D2-like dopamine receptor density in Tourette syndrome measured by PET.

UNLABELLED: Tourette syndrome (TS) is a chronic neurologic disorder characterized by the presence of involuntary motor and phonic tics. There is evidence that TS is associated with an abnormality of the dopaminergic system, involving postsynaptic D2 receptors. We tested the hypothesis that D2-like dopamine receptors are elevated in TS. METHODS: Twenty-nine adult patients with TS were studied by PET imaging with [11C]3-N-methylspiperone ([11C]NMSP). Two methods of data analysis were used. The first was a caudate-to-cerebellar ratio, measured at 45 min. The second method, applied in 20 subjects, was a two-PET scan procedure. Both used high specific activity [11C]NMSP, but the second scan was preceded by a dose of unlabeled haloperidol, which partially occupied the D2-like dopamine receptors. This was done to provide an absolute measure of receptor density (Bmax). All patients were compared to age- and sex-matched controls. RESULTS: Neither group showed significant differences from their control group in caudate-to-cerebellar ratio. However, the two-PET scan Bmax measurement demonstrated that 4 of the 20 patients had significantly elevated D2-like receptors. In this group of 20 patients, multiple linear regression analysis revealed a trend between the severity of vocal tics and Bmax values. This Bmax measure also revealed a significant (p < 0.05) association with performance on the Wisconsin Card Sorting Test. CONCLUSION: These findings suggest that not all patients with TS have an abnormality of D2-like receptors, but a subgroup of TS subjects has a significant D2-like dopamine receptor elevation. These findings also support the importance of applying a more quantitative method for Bmax determination to PET imaging analysis. The Bmax findings in the subgroup do not exclude an effect of intrasynaptic dopamine competition, but this effect may be less likely due to the high affinity of [11C]NMSP.

Cerebral glucose utilization is reduced in second test session.

Cerebral glucose utilization was higher during the first positron emission tomography (PET) session than during the second session, as assayed using the PET [18F]fluorodeoxyglucose method in male human volunteers. This difference was due largely to data from subjects with low-trait anxiety, since subjects with high anxiety showed similar metabolism in both PET sessions. High-anxiety subjects showed greater right/ left ratios of cerebral metabolism than low-anxiety subjects, particularly during the second PET session. These findings suggest that the level of anxiety may be an important variable to consider in PET studies using multiple sessions.

Cerebral glucose utilization in polysubstance abuse.

Regional cerebral glucose metabolism in subjects with histories of polysubstance abuse was compared to that in control subjects who were drawn from the same community. The substance abuse group showed lower absolute metabolic rates for glucose in lateral occipital gyrus and higher normalized metabolic rates in temporal and frontal areas, including orbitofrontal cortex. It is suggested that some patterns of brain function associated with polysubstance abuse may represent consequences of drug exposure, or they could reflect pre-existing differences that may be relevant to the etiology and maintenance of polysubstance abuse.

Dopamine D2 receptor density estimates in schizophrenia: a positron emission tomography study with 11C-N-methylspiperone.

Positron emission tomography (PET) with 11C-N-methylspiperone as the radioligand was carried out in 25 chronic schizophrenic patients to determine dopamine D2 receptor density estimates in the corpus striatum. The sample included 18 neuroleptic-naive and 7 neuroleptic-free patients. Dopamine D2 receptor density estimates (Bmax) were obtained using a two-scan/four-compartment model. The Bmax estimates for the entire group (33.39 +/- 3.43 pmole/g) were significantly elevated when compared with estimates for the control group (Bmax = 15.63 +/- 2.38). The Bmax values for the entire group of schizophrenic patients showed a significant decline as a function of age. The Bmax values were significantly related to duration of illness (y = 13.2 + 10.3795x - 0.7931x2; r = 0.48). Thirteen patients and seven control subjects were added to our original publication sample (Wong et al., 1986c). The patients' Bmax values, when adjusted for age and sex effects, were significantly different compared with those of control subjects. Clinical data from the entire group were compared with published data from other research groups that have estimated dopamine D2 receptor density using different radioligands and different methods of data analysis. Comparisons of the clinical characteristics of the published studies show significant differences in patient populations, suggesting that discrepancies among published studies may reflect, in part, heterogeneity among groups of schizophrenic patients. The D2 receptor abnormality described in this study may be a late manifestation of disease, and the implications of this observation are discussed.

Sensitivity to subjective effects of cocaine in drug abusers: relationship to cerebral ventricle size.

OBJECTIVE: The purpose of this study was to assess the functional significance of ventricle-brain ratio (VBR) in terms of how it might affect sensitivity to cocaine, an indirect dopamine agonist. METHOD: Relationships between VBR and subjective responses to acute intravenous cocaine hydrochloride were examined in 20 male polydrug abusers. Tests were performed in conjunction with positron emission tomography scans to measure cerebral glucose metabolism. RESULTS: Subjective measures of effects of cocaine, including self-report ratings of intensity of the drug effect, scores on the morphine-benzedrine scale of the Addiction Research Center Inventory, and several items on visual analogue scales, correlated negatively with VBR. VBR also differed significantly among subjects who were grouped according to scores on items ("rush" and "crash") of the Cocaine-Sensitive Scale (larger VBR in subjects with weaker responses). VBR was not correlated with cocaine-induced changes in cerebral metabolic rates for glucose. CONCLUSIONS: Relative insensitivity to the subjective effects of cocaine in polydrug abusers with ventricle enlargement suggests that ventriculomegaly may reflect changes in periventricular brain regions that mediate these effects of cocaine.

In vivo imaging of baboon and human dopamine transporters by positron emission tomography using [11C]WIN 35,428.

[11C]WIN 35,428 was evaluated as a specific in vivo radioligand for the dopamine transporter site by PET scanning in nonhuman primates and humans. In studies with a baboon (Papio anubis), [11C]WIN 35,428 accumulated in brain regions containing dopamine transporters, i.e., the striata. This accumulation was partially blocked by prior administration of (-)cocaine (4 mg/kg, i.v.). Placement of a unilateral lesion of dopamine-containing nerve terminals with MPTP resulted in a unilateral reduction in [11C]WIN 35,428 accumulation in the striatum on the side of the lesion. Imaging of D2 dopamine receptors with [11C]NMSP in the same MPTP-treated animals showed much less reduction in the postsynaptic D2 dopamine receptors as compared to the much larger reduction in the dopamine transporters labeled with [11C]WIN 35,428. A total of ten normal human volunteers (five males and five females) with ages ranging from 19 to 81 years were studied. The caudate/cerebellar and putamen/cerebellar ratios ranged from 4.4 to 5.7 90 min after injection of the tracer. Preliminary kinetic modeling with arterial plasma sampling resulted in an average binding potential (k3/k4) of 4.98 in the caudate nucleus and 5.13 in putamen. To demonstrate in vivo blockade with dopamine reuptake inhibitors, two subjects received prior oral doses of 6 mg mazindol. Subject 5 had significant reductions of 29% in the caudate/cerebellar ratio at 90 min, 35% in the putamen/cerebellar ratio at 90 min, 45% in the caudate k3/k4 ratio from 6.7 to 3.7, and 46% in the putamen k3/k4 from 4.7 to 2.5. Subject 8 had significant reductions of 20% in both the caudate/cerebellar ratio and the putamen/cerebellar ratio at 90 min. During the human PET studies, a number of neuropsychological tests and physiological measurements were performed. No significant changes were found after administration of the [11C]WIN 35,428 alone. Taken together, these data indicate that [11C]WIN 35,428 is a promising radioligand for future studies of neuropsychiatric disorders that involve the dopamine transporter site.

Effects of vasopressin on blood-brain transfer of methionine in dogs.

We used a simplified probe detection system for positron-emitting radionuclides in order to measure blood-brain barrier transport of amino acids in anesthetized dogs. Plasma and brain time-activity curves were recorded after intravenous bolus injection of L-[11C]methionine before and after administration of 1 microgram of vasopressin. Three-compartment models with three or four transfer coefficients were used to derive the kinetics of L-[11C]methionine uptake in brain. The blood-brain clearance of the tracer (K1) was 0.075 ml ml-1 min-1 before and 0.041 ml ml-1 min-1 after injection of vasopressin. The partition volume and the initial distribution (plasma) volume of methionine were unchanged and within the expected limits. The net accumulation rate of methionine (K), estimated by both the four-parameter (kinetic) and three-parameter (graphic) approaches, decreased after vasopressin injection in all six studies.

Weight and lymphocyte content of the female rat's thymus following first mating.

Eleven groups, each of ten Sprague-Dawley female rats, were sacrificed at 12 to 13 weeks of age; one group of virgins, the others at two-day intervals during the first ten days after either inbred or outbred mating. Observations were made on thymus weight, total white cell count, and thymic white cell density. Compared with the virgin group no significant differences were observed in the thymic weight at any stage after either inbred or outbred mating. In contrast the total white cell counts were significantly greater than the virgin count on the second postcoital day after both inbred and outbred mating. These increased total counts were maintained until the end of the observation period and were associated with significant increases in the thymic white cell densities. These observations suggest that mating and implantation initiate and sustain a mechanism of lymphocyte accumulation in the rat thymus.

Accumulation and proliferation of lymphocytes in the lymph nodes of the female rat following first mating.

Iliac and popliteal lymph nodes were removed from Sprague-Dawley female rats killed at 12-13 weeks of age in groups of 10 animals: one group of virgin controls and 10 groups at intervals of two days until the tenth day after either 'inbred' or outbred mating. The iliac lymph nodes on the second post-coital day after outbred mating were significantly heavier than those of virgin animals and on the fourth postcoital day were significantly heavier after outbred mating than 'inbred' mating. The total lymphocyte counts in the iliac and popliteal lymph nodes were significantly less in the virgin animals than those made on ;the second post-coital day after both 'inbred' and outbred mating. These increased counts were sustained until the tenth post-coital day and were associated with significantly increased lymphocyte cell densities in the nodes. Such lymphocyte accumulation probably results from an endogenous or exogenous hormonal stimulus. The proportions of proliferating cells in the lymphocyte population of the iliac and popliteal lymph nodes from the fourth until the tenth post-coital day were significantly greater after outbred mating than after 'inbred' mating. These observations indicate that after outbred mating the female animal mounts an immune response to the allogeneic spermatozoa and semiallogeneic products of conception within her reproductive tract.

Immune response to first mating in the female rat.

The iliac and popliteal lymph nodes were removed from 110 Sprague Dawley female rats taken from a closed colony. All were killed at age 12-13 wk in groups of 10 animals; one group of virgin controls, the others at 2-day intervals during the first 10 days of either inbred or allogeneic poregnancy. Every tenth section of the lymph nodes was stained with methyl green pyronin and counts were made of the large pyroninophilic cells in the thymus-dependent area of the cortex for evidence of T cell proliferation and the plasma cells in the medulla for evidence of B cell proliferation. After allogeneic mating significant T cell proliferation was evident in both the iliac and popliteal lymph nodes by the second post-coital day and this proliferative response was sustained until the sixth postcoital day and recurred on the tenth post-coital day. After inbred mating transient T cell proliferation was observed on the fourth post-coital day in the iliac lymph nodes. Significant B cell proliferation occurred in the iliac lymph nodes on the second day of allogeneic pregnancy and on the fourth day of inbred pregnancy, being sustained in both until the end of the observation period. These results suggest that allogeneic mating and possibly semi-allogeneic implantation induce an immune response in the female rat.