MRI Clinical Ratings and Cognitive Function in a Cross-Sectional Population Study of Dementia: The Cache County Memory Study.

BACKGROUND: White matter integrity in aging populations is associated with increased risk of cognitive decline, dementia diagnosis, and mortality. Population-based data can elucidate this association. OBJECTIVES: To examine the association between white matter integrity, as measured by a clinical rating scale of hyperintensities, and mental status in older adults including advanced aging. DESIGN: Scheltens Ratings Scale was used to qualitatively assess white matter (WM) hyperintensities in participants of the Cache County Memory Study (CCMS), an epidemiological study of Alzheimer's disease in an exceptionally long-lived population. Further, the relation between Mini-Mental State Exam (MMSE) and WM hyperintensities were explored. METHOD: Participants consisted of 415 individuals with dementia and 22 healthy controls. RESULTS: CCMS participants, including healthy controls, had high levels of WM pathology as measured by Scheltens Ratings Scale score. While age did not significantly relate to WM pathology, higher Scheltens Ratings Scale scores were associated with lower MMSE findings (correlation between -0.14 and -0.22; p < .05). CONCLUSIONS: WM pathology was common in this county-wide population sample of those ranging in age from 65 to 106. Increased WM burden was found to be significantly associated with decreased overall MMSE performance.

Neuropsychiatric symptoms as risk factors for progression from CIND to dementia: the Cache County Study.

OBJECTIVES: To examine the association of neuropsychiatric symptom (NPS) severity with risk of transition to all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD). DESIGN: Survival analysis of time to dementia, AD, or VaD onset. SETTING: Population-based study. PARTICIPANTS: 230 participants diagnosed with cognitive impairment, no dementia (CIND) from the Cache County Study of Memory Health and Aging were followed for a mean of 3.3 years. MEASUREMENTS: The Neuropsychiatric Inventory (NPI) was used to quantify the presence, frequency, and severity of NPS. Chi-squared statistics, t-tests, and Cox proportional hazard ratios were used to assess associations. RESULTS: The conversion rate from CIND to all-cause dementia was 12% per year, with risk factors including an APOE ε4 allele, lower Mini-Mental State Examination, lower 3MS, and higher CDR sum-of-boxes. The presence of at least one NPS was a risk factor for all-cause dementia, as was the presence of NPS with mild severity. Nighttime behaviors were a risk factor for all-cause dementia and of AD, whereas hallucinations were a risk factor for VaD. CONCLUSIONS: These data confirm that NPS are risk factors for conversion from CIND to dementia. Of special interest is that even NPS of mild severity are a risk for all-cause dementia or AD.

The association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer's disease.

OBJECTIVE: The use of psychotropic medications in Alzheimer's disease (AD) has been associated with both deleterious and potentially beneficial outcomes. We examined the longitudinal association of psychotropic medication use with cognitive, functional, and neuropsychiatric symptom (NPS) trajectories among community-ascertained incident AD cases from the Cache County Dementia Progression Study. METHODS: A total of 230 participants were followed for a mean of 3.7 years. Persistency index (PI) was calculated for all antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (atypical and typical), and benzodiazepines as the proportion of observed time of medication exposure. Mixed-effects models were used to examine the association between PI for each medication class and Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-Sum), and Neuropsychiatric Inventory - Total (NPI-Total) trajectories, controlling for appropriate demographic and clinical covariates. RESULTS: At baseline, psychotropic medication use was associated with greater severity of dementia and poorer medical status. Higher PI for all medication classes was associated with a more rapid decline in MMSE. For antidepressant, SSRI, benzodiazepine, and typical antipsychotic use, a higher PI was associated with a more rapid increase in CDR-Sum. For SSRIs, antipsychotics, and typical antipsychotics, a higher PI was associated with more rapid increase in NPI-Total. CONCLUSIONS: Psychotropic medication use was associated with more rapid cognitive and functional decline in AD, and not with improved NPS. Clinicians may tend to prescribe psychotropic medications to AD patients at risk of poorer outcomes, but one cannot rule out the possibility of poorer outcomes being caused by psychotropic medications.

Intracranial volume and dementia: some evidence in support of the cerebral reserve hypothesis.

The brain reserve hypothesis has been posited as being one important mediating factor for developing dementia, especially Alzheimer's disease (AD). Evidence for this hypothesis is mixed though different methodologies have made these findings difficult to interpret. We examined imaging data from a large cohort (N=194) of mixed dementia patients and controls, 65years old and older from the Cache County, Utah Study of Memory and Aging for evidence of the brain reserve hypothesis using total intracranial volume (TICV) as a quantitative measure of pre-morbid brain size and a vicarious indicator of reserve. A broader spectrum of non-demented elderly control subjects from previous studies was also included for comparison (N=423). In addition, non-parametric Classification and Regression Tree (CART) analyses were performed to model group heterogeneity and identify any subgroups of patients where TICV might be an important predictor of dementia. Parametrically, no main effect was found for TICV when predicting a dementia diagnosis; however, the CART analysis did reveal important TICV subgroups, including a sex differential wherein ε4 APOE allele presence in males and low TICV predicted AD classification. TICV, APOE, and other potential mediator/moderator variables are discussed in the context of the brain reserve hypothesis.

Does NSAID use modify cognitive trajectories in the elderly? The Cache County study.

BACKGROUND: Epidemiologic studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful for the prevention of Alzheimer disease (AD). By contrast, clinical trials have not supported NSAID use to delay or treat AD. Few studies have evaluated cognitive trajectories of NSAID users over time. METHODS: Residents of Cache County, UT, aged 65 or older on January 1, 1995, were invited to participate in the study. At baseline, participants provided a detailed inventory of their medications and completed a revised Modified Mini-Mental State Examination (3MS). Participants (n = 3,383) who were cognitively normal at baseline were re-examined after 3 and 8 years. The association between NSAID use and 3MS scores over time was estimated using random effects modeling. RESULTS: Associations depended upon when NSAIDs were started and APOE genotype. In participants who started NSAID use prior to age 65, those with no APOE epsilon4 alleles performed similarly to nonusers (a difference of 0.10 points per year; p = 0.19), while those with one or more epsilon4 allele(s) showed more protection (0.40 points per year; p = 0.0005). Among participants who first used NSAIDs at or after age 65, those with one or more epsilon4 alleles had higher baseline scores (0.95 points; p = 0.03) but did not show subsequent difference in change in score over time (0.06 points per year; p = 0.56). Those without an epsilon4 allele who started NSAID use after age 65 showed greater decline than nonusers (-0.16 points per year; p = 0.02). CONCLUSIONS: Nonsteroidal anti-inflammatory drug use may help to prevent cognitive decline in older adults if started in midlife rather than late life. This effect may be more notable in those who have one or more APOE epsilon4 alleles.

Risk factors for neuropsychiatric symptoms in dementia: the Cache County Study.

OBJECTIVE: To investigate the probability of individual neuropsychiatric symptoms in dementia patients as a function of eight risk factors. METHODS: In the Cache County Study, we administered the Neuropsychiatric Inventory (NPI) to 328 dementia patients at baseline. Approximately 18 months later, we re-administered the NPI to 184 participants available for follow-up. Generalized estimating equation methods were used to model the probability of individual neuropsychiatric symptoms as a function of: gender, age, education, dementia type and severity, APOE status, time of observation, and general medical health. RESULTS: Women showed increased tendency toward anxiety, [odds ratio (OR) 2.22, 95% confidence interval (CI) 1.31-3.76] and delusions (OR 2.15, CI 1.22-3.78), but older persons of both sexes showed less tendency toward anxiety. Dementia severity increased the tendency toward hallucinations and agitation (OR 2.42, CI 1.81-3.23) and decreased risk of depression. Positive APOE epsilon4 status increased the tendency toward aberrant motor behavior (OR 1.84, CI 1.05-3.22). Among dementia diagnoses, those with Alzheimer's disease showed decreased tendency toward agitation (OR 0.58, CI 0.35-0.95), depression (OR 0.56, CI 0.33-0.96) and disinhibition (OR 0.46, CI 0.24-0.88). Later time of observation increased risk of aberrant motor behavior and delusions, and more serious medical comorbidity increased risk of, agitation, irritability, disinhibition, and aberrant motor behavior. CONCLUSIONS: Gender, age, dementia severity, APOE epsilon4, dementia diagnosis, time of observation, and general medical health appear to influence the occurrence of individual neuropsychiatric symptoms.

Conversion to dementia from mild cognitive disorder: the Cache County Study.

OBJECTIVE: To examine 3-year rates of conversion to dementia, and risk factors for such conversion, in a population-based sample with diverse types of cognitive impairment. METHODS: All elderly (aged 65 or older) residents of Cache County, UT, were invited to undergo two waves of dementia screening and assessment. Three-year follow-up data were available for 120 participants who had some form of mild cognitive impairment at baseline. Of these, 51 had been classified at baseline with prodromal Alzheimer disease (proAD), and 69 with other cognitive syndromes (CS). RESULTS: Three-year rates of conversion to dementia were 46% among those with cognitive impairment at baseline. By comparison, 3.3% without impairment converted to dementia in the interval. Among converters, AD was the most common type of dementia. In individuals with at least one APOE epsilon4 allele, those with proAD or CS exhibited a 22- to 25-fold higher risk of dementia than cognitively unimpaired individuals (vs 5- to 10-fold higher risk in those without epsilon4). CONCLUSIONS: Individuals with all types of mild cognitive impairment have an elevated risk of dementia over 3 years, more so in those with an APOE epsilon4 allele. These results suggest value in dementia surveillance for broad groups of cognitively impaired individuals beyond any specific category, and utility of APOE genotyping as a prognostic method.

Identification of VaD and AD prodromes: the Cache County Study.

BACKGROUND: It is unclear whether vascular dementia (VaD) has a cognitive prodrome, akin to the mild cognitive impairment (MCI) prodrome to Alzheimer's dementia (AD). To evaluate whether VaD has a cognitive prodrome, and if it can be differentiated from prodromal AD, we examined neuropsychological test performance of participants in a nested case-control study within a population-based cohort aged 65 or older. METHODS: Participants (n = 485) were identified from the Cache County Study, a large population-based study of aging and dementia. After an average of 3 years of follow-up, a total of 62 incident dementia cases were identified (14 VaD, 48 AD). We identified a number of neuropsychological tests (executive and memory) that discriminated between diagnosed VaD and AD cases. Multivariate analyses sought to differentiate between these same groups 3 years before clinical diagnosis. RESULTS: The Consortium to Establish a Registry for Alzheimer's Disease Word List Recognition Test correct recognition of foils (mean difference, 1.25; 95% confidence interval [CI], 0.42 to 2.07; p < 0.01), Logical Memory I (mean difference, 7.16; 95% CI, 0.78 to 13.55, p < 0.05), Logical Memory II delayed recall (mean difference, 8.67; 95% CI, 1.59 to 15.74, p < 0.05), and percent savings (mean difference, 51.07; 95% CI, 32.58 to 69.56, p < 0.0001) differentiated VaD from AD cases after adjustment for age, sex, education, and dementia severity. Three years before dementia diagnosis, word list recognition ("no" responses mean difference, 1.40; 95% CI, 0.64 to 2.17; p < 0.001, and "yes" responses mean difference, -1.14; 95% CI, -2.14 to -0.13; p < 0.03) discriminated between prodromal VaD and AD. CONCLUSION: These results suggest that VaD has a prodromal syndrome, the cognitive features of which are distinguishable from the cognitive prodrome of AD.

Dementia: the leading predictor of death in a defined elderly population: the Cache County Study.

OBJECTIVE: To examine the relative risk and population attributable risk (PAR) of death with dementia of varying type and severity and other risk factors in a population of exceptional longevity. METHODS: Deaths were monitored over 5 years using vital statistics records and newspaper obituaries in 355 individuals with prevalent dementia and 4,328 without in Cache County, UT. Mean age was 83.3 (SD 7.0) years with dementia and 73.7 (SD 6.8) years without. History of coronary artery disease, hypertension, diabetes, and other life-shortening illness was ascertained from interviews. RESULTS: Death certificates implicated dementia as an important cause of death, but other data suggested a stronger association. Adjusted Cox relative hazard and PAR of death were higher with dementia than with any other illness studied. Relative hazard of death with dementia was highest at ages 65 to 74, but the high prevalence of dementia after age 85 resulted in 27% PAR among the oldest old. Mortality increased substantially with severity of dementia. Alzheimer disease shortened survival time most dramatically in younger participants, but vascular dementia posed a greater mortality risk among the oldest old. CONCLUSION: In this population, dementia was the strongest predictor of mortality, with a risk two to three times those of other life-shortening illnesses.

Hormone replacement therapy and reduced cognitive decline in older women: the Cache County Study.

OBJECTIVE: To examine the association between postmenopausal hormone replacement therapy (HRT) and the trajectory of global cognitive change with age. METHODS: The Modified Mini-Mental State Examination (MMSE) was administered to a population sample of 2,073 nondemented, community-dwelling female residents of Cache County, UT, aged 65 and older. Current and past HRT and other medications at a baseline interview and at follow-up 3 years later were assessed. Between interviews, a telephone Women's Health Questionnaire was administered to assess initial exposure, duration, and recency of HRT. Generalized estimating equation marginal models were used to evaluate the cross-sectional and longitudinal relations of HRT and modified MMSE score. Also assessed were effects with multivitamins and calcium supplements as exposures likely to reflect a "healthy lifestyle" among HRT users. Model covariates included the presence of APOE epsilon4 alleles, age, education, concurrent depression, several chronic diseases, and self-perceived general health. RESULTS: Age, lower education, depression, and APOE epsilon4 were all associated with lower baseline modified MMSE scores. With these covariates in the model, lifetime HRT use was associated with better baseline modified MMSE scores and a slower rate of decline. Stratification by APOE genotype did not alter these effects. Apparent benefits with HRT were attenuated but remained significant after elimination of scores from participants with incident dementia. A significant interaction between age and HRT indicated the strongest effects in women aged 85 and older. Measures of age at initial use of HRT, duration, and recency of exposure did not improve the models. No effects were seen with the "healthy lifestyle" control exposures. CONCLUSIONS: In a population cohort of older women, lifetime HRT exposure was associated with improved global cognition and attenuated decline over a 3-year interval. Improvements were greatest in the oldest old.

Prevalence of depression and its treatment in an elderly population: the Cache County study.

BACKGROUND: Previous estimates of the prevalence of geriatric depression have varied. There are few large population-based studies; most of these focused on individuals younger than 80 years. No US studies have been published since the advent of the newer antidepressant agents. METHODS: In 1995 through 1996, as part of a large population study, we examined the current and lifetime prevalence of depressive disorders in 4,559 nondemented individuals aged 65 to 100 years. This sample represented 90% of the elderly population of Cache County, Utah. Using a modified version of the Diagnostic Interview Schedule, we ascertained past and present DSM-IV major depression, dysthymia, and subclinical depressive disorders. Medication use was determined through a structured interview and a "medicine chest inventory." RESULTS: Point prevalence of major depression was estimated at 4.4% in women and 2.7% in men (P= .003). Other depressive syndromes were surprisingly uncommon (combined point prevalence, 1.6%). Among subjects with current major depression, 35.7% were taking an antidepressant (mostly selective serotonin reuptake inhibitors) and 27.4% a sedative/hypnotic. The current prevalence of major depression did not change appreciably with age. Estimated lifetime prevalence of major depression was 20.4% in women and 9.6% in men (P<.001), decreasing with age. CONCLUSIONS: These estimates for prevalence of major depression are higher than those reported previously in North American studies. Treatment with antidepressants was more common than reported previously, but was still lacking in most individuals with major depression. The prevalence of subsyndromal depressive symptoms was low, possibly because of unusual characteristics of the population.

Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging.

OBJECTIVE: The authors report findings from a study of 5,092 community residents who constituted 90% of the elderly resident population of Cache County, Utah. METHOD: The 5,092 participants, who were 65 years old or older, were screened for dementia. Based on the results of this screen, 1,002 participants (329 with dementia and 673 without dementia) underwent comprehensive neuropsychiatric examinations and were rated on the Neuropsychiatric Inventory, a widely used method for ascertainment and classification of dementia-associated mental and behavioral disturbances. RESULTS: Of the 329 participants with dementia, 214 (65%) had Alzheimer's disease, 62 (19%) had vascular dementia, and 53 (16%) had another DSM-IV dementia diagnosis; 201 (61%) had exhibited one or more mental or behavioral disturbances in the past month. Apathy (27%), depression (24%), and agitation/aggression (24%) were the most common in participants with dementia. These disturbances were almost four times more common in participants with dementia than in those without. Only modest differences were observed in the prevalence of mental or behavioral disturbances in different types of dementia or at different stages of illness: participants with Alzheimer's disease were more likely to have delusions and less likely to have depression. Agitation/aggression and aberrant motor behavior were more common in participants with advanced dementia. CONCLUSIONS: On the basis of their findings in this large community population of elderly people, the authors conclude that a wide range of dementia-associated mental and behavioral disturbances afflict the majority of individuals with dementia. Because of their frequency and their adverse effects on patients and their caregivers, these disturbances should be ascertained and treated in all cases of dementia.

Dementia diagnoses from clinical and neuropsychological data compared: the Cache County study.

OBJECTIVE: To validate a neuropsychological algorithm for dementia diagnosis. METHODS: We developed a neuropsychological algorithm in a sample of 1,023 elderly residents of Cache County, UT. We compared algorithmic and clinical dementia diagnoses both based on DSM-III-R criteria. The algorithm diagnosed dementia when there was impairment in memory and at least one other cognitive domain. We also tested a variant of the algorithm that incorporated functional measures that were based on structured informant reports. RESULTS: Of 1,023 participants, 87% could be classified by the basic algorithm, 94% when functional measures were considered. There was good concordance between basic psychometric and clinical diagnoses (79% agreement, kappa = 0.57). This improved after incorporating functional measures (90% agreement, kappa = 0.76). CONCLUSIONS: Neuropsychological algorithms may reasonably classify individuals on dementia status across a range of severity levels and ages and may provide a useful adjunct to clinical diagnoses in population studies.

Enhanced cognitive performance with estrogen use in nondemented community-dwelling older women.

OBJECTIVE: To examine the association between history of postmenopausal estrogen use and cognitive function in a large sample of nondemented community-dwelling older women. SETTING: A community of older residents in Cache County, Utah. PARTICIPANTS: A total of 2338 nondemented women aged 65 and older. MEASUREMENTS: All subjects were administered the Modified Mini-Mental State Examination (3MSE). Self-reported information on current and past use of estrogen after menopause was also obtained using a structured interview. Estrogen use was trichotomized as: no use, past use, and current use. Apolipoprotein E (APOE) genotype was determined and was dichotomized by the presence of an epsilon4 allele. A series of variance/covariance models was conducted with the 3MSE score as the dependent variable, first considering estrogen use alone, then adding, sequentially as covariates, education, age, health status, APOE genotype, current depression status, and history of head injury. RESULTS: In the simplest bivariate model, the 3MSE means (and confidence intervals) were 92.1 (91.7-92.4), 93.5 (93.1-93.9), and 94.4 (94.0-94.7) for never-, past-, and current users, respectively. In the final model (R2 = 0.28), no use of estrogen replacement therapy (P = .006), lower education (P < .001), poorer perceived health status (P = .035), current depression (P = .014), and presence of at least one APOE epsilon4 allele (P < .001) each independently predicted lower 3MSE score. Both current and past estrogen users had significantly higher 3MSE scores than never-users (P = .0063 and P = .0096, respectively). CONCLUSIONS: In this large community study, women who had used estrogen after menopause scored higher on the 3MSE. This finding remained, even after controlling for the effects of age, education, APOE genotype, and other variables that may affect cognition. These data support studies reporting a beneficial role of estrogen on cognition in postmenopausal women, particularly among current estrogen users.

APOE-epsilon4 count predicts age when prevalence of AD increases, then declines: the Cache County Study.

OBJECTIVE: To examine the prevalence of Alzheimer's disease (AD) and other dementias in relation to age, education, sex, and genotype at APOE. Recent studies suggest age heterogeneity in the risk of AD associated with the APOE genotype and a possible interaction between APOE-epsilon4 and female sex as risk factors. We studied these topics in the 5,677 elderly residents of Cache County, Utah, a population known for long life expectancy and high participation rates. METHODS: We screened for dementia with a brief cognitive test and structured telephone Dementia Questionnaire, then examined all individuals with apparent cognitive symptoms and a sample of others. We estimated age-specific prevalence of AD and other dementias and used multiple logistic regression models to describe relation of AD prevalence to age, sex, education, and APOE genotype. RESULTS: We found 335 demented individuals, 230 (69%) with definite, probable, or possible AD (positive predictive value versus autopsy confirmation 85%). The adjusted prevalence estimate for AD was 6.5% and for all dementias 9.6%. After age 90, the adjusted prevalence estimate for AD was 28% and for all dementias 38%. Regression models showed strong variation in AD prevalence with age, sex, education, and number of epsilon4 alleles (effect of epsilon2 not significant). Models were improved by a term for age-squared (negative coefficient) and by separate terms for interaction of age with presence of one or two epsilon4 alleles. An association of AD with female sex was ascribable entirely to individuals with epsilon4. CONCLUSIONS: In participants with no epsilon4 alleles, the age-specific prevalence of AD reached a maximum and then declined after age 95. In epsilon4 heterozygotes a similar maximum was noted earlier at age 87, in homozygotes at age 73. Female sex was a risk factor for AD only in those with epsilon4. The epsilon4 allele accounted for 70% of the population attributable risk for AD.

Amphetamine effects on striatal neurons: implications for models of dopamine function.

Models of dopamine function based on the bidirectional neuromodulation of afferents (40, 95) were tested by determining whether cortical ablation would affect the excitatory and inhibitory effects of amphetamine (AMPH) on striatal neurons in freely moving rats. By minimizing pre-and post-AMPH behavioral differences, behavioral clamping revealed that cortical ablation blocked the capacity of AMPH to produce a net excitation of striatal neurons that had shown AMPH-induced excitations under non-clamping conditions. Cortical ablation did not affect AMPH-induced neuronal inhibitions under behavioral clamping conditions. These results suggest that AMPH, possibly by enhancing dopaminergic neuromodulation, facilities or inhibits the activity of neurons that respectively receive substantial or little cortical input. Thus, the findings support models that assign dopamine the capacity to increase the gain of neuronal information processing. Basic research relevant to these models is reviewed and potential clinical implications are discussed.

Cortical lesions attenuate the opposing effects of amphetamine and haloperidol on neostriatal neurons in freely moving rats.

Neuronal activity was recorded from the neostriatum of freely moving rats at least 1 week following either sham or bilateral ablations of frontal and somatosensory cortex. In both groups of animals, the majority of neurons increased firing rate in close temporal association with spontaneous movement. No group differences emerged either with respect to baseline firing rates or open-field behavior. Following amphetamine administration, however, the excitatory response of motor-related neurons was suppressed in cortical-lesioned rats. A behavioral clamping procedure, which assessed neuronal activity during matched pre- and post-amphetamine behaviors, confirmed these results, suggesting that the amphetamine-induced changes in neuronal activity reflect a direct drug effect independent of behavioral feedback. In animals that received a subsequent injection of 1.0 mg/kg haloperidol, cortical lesions attenuated the ability of this neuroleptic to block both the behavioral and neuronal effects of amphetamine. Collectively, these results support mounting evidence for an important modulatory influence of cortical afferents on the amphetamine-induced excitation of neostriatal neurons and the reversal of this effect by haloperidol.

Striatal single-unit responses to amphetamine and neuroleptics in freely moving rats.

Single-unit recordings from 50 striatal neurons in freely moving rats revealed generally low activity (< 3 spikes/sec) during resting behavior and movement-related excitations in most (n = 36) neurons. While activating behavior, d-amphetamine (1.0 mg/kg, sc) usually excited and inhibited motor- and nonmotor-related neurons, respectively, relative to resting baseline firing rates. A behavioral clamping analysis, which controlled for neuronal effects secondary to behavior, yielded results suggesting a primary, amphetamine-induced excitation of striatal motor-related neurons. Haloperidol (0.1-1.0 mg/kg) strongly inhibited behavior and neuronal activity when injected 30 min after amphetamine. Clozapine (5.0-30.0 mg/kg) inhibited only selected behaviors, but reliably produced haloperidol-like reversals of amphetamine-induced neuronal excitations. A literature review revealed that the neuronal results in behaving animals differ markedly from the inhibitory striatal responses to amphetamine and the excitatory responses to dopamine antagonists often found in immobilized or anesthetized rat preparations. These contrasting, preparation-dependent results support a model based on drug interactions with a proposed neuromodulatory function of striatal dopamine, which is to facilitate or attenuate the activity of neurons receiving, respectively, substantial, or little excitatory afferent input.

Bilateral cortical ablations attenuate amphetamine-induced excitations of neostriatal motor-related neurons in freely moving rats.

Single-unit recordings from neostriatal neurons showing movement-related excitations were obtained in freely moving, cortically ablated rats and sham-lesioned controls. D-Amphetamine (AMPH, 1.0 mg/kg s.c.) increased neuronal activity relative to resting baseline firing rates in both groups of animals, but cortical ablation significantly attenuated this effect. A behavioral clamping analysis, which compared neuronal activity during identically rated pre- and post-AMPH behaviors, revealed that: (a) AMPH enhanced movement-related neuronal activity in sham-lesioned controls, but not in cortically ablated rats; and (b) the drug-induced neuronal activation in control rats was not simply secondary to the behavioral activation produced by AMPH. In contrast to its neuronal effects, cortical ablation did not affect ratings of AMPH-induced locomotion, rearing, or head movements, though sniffing scores showed a positive correlation with lesion size. Thus, corticostriatal projections are critically involved in AMPH-induced excitations of neostriatal motor-related neurons.