Biomedical subjects
D X Freedman
Publications and source records attributed to D X Freedman.
Tryptophan loading in hyperserotonemic and normoserotonemic adults.
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Violence (and a message for the 90s?)
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The search: body, mind, and human purpose.
Psychiatry's appropriate agenda and severe distractions in sustaining it are presently a concern and have historically been so as we struggle with the issues of linking body, mind, and human purpose. Biology requires behaving, variability, and the development of regulations to implement "purpose" in coping with the milieu. Psychiatry begins and ends with our patients--with their diseases and dysfunctions, their biographies and aspirations--which, as a clinical medical science, we must systematically study. Doing that, we will borrow from and pose problems for all the life sciences. New knowledge about how cells and biological systems acquire, code, and exchange information challenges all of medicine. In assessing our advances and future, we consider the history of biological issues in psychiatry and the "sins" of biologism or reductionism. We will see that research questions and strategies in the current study of disease and therapeutics have not fundamentally shifted from Freud and Meyer to modern molecular neurobiology. The tension between the socially conditioned purposive self and impersonal biological processes is an inescapable intrinsic tension for psychiatry of which we must be cognizant as we continue the search.
Pharmacology: policy implications of new psychiatric drugs.
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Platelet 5-HT2 serotonin receptor binding sites in autistic children and their first-degree relatives.
We examined platelet serotonin2 [5-hydroxytryptamine2 (5-HT2)] receptor binding sites, whole blood serotonin (5-HT), and plasma norepinephrine (NE) in male autistic children and their first-degree relatives. Saturation studies utilizing 125I-spiroperidol labeled the 5-HT2 sites with an affinity of 224.6 +/- 84.4 pmol/L (Kd). No group differences, i.e., autistic (n = 12), siblings (n = 6), parents (n = 22), control (adult; n = 7: child; n = 10), were seen for either the Kd or the total number of sites (Bmax: 14.3 +/- 10.9 fmol/mg protein). No correlations were found in any group between binding parameters (Kd or Bmax) and whole blood 5-HT. For the parental group, inverse correlations were found between NE and Bmax (standing NE, rs = -0.67, n = 21, p = 0.001; supine NE, rs = -0.49, n = 22, p = 0.021). In the autistic group, no correlation was seen between plasma NE and Bmax. A correlation between the autistic boys' Bmax and their fathers' Bmax was observed (rs = 0.79, n = 11, p = 0.004). These findings suggest (1) circulating NE may be involved in heterologous regulation of 5-HT2 receptors in the platelet and (2) genetic (paternal-filial) factors may play a role in the expression of 5-HT2 binding sites in the platelet. These preliminary findings are discussed in relation to heterologous receptor regulation. The relationships between these findings and either the pathophysiology of autism or hyperserotonemia in autism are unknown.
Of chairs and stools: or, what's academic about academic medicine?
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Relationships of whole blood serotonin and plasma norepinephrine within families.
Whole blood serotonin (5HT) and plasma norepinephrine (NE) levels were determined in 47 families of autistic probands to study relationships within families of these measures. Whole blood 5HT, but not plasma NE, was significantly positively correlated between autistic children and their mothers, fathers, and siblings. Twenty-three of the 47 families studied had at least 1 hyperserotonemic member. Of these 23 families, 10 (43.5%) had 2 or more hyperserotonemic members; 5 families were identified in which each family member studied had hyperserotonemia (whole blood 5HT greater than 270 ng/ml). If the autistic child of a family was hyperserotonemic, the first-degree relatives were 2.4 times more likely to be hypersertonemic than if the autistic child was not hyperserotonemic. Mean whole blood 5HT levels were higher in autistic subjects than their parents or siblings. Siblings were found to have lower plasma NE than autistic probands. This study replicates a previous study showing familial relationships of hyperserotonemia within families with autistic children.
Benzodiazepines: therapeutic, biological and psychosocial issues. Symposium summary.
In approaching the end of this symposium discussed at this conference, we have examined a wealth of information on the appropriate use of benzodiazepines, and find ourselves paradoxically only at the beginning. The issues we have approached extend from molecules to society. Many questions remain unanswered; many issues remain unresolved. In essence, the future requires far more systematic studies than are yet in hand. Relative value must be assigned to the topics in an attempt to distinguish issues that truly are problematic from those that are nonissues. It is clear that as physicians, we want to be more informed in the management of complications of all beneficial medications, including benzodiazepine use. After all, balancing the risks and benefits of any therapeutic option in the treatment of human ailments is what the art and science of medicine are all about. Furthermore, if we are to counter the hysteria that can surround almost any form of medical therapy, we have a responsibility to educate patients, physicians, and the general public about the burden of psychiatric disorders, and the risks and benefits of treatment.
Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine levels and intelligence.
Whole-blood serotonin (5-HT) and plasma norepinephrine (NE) were studied in 16 autistic children, 21 siblings of autistic children, and 53 parents of autistic children. Both plasma NE and whole-blood 5-HT were negatively correlated with vocabulary performance. Whole-blood 5-HT and plasma NE did not differ between autistic children with or without histories of self-injurious behavior or decreased pain sensitivity. Eighteen subjects were hyperserotonemic (whole-blood 5-HT greater than 270 ng/ml). For these subjects, plasma NE was significantly higher than for subjects without hyperserotonemia. Seven of 10 families with one hyperserotonemic member had two or more hyperserotonemic members. Observations of familiarity of whole-blood 5-HT suggest that larger-scale and more focused study of whole-blood 5-HT as a possible genetic marker may be productive.
Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin2 receptors in rat brain.
A dosage regimen of lysergic acid diethylamide (LSD) that reliably produces behavioral tolerance in rats was evaluated for effects on neurotransmitter receptor binding in rat brain using a variety of radioligands selective for amine receptor subtypes. Daily administration of LSD [130 micrograms/kg (0.27 mumol/kg) intraperitoneally (IP)] for 5 days produced a decrease in serotonin2 (5-hydroxytryptamine2, 5-HT2) binding in cortex (measured 24 hours after the last drug administration) but did not affect binding to other receptor systems (5-HT1A, 5-HT1B, beta-adrenergic, alpha 1- or alpha 2-adrenergic, D2-dopaminergic) or to a recognition site for 5-HT uptake. The decrease was evident within 3 days of LSD administration but was not demonstrable after the first LSD dose. Following 5 days of LSD administration the decrease was still present 48 hours, but not 96 hours, after the last administration. The indole hallucinogen psilocybin [1.0 mg/kg (3.5 mumol/kg) for 8 days] also produced a significant decrease in 5HT2 binding, but neither the nonhallucinogenic analog bromo-LSD [1.3 mg/kg (2.4 mumol/kg) for 5 days] nor mescaline [10 mg/kg (40.3 mumol/kg) for 5 or 10 days] affected 5-HT2 binding. These observations suggest that LSD and other indole hallucinogens may act as 5-HT2 agonists at postsynaptic 5-HT2 receptors. Decreased 5-HT2 binding strikingly parallels the development and loss of behavioral tolerance seen with repeated LSD administration, but the decreased binding per se cannot explain the gamut of behavioral tolerance and cross-tolerance phenomena among the indole and phenylethylamine hallucinogens.
Serotonin and measured intelligence.
Blood serotonin (5HT) has been shown to be elevated in 30% of autistic children and 50% of severely mentally retarded children. Ninety-eight normal adult subjects were studied to determine if there was an inverse relationship between whole blood 5HT in normal adults of average and above-average intelligence. There was a trend toward a negative correlation between whole blood 5HT and Vocabulary scores that would not account for hyperserotonemia in autistic or mentally retarded individuals. Female subjects had significantly greater whole blood 5HT than male subjects. There was no difference in whole blood 5HT collected before and after volume depletion of 450 ml, providing further evidence of the intraindividual stability of whole blood serotonin levels. There was no relationship between age and whole blood 5HT in a group of normal adult subjects.
Free serotonin in plasma: autistic children and their first-degree relatives.
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Serotonin2 agonist administration down-regulates rat brain serotonin2 receptors.
Daily administration of D-lysergic acid diethylamide (LSD) was previously shown to decrease serotonin2 (5-HT2) receptor binding in rat brain. Recently, 4-substituted derivatives of 1-(2,5-dimethoxyphenyl)-2-aminopropane, the substitution being with either iodine (DOI) or bromine (DOB), have been suggested to be relatively selective 5-HT2 agonists. These compounds share common behavioral and neurophysiological effects with LSD, suggested to be 5-HT2 receptor mediated, and the purpose of the present study was to determine whether they also affect 5-HT2 receptor binding after systemic administration in a similar way to LSD. Administration of DOI (1.0 mg/kg) or DOB (0.5 mg/kg) for 7 days resulted in a decrease in 5-HT2 binding, as evaluated with [3H]ketanserin, similar to the decrease after LSD. In a further evaluation of the parallelism of LSD and 5-HT2 agonists, it was found that 24 hr after one administration of a low dose of LSD (130 ug/kg) or DOI (1.0 mg/kg), there was no change in binding, but there was a decrease 24 hr after a high dose (LSD, 650 micrograms/kg; DOI, 7.0 mg/kg). Four hours after the high dose of LSD or DOI there was also a decrease in 5-HT2 binding. Thus, results have shown that 5-HT2 agonists are capable of down-regulating 5-HT2 receptors and that LSD acts in a parallel fashion. This study has also demonstrated that 5-HT2 receptors can be modified within hours after drug administration.
Effects of LSD-25 on classical trace conditioning.
This study examined the effects of LSD-25 on the excitatory properties of auditory conditioned stimuli as a function of the interstimulus interval. The rabbit's eyeblink response was conditioned using a discriminative trace procedure by the pairing of a 500-msec auditory conditioned stimulus with a 100-msec shock unconditioned stimulus at intervals of 1000, 2000, 4000 and 8000 msec. Animals were able to acquire conditioned responses across all intervals. They then received doses of 35 or 85 micrograms/kg of LSD-25 prior to additional conditioning sessions. LSD-25 produced an increase in the magnitude of conditioned responses to both the positive and negative conditioned stimuli at all interstimulus intervals. It was concluded that LSD did not alter discriminative conditioning but rather enhanced the excitatory properties of both positive and negative conditioned stimuli.