Arjun Sahgal

Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer's and Parkinson's diseases

The binding of the selective 5-HT2 antagonist [3H]ketanserin has been investigated in the temporal cortex of patients with Alzheimers disease (SDAT), Parkinsons disease (PD), senile dementia of Lewy body type (SDLT) and neuropathologically normal subjects (control). 5-HT2 binding was reduced in SDAT, PD with dementia and SDLT. SDAT showed a 5-HT2 receptor deficit across most of the cortical layers. A significant decrease in 5-HT2 binding in the deep cortical layers was found in those SDLT cases without hallucinations. SDLT cases with hallucinations only showed a deficit in one upper layer. There was a significant difference in cortical layers III and V between SDLT without hallucinations and SDLT with hallucinations. The results confirm an abnormality of serotonin binding in various forms of dementia and suggest that preservation of 5-HT2 receptor in the temporal cortex may differentiate hallucinating from non-hallucinating cases of SDLT.

A Comparative Study of Attentional Deficits in Senile Dementias of Alzheimer and Lewy Body Types

Most neuropsychological studies of senile dementia, including Alzheimers type (SD AT) and Lewy body type (SDLT), have investigated mnemonic deficiencies. In this study, we compared and contrasted att

Memory following cholinergic (NBM) and noradrenergic (DNAB) lesions made singly or in combination: Potentiation of disruption by scopolamine☆

Groups of rats were trained on either delayed matching or nonmatching to position tasks, then divided into four subgroups and given the following bilateral lesions: (a) SHAM [vehicle injection into the nucleus basalis magnocellularis (NBM) and dorsal noradrenergic bundle (DNAB)], (b) DNAB (6-hydroxydopamine lesion of the DNAB, vehicle into the NBM), (c) NBM (quisqualic acid lesion of the NBM, vehicle into the DNAB) and (d) DUAL (neurotoxin lesions of both DNAB and NBM). Following postoperative recovery, the DUAL lesion subjects were slightly impaired, but by the seventh day of testing all groups were performing at similar levels. This strongly suggests that quisqualate lesions of the NBM are not sufficient to produce severe and lasting mnemonic disorders resembling those seen in Alzheimers disease (AD). These data also indicate that the noradrenergic system may not be of critical importance with respect to cognition. It was reasoned that an additional anticholinergic treatment might exacerbate an underlying deficiency. All groups were injected, peripherally, with the cholinergic antagonist scopolamine (0-0.5 mg/kg). This drug dose-dependently disrupted performance in all groups. Moreover, the highest dose had a marked effect in the DUAL group, impairing performance even when no mnemonic burden was present (at zero delay). The results suggest that cholinergic NBM and noradrenergic DNAB lesions produce only transient mnemonic deficiencies. A combination of the two can be disruptive, but longer term task (or reference) memory is the primary process affected, and only under certain conditions. The implication of these findings to research concerning animal models relating to Alzheimers disease is discussed.

Examination of Parameters Influencing [3H]MK-801 Binding in Postmortem Human Cortex

Abstract: [3H]MK‐801 binding was used as an index of the glutamate receptor W‐methyl‐D‐aspartate‐subtype channel to examine the influence of gender, age, mode of death (agonal status), interval between death and autopsy (postmortem delay), and time in storage at ‐70°C in well washed homogenate preparations from postmortem human frontal cortex. Basal binding and the modulatory effects of glutamate, glycine, spermidine, and zinc were examined with respect to these variables. Basal binding was sensitive to agonal status, being higher in sudden death cases. The effect of added glutamate and glycine was sensitive to age, with a trend toward lower binding with increasing age. The effect of added spermidine alone was sensitive to storage time at ‐70°C, the binding being higher with longer storage time. The effect of added zinc was also sensitive to postmortem delay, with zinc causing a greater reduction in binding with shorter postmortem delays. Thus, with the exception of gender, all variables examined influenced [3H]MK‐801 binding, highlighting the attention that should be given to these factors in postmortem studies in normal and diseased human subjects.

The effects of thyrotropin releasing hormone on a visual discrimination task in rats.

The effects of intracerebroventricular (ICV) administration of thyrotropin releasing hormone (TRH, 1 and 50 micrograms) were assessed on a two-choice visual discrimination task. The data were analysed using signal detection theory techniques in order to test for changes in cognitive and response factors. No significant changes in performance were observed. In a second experiment, the effects of TRH (100 micrograms ICV) on performance were compared with amphetamine (AMP, 1 mg/kg, intra-peritoneally, IP) and a metabolite of TRH, histidyl-proline diketopiperazine (DKP, 100 micrograms ICV). No significant effects on performance as measured by standard indices were observed. However, both TRH and AMP, but not DKP, significantly increased perseverative responding on one lever with respect to saline. In keeping with recent evidence, it is concluded that the traditional non-parametric signal detection parameters of sensitivity and bias are insensitive to certain strategies. Possible mechanisms for the perseveration of responding, and its relationship to stereotypic behaviour, are discussed in the light of the known effects of each compound on dopaminergic systems.

The effects of thyrotropin releasing hormone on rats with lesions of the mesolimbic and nigrostriatal dopamine systems

We report the effects of intracerebroventricular (ICV) administration of thyrotropin releasing hormone (TRH), a TRH metabolite histidyl-proline diketopiperazine (DKP) and systemically administered d-amphetamine (AMP) on the locomotor activity of two groups of rats which had previously received bilateral injections of either 6-hydroxydopamine (6-OHDA) or saline into the nucleus accumbens. Both TRH and AMP enhanced locomotor activity in control, but not lesioned animals, whereas DKP had very little effect. In a second experiment, the effects of ICV administration of saline, TRH and DKP were tested on rotational behaviour in rats with unilateral lesions of the substantia nigra. Neither peptide induced significant circling on its own. However, coadministration of TRH or DKP with systemically administered AMP enhanced rotation above that found after injection of AMP alone. These results suggest that TRH can act on mesolimbic and nigrostriatal dopamine systems, either directly or by modulating the effects of other dopaminergic agents.