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Somatostatin levels and high-affinity (somatostatin-1) binding sites are decreased in post-mortem cortical samples of Alzheimer's disease patients but the relationships between such modifications and the cognitive deficits remain to be established. We investigated these relationships in the ageing rat. Three age groups (3-4, 14-15 and 26-27 months) were tested in a modified version of the Morris water maze. Somatostatin mRNA levels were quantified by in situ hybridization and somatostatin binding sites by radioautography using the selective agonist octreotide (SMS 201995) as a competing drug to evaluate high-affinity (somatostatin-1) and low-affinity (somatostatin-2) binding sites. The number of somatostatin mRNA-containing cells was not modified with age or memory performance in cortical, hippocampal and hypothalamic regions, but somatostatin mRNA densities were significantly decreased with age and with memory performance in the frontal and parietal cortex. In the frontal cortex somatostatin mRNA densities were already decreased in 14- to 15-month-old rats, whereas the decrease was observed only in 26- to 27-month-old rats in the parietal cortex. A decrease in somatostatin-1 binding was observed with memory performance, independently of age, in the basolateral amygdala only, while somatostatin-2 binding sites were not affected. In the frontal and parietal cortex, a significant correlation occurred between the latency to find the invisible platform in the water maze and somatostatin mRNA (r = -0.54 and 0.59 respectively, P < 0.02). These results indicate that ageing rats with memory impairments display some of the features of the somatostatinergic deficits observed in Alzheimer's disease.

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The effects of the centrally acting anticholinesterase metrifonate (MFT) and its metabolite dichlorvos (2,2-dichlorovinyl dimethyl phosphate; DDVP) on local cerebral glucose utilization (LCGU) have been studied in 3- and 27-month-old rats, using the autoradiographic [14C]deoxyglucose technique. In 3-month-old rats, MFT (80 mg/kg i.p.) increased LCGU significantly in 17 of the 54 regions studied, including insular, cingulate, and temporal cortices, ventral hippocampus, thalamus, lateral habenula, substantia nigra, and superior colliculus. In these regions, the average MFT-induced increase in LCGU was 23% above control. The average hemispheric LCGU increased by 10% (p < 0.01). DDVP (5 mg/kg) increased LCGU in 19 regions (average increase 26%). The average hemispheric LCGU increased by 9% (p < 0.01). Regional distributions of MFT- and DDVP-induced increases in LCGU were similar and overlapped the distribution of the acetylcholinesterase activity. In 27-month-old rats, MFT was active in 18 regions (average increase 25%). The whole-brain mean LCGU increased by 10% (p < 0.01). MFT compensated for the age-related hypometabolism in some brain areas including insular, temporal, and retrosplenial cortices, substantia nigra, and superior colliculus. The effects of MFT on LCGU were preserved in old rats, at variance with other anticholinesterases (tacrine, physostigmine), which are less active in the aged rat brain.

Summary: The effects of the centrally acting anti cholinesterases tacrine (tetrahydroaminoacridine, THA) and physostigmine (PHY), on local cerebral glucose uti lization (LCGU) have been studied in 27-month-old rats, using the autoradiographic e4Cjdeoxyglucose technique. THA (10 mg/kg i.p.) increased LCGU significantly in 13 of the 54 regions studied (24%) including insular, parietal, temporal, and retrosplenial cortices, septohippocampal system, thalamus, lateral habenula, and superior collicu Ius. In these regions, the average THA-induced increase in LCGU was 24% above control. The whole brain mean LCGU was not significantly increased. PHY (0. 5 mg/kg) increased LCGU in 18% of the regions (average eleva tion, 23%). The whole brain mean LCGU increased byThe centrally acting cholinesterase inhibitor tet rahydroaminoacridine (THA, tacrine) has been re ported to improve cognitive deficits in subpopula tions of Alzheimer's disease (AD) patients. Several multicenter studies (Eagger et aI., 1991; Davis et aI. , 1992; Farlow et aI., 1992; Knapp et aI., 1994) have confirmed the initial positive results of Sum mers (S ummers et aI., 1986). The effects of THA in mildly demented AD patients persist during long term treatment and indicate that THA might not only act on symptoms but also delay the disease process (Nordberg et aI., 1992). The mechanisms mediating the effects of THA are far from clear, but experimental data indicate that THA may produce its therapeutic effects, at least in part, via its action on cholinergic transmission (for review, see Free man and Dawson, 1991). In experimental animals, 1093 7% (p < 0.05). The regional distributions of THA-and PHY-induced increases in LCGU were extremely similar and overlapped the distribution of the M2 muscarinic re ceptors and that of acetylcholinesterase activity, suggest ing that the major effects of THA and PHY on LCGU result from their anticholinesterase action. As compared to those of 3-month-old rats, both the number of regions affected and the amplitude of the metabolic activation were significantly less in aged rats. However, the drugs were still active in old rats and compensated for the age related hypometabolism in some brain areas.