Thomas B. Cooper

Behavioral and Cardiovascular Effects of Intravenous Methylphenidate in Normal Subjects and Cocaine Abusers

This study compares the behavioral and cardiovascular response to methylphenidate (0.5 mg i.v.) in 10 cocaine abusers and 20 controls. Methylphenidate induced a long-lasting increase in blood pressure and pulse rate in both groups of subjects. It also induced a short-lasting ‘high’ (27 min) and longer-lasting ‘restlessness’ (67 min). In the normal subjects, but not in the cocaine abusers, methylphenidate significantly increased sexual desire and induced a subjective experience of ‘loss of control’. In the cocaine abusers, methylphenidate consistently induced cocaine craving. While 90% of the cocaine abusers reported methylphenidate as pleasurable, only 50% of the normal subjects did. Cocaine abusers reported that the ‘high’ induced by methylphenidate was similar to that of cocaine but lasted longer and was associated with more physical effects.

Disappearance of memory deficits in outpatient depressives responding to imipramine

We evaluated learning and memory in 50 depressed patients prior to and following 4 week treatment with imipramine compared to 21 normal controls tested at corresponding times. At baseline, the depressives did worse than normals on most memory tasks with the difficult memory tasks, regardless of store, modality or type of task best distinguishing between depressive and normal memory. Following imipramine treatment, responders performed better than nonresponders on the difficult memory tasks, and not significantly differently from controls on most tasks. This, as well as the fact that the responders improved to a greater degree than controls on most measures (in a few cases the difference was statistically significant) and the fact that at 4 weeks complete responders to imipramine did significantly better than partial responders to imipramine, indicates that relief from depression is highly related to improved memory functioning. The finding that complete responders to imipramine were not significantly worse than normal controls suggests that imipramine did not have significant adverse effects on memory.

Effects of chronic antidepressant treatment on serotonin receptor activity in mice.

The effect of acute and chronic treatments with conventional and atypical antidepressant drugs on serotonin receptor activity was assessed by the responsiveness of mice to the serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine. Acute treatment with 10 mg/kg of amitriptyline, imipramine, trazodone, mianserin or viloxazine reduced the head twitch response measured 1 h following a challenged dose of the serotonin agonist. Acute iprindole and desmethylimipramine, however, had no effect on the serotonergic response. Chronic treatment with the clinically effective antidepressants amitriptyline, imipramine, desmethylimipramine, iprindole, and trazodone produced an enhanced responsiveness to 5-MeODMT. The enhanced responsiveness was first observed 24 h after cessation of treatment with most drugs. The effect lasted for at least 48 h. Chronic treatment with the neuroleptic haloperidol did not result in altered responsivity to the serotonin agonist. Brain accumulation of imipramine and amitriptyline and their deaminated metabolites were measured. Brain drug and metabolite levels peaked 1 h following both acute and chronic treatments. Brain accumulations of amitriptyline and its metabolite were much greater than those of imipramine and its metabolite. This pharmacokinetic data is consistent with an early (1 h) antagonism of the 5-MeODMT response and the emergence of hightened responsiveness to 5-MeODMT after chronic treatment, when brain drug levels are reduced. These findings are also consistent with the greater inhibitory effect found after treatment with amitriptyline than with imipramine. It is concluded that enhanced serotonin neurotransmission which develops during chronic treatment with antidepressant drugs may be related to the clinical action of these drugs.

Ethanol alters lipid profiles and phosphorylation status of AMP-activated protein kinase in the neonatal mouse brain.

Previously, we have shown that ethanol‐induced apoptosis in cultured neurons is accompanied by changes in cellular lipid profiles. In the present study, the effects of ethanol on brain lipid metabolism were studied using 7‐day‐old C57BL/6ByJ mice, which display apoptotic neurodegeneration upon exposure to ethanol. The brain lipids were extracted 4–24 h after the ethanol or saline treatment, and analyzed by TLC. We found that the levels of triglyceride, cholesterol ester, ceramide, and N‐acylphosphatidylethanolamine increased significantly in the brains of ethanol‐treated mice compared to those of saline‐treated mice. Concomitantly, ethanol reduced Thr172 phosphorylation of AMP‐activated protein kinase (AMPK) α subunits. Ethanol also reduced phosphorylation of acetyl‐CoA carboxylase, a substrate of AMPK and a lipogenic enzyme known to be activated by dephosphorylation. In contrast, lipid profiles of 19‐day‐old mouse brains, which scarcely manifested neurodegeneration upon ethanol exposure, were not significantly affected by ethanol. Also, the basal levels of Thr172‐phosphorylated AMPK α were lower in these brains than in 7‐day‐old mouse brains, and no detectable changes in the phosphorylation status were observed by ethanol treatment. Our findings indicate that the ethanol‐induced apoptotic neurodegeneration observed in mice during restricted developmental periods is accompanied by alterations in both the lipid content and the activity of AMPK in the brain.

Plasma clozapine concentration coefficients of variation in a long-term study

Kurz et al. conducted the first study of the intra-individual variability of clozapine plasma concentrations but did not take into account the effect of smoking and co-medication. As patients were receiving varying doses, Kurz et al. standardized plasma levels by using a plasma level/dose/kg ratio. In 15 patients, the mean coefficient of variation (CV) was 53% (S.D. = 21). In this new study, plasma clozapine and norclozapine concentrations were measured every 2 weeks in 47 patients randomized to 100, 300, or 600 mg/day for 16-week double-blind clozapine trials under controlled conditions (stable smoking, limited co-medication and absence of caffeinated beverages). For 100, 300 and 600 mg/day, the respective mean CVs for plasma clozapine concentrations were 23% (S.D. = 14), 19% (S.D.= 11) and 18% (S.D. = 8). For the combined concentrations of clozapine and norclozapine, the respective mean CVs were 20% (S.D. = 13), 16% (S.D. = 9) and 15% (S.D. = 7). Under 100 mg/day, the mean CV for clozapine concentrations was significantly higher for heavy smokers than non-heavy smokers (32%, S.D. = 3 vs. 19%, S.D. = 8) (p = 0.03). Studies of CVs in other environments are needed. Clozapine CVs may be important in order to understand the importance of variations around the therapeutic range and to interpret drug interactions above the usual noise of measuring plasma concentrations.

High-dose treatment with haloperidol: the effect of dose reduction.

High doses of antipsychotic medications are sometimes prescribed in clinical practice, although the efficacy and safety of such treatment have not been established. The purpose of this study was to determine whether high-dose, long-term antipsychotic treatment prescribed on the basis of clinical judgment can be justified. Patients who were receiving high doses of haloperidol were screened, and those patients whose plasma levels were at least 15 ng/mL were randomly assigned to an experimental group (N = 11) or to a control group (N = 12). The experimental group underwent a dose reduction to achieve the target plasma level of 10 ng/mL. The reduction was gradual over a period of 12 weeks. The control group treatment was maintained at the original level. Both groups were then followed up for another 16 weeks, during which the plasma levels of haloperidol were kept constant. The study used double-blind procedures. Both groups showed an average slight symptom reduction. There was no significant difference in the severity of symptoms between the two groups at any time point. The dose reduction had no apparent adverse effects. Thus, the results of this study did not provide justification for high-dose, long-term antipsychotic treatment. However, these results must be interpreted with caution because the sample studied here was small and biased.

The effect of imipramine treatment on brain serotonin receptors and β-adrenoceptors and on pineal β-adrenergic function in adult and aged rats

Abstract The effect of age and of imipramine treatment on cortical serotonin and β-adrenergic binding sites and on pineal N-acetylserotonin and melatonin were examined in Fischer-344 rats. Cortical serotonin-1 and -2 receptor binding was reduced by 15 and 22.5% respectively, in 24 vs. 6 months old animals. Ten single daily imipramine (10 mg/kg) injections in the aged animals resulted in reductions in both types of serotonin sites, while in adult animals significant binding reduction occurred only at the 5HT 2 site. Cortical β-adrenoceptor binding was also diminished in the aged rats. Imipramine treatment elicited a significantly greater decrease in these adrenergic sites in the aged (39.2%) than in the adult (27.6%) animals. In the pineal gland, N-acetylserotonin and melatonin content were reduced by age; imipramine treatment induced decreases in both indoles in the adult animals and a reduction in N-acetylserotonin in the aged animals. These age-related effects of imipramine on cortical serotonin receptor and β-adrenoceptor binding and on pineal indoles may be a consequence of the higher drug and metabolite (desmethylimipramine) blood and tissue concentrations which were found in the aged animals.

Cannabinoid receptor 1 signaling in embryo neurodevelopment.

In utero exposure to tetrahydrocannabinol, the psychoactive component of marijuana, is associated with an increased risk for neurodevelopmental defects in the offspring by interfering with the functioning of the endocannabinoid (eCB) system. At the present time, it is not clearly known whether the eCB system is present before neurogenesis. Using an array of biochemical techniques, we analyzed the levels of CB1 receptors, eCBs (AEA and 2-AG), and the enzymes (NAPE-PLD, DAGLα, DAGLβ, MAGL, and FAAH) involved in the metabolism of the eCBs in chick and mouse models during development. The findings demonstrate the presence of eCB system in early embryo before neurogenesis. The eCB system might play a critical role in early embryogenesis and there might be adverse developmental consequences of in utero exposure to marijuana and other drugs of abuse during this period.

Change in plasma prolactin and clinical response to haloperidol in schizophrenia and schizoaffective disorder

There has been a long-standing interest in plasma prolactin as a potential in vivo indicator of blockade of tuberoinfundibular D2 dopamine receptors. Potential relationships between prolactin response and neuroleptic treatment have been obscured by the use of high doses which have caused prolactin to plateau. With lower doses of neuroleptic now commonly in use, prolactin may be more valuable as a correlate of clinical response. In this study, 23 acutely exacerbated schizophrenic and schizoaffective patients were washed out for at least 6 days and were then treated with haloperidol to achieve fixed low to moderate plasma levels under double-blind conditions. Clinical response, plasma prolactin, and haloperidol plasma levels were measured weekly for 3 weeks. Clinical symptoms at endpoint were related to both prolactin change and final prolactin level during haloperidol treatment. Specifically, fewer symptoms at endpoint were associated with a greater increase in prolactin over time and a higher prolactin level at endpoint. Thus, prolactin increase caused by low to moderate doses of haloperidol may be a correlate of endpoint symptomatology. As lower doses of typical neuroleptics are now in use, prolactin response as a predictor of clinical response may have more clinical utility. Further study of prolactin and clinical response to typical neuroleptics should focus on low neuroleptic doses.

Concurrent lithium administration results in higher haloperidol levels in brain and plasma of guinea pigs

The effects of lithium (Li) on brain and plasma levels of concurrently administered haloperidol (HAL) were investigated. One group of guinea pigs (n = 12) was also treated with HAL for 11 days, but Li was added during the last 5 days of treatment. At the end of treatment, the HAL + Li group had significantly higher brain and plasma levels of HAL than the group treated with HAL alone. The correlation coefficient between plasma and brain HAL (0.97) indicated that plasma levels of HAL determine brain levels of this drug.