effects of anticholinergic, antidopaminergic, and antiserotonergic agents given alone and in combination to normal volunteers. Twelve young male volunteers took part in this double-blind, randomized, placebo-controlled, crossover study of six drug conditions, each administered on separate days [haloperidol (2 mg PO) ± scopolamine (0.5 mg IV), metergoline (4 mg PO) ± scopolamine (0.5 mg IV), placebo, and scopolamine alone (0.5 mg IV)]. Scopolamine-induced sedation (p <. 01), slowed information processing (p <. 01) and impaired new learning and memory (p <. 01), but did not affect attention or retrieval from semantic memory. Given alone, haloperidol selectively impaired the ability to rapidly switch cognitive sets (p <. 05), and metergoline decreased pupil size (p <. 01) but did not induce cognitive deficits. In combination with scopolamine, neither haloperidol nor metergoline produced a worsening of the subjects′ cognitive performance above and beyond that seen with scopolamine alone. On the contrary, a trend (p <. 10) for haloperidol to reverse some of the scopolamine-induced exacerbation of verbal short-term forgetting was observed. The data indicate that scopolamine and haloperidol can independently and selectively affect cognition and that at the doses tested in this study no synergistic exacerbation of cognitive functioning was found when cholinergic blockage was coupled with dopaminergic or serotonergic blockade.