The role of dopaminergic (DA) neurons in brain stimulation reward produced by electrical stimulation of the ventral tegmental area (VTA) was investigated in the rat. In the first experiment, extensive 6- hydroxydopamine lesions of the ascending fibers of the mesotelencephalic DA projections resulted in significant changes in intracranial self-stimulation (ICS) rate-current intensity functions when the lesion was ipsilateral to the stimulating electrode. Similar contralateral lesions had no effect on these functions, thus ruling out lesion-induced performance deficits as being responsible for the decreases in ICS rates across the wide range of current intensities that occurred after the ipsilateral lesions. In the second experiment, ICS obtained from electrodes in the VTA resulted in significant increases in the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum, nucleus accumbens, and olfactory tubercle ipsilateral to the stimulating electrode. The ratios of DOPAC and HVA to DA, considered to be indices of DA utilization, were also increased in these brain regions ipsilateral to the electrode. No changes were observed in the contralateral striatum, nucleus accumbens, and olfactory tubercle. Similar increases were observed in stimulated “yoked” animals that received brain stimulation at identical rates and currents but did not lever-press for this stimulation. The third experiment examined the effects of lever- pressing for food on an FR8 schedule of reinforcement on DA utilization in the striatum, nucleus accumbens, and olfactory tubercle. Despite high rates of responding, no effects were observed on DOPAC:DA or HVA:DA ratios in these brain regions.

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The conditioned place preference (CPP) paradigm is used widely as a measure of a drug's rewarding properties. The present study examined whether the CPP produced by amphetamine is dependent on the locomotor stimulation that is produced by the drug. An earlier study (Swerdlow and Koob 1984) found that interfering with locomotor stimulation using restraint during the drug treatment blocked CPP. The present study examined whether this effect of restraint was indeed due to restriction of locomotion or was due to restraint maintaining the stimulus novelty of the CPP apparatus. The first experiment showed that novelty of the apparatus itself was a potent factor in the CPP paradigm and was capable of producing a place preference. The second experiment showed that restraint alone could produce a CPP, as would be expected if it maintained stimulus novelty of the apparatus. It also showed that although a CPP to amphetamine could be blocked by restraining the animals during drug treatment, prior habituation to the apparatus to reduce stimulus novelty before treatment negated the effect of restraint on amphetamine CPP. These results indicate that rats can demonstrate a CPP produced by amphetamine even when their activity is restrained. This suggests that the drug's rewarding properties are not dependent on locomotor stimulation.

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Alzheimer's disease (AD) is associated with an early impairment in memory and is the major cause of dementia in the elderly. b-Amyloid (Ab) is believed to be a primary factor in the pathogenic pathway leading to dementia. Mounting evidence suggests that this syndrome begins with subtle alterations in synaptic efficacy prior to extensive neuronal degeneration and that the synaptic dysfunction could be caused by diffusible oligomeric assemblies of Ab. This paper reviews the findings from behavioral analysis, electrophysiology, neuropathology and nootropic drug screening studies involving exogenous administration of Ab in normal rodent brains. This non-transgenic model of amyloid pathology in vivo is presented as a complementary alternative model to transgenic mice to study the cellular and molecular pathways induced by amyloid, which in turn may be a causal factor in the disruption of cognition. The data reviewed here confirm that the diffusible form of Ab rapidly induces synaptic dysfunction and a secondary process involving cellular cascades induced by the fibrillar form of amyloid. The time-course of alteration in memory processes implicates at least two different mechanisms that may be targeted with selective therapies aimed at improving memory in some AD patients.Keywords: Alzheimer's disease, amyloid, learning and memory, microglia, rodents, synaptic plasticity The familial and sporadic form of AD share the same neuropathological pattern, characterized by extracellular amyloid plaques comprised of b-amyloid (Ab), a metabolic product of the transmembrane protein amyloid precursor protein (APP), and intracellular neurofibrillary tangles comprised of hyperphosphorylated protein (see Selkoe 2001 for review). The accumulation of Ab and neurofibrillary tangles mainly in the temporal cortex and hippocampus produces local inflammation, characterized by glial and microglial activation, synaptic loss and local neurodegeneration which together account for the clinical signs of the disease. Despite the remarkable progress in our genetic and cellular understanding of the pathogenic pathway, the relationship between the different molecular players in AD and the link with the amnesic symptoms are still to be ascertained. The evolving amyloid hypothesisOne predominant hypothesis of AD pathogenesis is that Ab accumulation in the brain parenchyma is a primary event that triggers the pathological cascade leading to neurodegeneration. In support of this hypothesis, mutations of the APP and presenilin (PS ) genes and duplication of chromosome 21 (trisomy 21), which alter Ab production, are dominant genetic factors leading to AD (Hardy & Higgins 1992). Most of the mutations cluster at, or very near to, the sites within APP that are normally cleaved by proteases called a-, b-, g-and e-secretases (see Selkoe & Schenk 2003 for review). These mutations promote the generation of Ab by favoring proteolytic processing of APP by b-and g-secretases (Cai et al. 1993;Citron et al. 1992;Suzuki et al. 1994). Furthermore, APP mutations within ...