Loss of D2 receptor binding with age in rhesus monkeys: importance of correction for differences in striatal size.

The relation between striatal dopamine D2 receptor binding and aging was investigated in rhesus monkeys with PET. Monkeys (n = 18, 39 to 360 months of age) were scanned with 11C-raclopride; binding potential in the striatum was estimated graphically. Because our magnetic resonance imaging analysis revealed a concomitant relation between size of striatum and age, the dynamic positron emission tomography (PET) data were corrected for possible partial volume (PV) artifacts before parameter estimation. The age-related decline in binding potential was 1% per year and was smaller than the apparent effect if the age-related change in size was ignored. This is the first in vivo demonstration of a decline in dopamine receptor binding in nonhuman primates. The rate of decline in binding potential is consistent with in vitro findings in monkeys but smaller than what has been measured previously in humans using PET. Previous PET studies in humans, however, have not corrected for PV error, although a decline in striatal size with age has been demonstrated. The results of this study suggest that PV correction must be applied to PET data to accurately detect small changes in receptor binding that may occur in parallel with structural changes in the brain.

Age-related decline in striatal volume in monkeys as measured by magnetic resonance imaging.

Age-related declines in striatal markers for the dopamine system have been demonstrated in several species. The current study investigated structural changes during aging in the rhesus monkey striatum. Male monkeys were studied using a volumetric spoiled gradient recall (SPGR) magnetic resonance imaging protocol. The caudate nucleus and putamen were segmented by manual tracing using landmarks made in the orthogonal planes. The whole brain volume (defined as volume of gray and white matter plus cerebrospinal fluid in ventricles and sulci) was measured using a semi-automated algorithm. There was no correlation between age and whole brain volume. There were age-related declines in normalized (i.e. brain region/whole brain volume) caudate nucleus and putamen volumes. Monkeys in the young group (n = 7, 39-45 months old) had larger volumes of both the caudate nucleus and putamen than animals in the middle-age (n = 5, 120-180 months) or old (n = 7, 291-360 months) groups. The current results provide normative data to assess potential interventions (e.g. caloric restriction) in the aging process.

Regional brain glucose metabolism after acute alpha 2-blockade by idazoxan.

BACKGROUND: Several classes of antidepressant drugs act on alpha 2-adrenergic receptors. Studies of patients with disorders responsive to treatment with these drugs report group differences in ex vivo measures of alpha 2-binding and in vivo responses mediated by alpha 2-receptors. Measurement of regional brain metabolic response to an alpha 2-antagonist may be a useful method for further definition of the role alpha 2-receptor regulation plays in the treatment of neuropsychiatric disorders. METHODS: Regional brain glucose metabolism was measured before and after infusion with 200 micrograms/kg idazoxan with use of 18F-fluoro-2-deoxyglucose positron emission tomography in 13 healthy men. Arterial drug concentration, behavioral responses, and cardiovascular responses were also measured. RESULTS: The absolute and normalized glucose metabolic rate significantly increased in primary visual cortex. Significant increases and decreases occurred in normalized metabolic rates in prefrontal cortical regions. Measurement of metabolic effects occurred during the peak cardiovascular response. CONCLUSIONS: Our findings are consistent with regionally specific effects of alpha 2-blockade. This method may be useful for the study of alpha 2-receptor function in humans.

High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity, and impulsivity. Despite extensive investigation of the neuropathophysiology of ADHD by a wide array of methodologies, the neurobiochemical substrate of this disorder is still unknown. Converging evidence, however, suggests a primary role of the dopaminergic system. METHOD: This study examined the integrity of presynaptic dopaminergic function in children with ADHD through use of positron emission tomography and the tracer [18F]fluorodopa ([18F]DOPA). Accumulation of [18F]DOPA in synaptic terminals, a measure of dopa decarboxylase activity, was quantified in regions rich in dopaminergic innervation, including caudate nucleus, putamen, frontal cortex, and midbrain (i.e., substantia nigra and ventral tegmentum). RESULTS: Accumulation of [18F]DOPA in the right midbrain was higher by 48% in 10 children with ADHD than in 10 normal children. Despite its magnitude, this difference would not have reached statistical significance if corrected by the Bonferroni test for multiple comparisons. However, [18F]DOPA in the right midbrain was correlated with symptom severity. No other dopamine-rich regions significantly differed between groups. CONCLUSIONS: These findings are suggestive of dopaminergic dysfunction at the level of the dopaminergic nuclei in children with ADHD. Abnormality in dopa decarboxylase activity may be primary or secondary to deficits in other functional units of the dopamine pathway (e.g., receptor, uptake transporter, vesicular transporter, degradation enzymes). Efforts toward defining the origin of this abnormality should help delineate mechanisms of midbrain control of attention and motor behavior important for the understanding of the causes and treatment of ADHD.

Cerebral glucose metabolism in adults with attention deficit hyperactivity disorder after chronic stimulant treatment.

OBJECTIVE: The authors examined the effects of chronic stimulant treatment on cerebral glucose metabolism in adults diagnosed with attention deficit hyperactivity disorder (ADHD), who were studied by means of positron emission tomography (PET) with [18F]fluorodeoxyglucose as the tracer. METHOD: Each subject received two PET scans, the first before drug treatment and the second after treatment with daily oral doses, individually titrated for clinical effect, of either methylphenidate (N = 19) or d-amphetamine (N = 18) for a minimum of 6 weeks. The subjects completed behavioral self-report measures before and at the end of the medication period. RESULTS: Neither stimulant medication changed global, or whole-brain, metabolism, although both drugs increased systolic blood pressure. Metabolism in only two of the 60 brain regions sampled was changed by methylphenidate, while d-amphetamine exhibited no effect on regional metabolism. Both drugs were associated with significant improvement in behavior, as evidenced by improved ratings for restlessness and ability to maintain attention. CONCLUSIONS: While the present study does not demonstrate any robust metabolic effects of chronic stimulant treatment, the behavioral data strongly indicate that methylphenidate and d-amphetamine are effective agents for the treatment of adults with ADHD.

Smaller volume of prefrontal lobe in polysubstance abusers: a magnetic resonance imaging study.

The present study was conducted to test the hypothesis that individuals with substance abuse disorder exhibit structural deficits in the prefrontal cortex. Volumes of the prefrontal lobe in subjects with histories of polysubstance abuse (n = 25) were measured and compared with those in normal volunteers (n = 14), using high-resolution volumetric magnetic resonance imaging (MRI). The research participants were men, 22 to 41 years of age. Polysubstance abusers were abstinent from drugs of abuse (except nicotine) for at least 15 days before MRI scanning. The total volumes of the prefrontal lobe (left and right hemispheres) were significantly smaller in the substance abuse group than in the control group. When the prefrontal lobe was segmented for gray and white matter, the deficit in the substance abusers was seen as significantly smaller volumes of gray but not of white matter. These results indicate that hypoplasia and/or atrophy in the prefrontal cortex accompany substance abuse and suggest that structural deficits in the prefrontal cortex may play an essential role in the neuropathological basis of functional impairments in substance abuse disorder, as demonstrated by functional brain imaging and cognitive studies.

Gender differences in brain metabolic and plasma catecholamine responses to alpha 2-adrenoceptor blockade.

alpha 2-Adrenergic receptors modulate the release of several neurotransmitters implicated in the treatment and pathophysiology of mood and anxiety disorders. Significant sex differences occur in the prevalence of both disorders. To test whether gender affects alpha 2 function, the plasma catecholamine and brain metabolic responses to alpha 2 blockade were measured in male and female volunteers. Ten female and thirteen male volunteers underwent [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans before and after infusion of idazoxan (200 micrograms/kg). Measures of plasma catecholamines, blood pressure, and anxiety were obtained. Norepinephrine responses were larger in males. Women showed global increases in metabolism, whereas males had no global changes and some regional decreases in FDG uptake following idazoxan administration. The differences in norepinephrine increases are consistent with previously reported effects of gender on sympathetic activation. The PET data suggest gender differences in responses to alpha 2-receptor blockade in brain as well.

Effects of acute stimulant medication on cerebral metabolism in adults with hyperactivity.

Recent work in our laboratory has demonstrated both global and regional reductions in cerebral glucose metabolism in adult subjects with attention-deficit hyperactivity disorder (ADHD). The purpose of the present study was to examine the effects of an acute dose of stimulant medication on cerebral metabolism in adults with ADHD using positron emission tomography with fluorodeoxyglucose-18 as the tracer. Each subject underwent scanning twice, once off-drug and again after receiving a single oral dose of either dextroamphetamine (0.25 mg/kg) or methylphenidate (0.35 mg/kg). Subjects completed behavioral self-report measures before and after the scan and performed an auditory continuous performance task during the tracer uptake period. Neither drug changed global metabolism. Both drugs increased systolic blood pressure, and dextroamphetamine improved performance on the auditory attention task. Each stimulant produced a differential pattern of increases and decreases in regional metabolism throughout the regions of interest that were sampled. Rather than increasing glucose utilization in specific brain regions with lowered metabolic rates in adults with ADHD, stimulants may act by altering glucose use throughout the brain.

A double FDG/PET study of the effects of scopolamine in older adults.

Two consecutive positron emission scans were done in one session using a double injection method of [18F]2-fluoro-2-deoxyglucose administration to examine the effects of the antimuscarinic drug scopolamine on cerebral glucose metabolism in ten older adults. Scopolamine causes temporary memory impairment, and its effects have been used to model aspects of the cognitive impairment that occur in Alzheimer's disease (AD). Cortical metabolic rates of patients with AD have been reported to be depressed, especially in parietal, temporal, and frontal association areas. After scopolamine administration to the elderly volunteers, absolute and normalized glucose metabolic rates were depressed in prefrontal and occipital regions and increased in parietal-occipital cortical regions and a left middle temporal region. These changes in the older volunteers are generally not consistent with changes seen in AD. We conclude that deficits in muscarinic system function may contribute to some but not all of the hypometabolic changes seen in AD patients.

Adrenergic and noradrenergic plasma levels in Lesch-Nyhan disease.

Noradrenergic dysfunction and abnormality in monoamine oxidase (MAO) enzyme activity have been reported previously in Lesch-Nyhan (LN) disease. This study examines peripheral indices of adrenergic, noradrenergic, and MAO function in children and young adults with LN disease (n = 11), and healthy subjects (n = 9). Blood samples, collected in identical conditions prior to a positron emission tomography (PET) study, were assayed for concentrations of epinephrine (EPI), norepinephrine (NE), and 3-methoxy-4-hydroxyphenylglycol (DHPG) (which results from the degradation of NE by monoamine oxidase type A [MAO-A]). The LN subjects had significantly higher EPI levels by 245% (p < .00) and lower DHPG levels by 42% (p < .00) compared to the control group. No group differences were noted in NE plasma levels. Cognitive function (IQ tested by Stanford Binet Intelligence Scale) was associated with EPI in the LN group (r = 0.77, p = .009), but not in the control group. The abnormally high EPI plasma concentrations may indicate another biochemical dysfunction secondary to the absence of the HPRT enzyme in LN patients. Such a biochemical deficit is likely to originate from the adrenal medulla, which is the primary site of EPI synthesis. The adrenal medulla may be directly affected by the absence of hypoxanthine guanine phosphoribosyl transferase (HPRT) enzyme, or may receive inappropriately high descending activation input from the brain. The abnormally low DHPG levels, in the context of normal NE levels, indicates low MAO activity, either as a primary deficit, or as secondary adaptive changes to spare NE levels that would otherwise be too low for adequate noradrenergic function.

Cerebral glucose metabolism during pharmacologic studies: test-retest under placebo conditions.

UNLABELLED: The reliability of serial [18F]fluorodeoxyglucose (FDG) PET scans for psychopharmacologic studies was tested by using placebo infusions. METHODS: FDG scans were obtained before and after a 30 min placebo infusion (n = 10; Group 1) or after each of two bolus infusions with placebo (n = 8; Group 2). Subjects performed a continuous performance task (CPT) during each scan. Cardiovascular measures and ratings of anxiety were obtained in all subjects. Samples for determination of plasma norepinephrine (NE) were taken at multiple time points in Group 1. RESULTS: A slight increase in apparent global metabolism occurred between scans in both Groups 1 and 2. A few regions significantly increased in both groups. While an apparent increase in sympathetic activity occurred during the placebo infusion, neither NE levels, anxiety ratings nor cardiovascular measures correlated with global or regional FD6 uptake. CONCLUSION: Test-retest differences of global and regional glucose metabolism were highly consistent across two experimental designs. While increases in cerebral glucose metabolism appeared to occur during the second scan, differences between scans were small. This method may offer advantages for selected psychopharmacologic studies.

High presynaptic dopaminergic activity in children with Tourette's disorder.

OBJECTIVE: Tourette's disorder is characterized by chronic fluctuating motor and vocal tics. Despite extensive investigation of the neuropathophysiology of the disorder by a wide array of methodologies, its neurobiochemical substrate is still unclear. Converging evidence, however, suggests a primary role of the dopaminergic system, particularly within the basal ganglia. METHOD: This study examined the integrity of presynaptic dopaminergic function in children with Tourette's disorder, using positron emission tomography and the tracer [18F]fluorodopa (FDOPA). Accumulation of FDOPA in synaptic terminals, a measure of DOPA decarboxylase activity, was quantified in caudate nucleus, putamen, frontal cortex, and midbrain (i.e., substantia nigra and ventral tegmentum). RESULTS: Subjects with Tourette's disorder showed higher FDOPA accumulation than controls in the left caudate nucleus (by 25%; p = .03) and right midbrain (by 53%; p = .08). CONCLUSION: These findings provide evidence of dopaminergic dysfunction in children with Tourette's disorder which affects both cell nuclei and nerve terminals. Based on the known regulation of DOPA decarboxylase activity by post- and presynaptic receptors, and by extracellular dopamine concentration, abnormal activity in this enzyme may reflect deficits in a variety of functional elements of the dopamine system. The precise mechanism underlying an up-regulation of DOPA decarboxylase activity needs to be identified in future studies.

Intracranial androgenic activation of male-typical behaviors in house mice: motivation versus performance.

Castrated male mice were bilaterally implanted with 27 ga cannulae containing testosterone into either the septum, medial preoptic area (MPO), or corticomedial amygdala. One additional group of castrates received no hormone and another received only systemic testosterone via subcutaneous silastic capsules. All males were subsequently tested for ultrasonic mating vocalizations, urine marking, mounting behavior, aggression and gender preference, all of which are androgen-dependent, male-typical behaviors. In general castrates receiving no hormone performed these behaviors at low levels and animals receiving systemic testosterone performed the behaviors at normal male-typical levels. Ultrasonic vocalizations in response to female urine were activated by MPO implants. Urine marking in response to female urine appeared to be partially activated only with MPO implants. Very little mounting or fighting were seen in the brain implanted groups. Gender preference (for females over males) was restored with MPO implants and appeared to be partially activated with septal implants. The seminal vesicles of the castrates receiving brain implants were not significantly different from those receiving no hormone indicating that little or no implanted hormone was exiting the brain into general circulation. The implications of these findings for the neuroanatomy of sexual motivation and performance are discussed.

Correlation of dopamine release in the nucleus accumbens with masculine sexual behavior in rats.

Extracellular dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens (N. Acc.) were measured by in vivo microdialysis during male sexual activity. DA and DOPAC were significantly increased during copulation, but not during mild tail pinch. These results are consistent with studies showing increases in N. Acc. DA associated with positively reinforcing environmental stimuli.

Abnormalities in sustained attention and anterior cingulate metabolism in subjects with resistance to thyroid hormone.

Attention deficit disorders are a frequent manifestation of resistance to thyroid hormone (RTH), a disorder caused by mutations in the hormone-binding domain of the human thyroid hormone receptor beta gene. Positron emission tomography was used to measure cerebral glucose metabolism in regions known to be biological determinants of sustained attention in 13 adult RTH and 13 unaffected subjects. Compared to the control group, performance on a continuous auditory discrimination task was severely impaired in the RTH subjects, while metabolism was higher both in the right parietal cortex and the anterior cingulate gyrus. Abnormally high functional activity of the anterior cingulate during sustained attention may be associated with a decreased signal-to-noise ratio for the neural processing of task stimuli in subjects with RTH.

Role of the main olfactory system in recognition between individual spiny mice.

Recognition between spiny mice requires a period of exposure to learn the olfactory cues of individual conspecifics that can serve as recognition signatures in subsequent discrimination. Animals received nasal irrigations of zinc sulfate to disrupt sensory input to the main olfactory system (MOS) either prior to the 9-day exposure period (Experiment 1) or immediately after the exposure period (Experiment 2). Animals rendered anosmic by zinc sulfate did not show evidence of recognition as defined by huddling preferences. In contrast, animals who received irrigations of saline were able to preferentially huddle with their cagemate who they had been housed with during the exposure period. The results suggest that the MOS is necessary in mediating behavioral discrimination between conspecifics.

Dissociation of androgen-dependent sociosexual behaviors in response to castration in Long-Evans rats.

Copulatory behavior and associated social behaviors such as ultrasonic vocalizations and scent marking are reduced in frequency following castration and are restored by exogenous administration of androgens. In the present study, we report the behavior of a subgroup of male Long-Evans rats in which there was a dissociation between the responses of androgen-dependent behaviors to castration. Five weeks after castration, 52% of the males tested (13 of 25) had higher 50 kHz vocalization frequencies than during precastration tests. This group continued to emit vocalizations after castration and actually increased their number of vocalizations over postcastration tests (pretest: 34.5 +/- 4.8 to week 15: 62.8 +/- 10.9/10 min test). The remaining males (n = 12) exhibited a decline in vocalizations (pretest: 29.7 +/- 5.1 to week 15: 6.5 +/- 2.7) that we typically observe in our laboratory. Both groups showed the expected decline in scent-marking frequency over the postcastration tests and were impaired in performance of copulatory behavior. Seminal vesicle and adrenal gland weights did not differ between the two groups. The 25 males were of the same genetic strain as previous animals in our laboratory except that they were born and raised in a different location prior to shipment to our laboratory. Androgens, therefore, may be only one of the possible influences mediating ultrasonic vocalizations.

Variations in scent marking and ultrasonic vocalizations by Long-Evans rats across the estrous cycle.

The purpose of the present study was to investigate whether the signaling behaviors of female Long-Evans rats varies over the estrous cycle. Scent marking and 50-kHz ultrasonic mating vocalizations, in response to a devocalized sexually experienced male, changed in frequency across the cycle, both behaviors being highest at proestrus/early estrus. Vocalizations were recorded on every day of the cycle and also in females showing no regular cycles. In contrast, scent marking was rarely observed during the estrous cycle except at proestrus/early estrus. These results suggest that both behaviors, which increase around the time of sexual receptivity, may help to coordinate reproduction and further suggest an endocrine basis for the changes observed over the estrous cycle.

Short photoperiods increase ultrasonic vocalization rates among male Syrian hamsters.

Two experiments investigated the effects of daylength on the emission of 35 kHz ultrasonic (US) calls among male hamsters. In Experiment 1, castrated males received Silastic implants subcutaneously that contained either low doses of testosterone in oil or oil alone; US calls were recorded when these males were paired with receptive females. Males exposed to eight hours of light per day (short photoperiod) called more often than males exposed to fourteen hours of light per day (long photoperiod). This was true whether or not they received testosterone. In Experiment 2, a similar testing and photoperiod exposure paradigm was used, but the subjects were gonadally intact. Among males exposed to short photoperiods, US call rates increased while endogenous testosterone levels decreased. In contrast, hamsters exposed to long photoperiods maintained stable calling rates and testosterone levels. These findings are related to recent studies concerning the neural mechanisms that regulate ultrasonic vocalizations and to the possible role of photoperiod in modulating conspecific aggression.

Male hamster sociosexual behaviors: effects of testosterone and its metabolites.

Male hamsters were tested for copulatory behavior (CB) with receptive females, for investigatory responses to the females' ano-genital region (A/G), and for attraction to female hamster vaginal secretion (FHVS). After castration, the males received Silastic capsules containing one of two doses of testosterone (T), 5 alpha-dihydrotestosterone (DHT), estradiol (E2) or DHT + E2, and the maintenance of their copulatory and chemoinvestigatory responsiveness was assessed during weekly tests for the next month. The major findings were: (1) T thresholds for the maintenance of CB were lower than they were for the maintenance of A/G behavior and FHVS attraction; (2) DHT + E2 or DHT alone were more effective in maintaining A/G and FHVS attraction than was E2 alone; (3) DHT + E2 or DHT alone maintained ejaculatory behavior in some animals but E2 did not; (4) the posttreatment maintenance of normal ejaculation latencies and intromissions to ejaculation shown by intact and T-treated males was not demonstrated by males receiving DHT or DHT + E2. These results are consistent with the hypothesis that copulatory and chemoinvestigatory behaviors may be subserved by distinct neuroendocrine mechanisms in male hamsters.