Biomedical subjects

P Jatlow

Publications and source records attributed to P Jatlow.

At least 19 recordsLinked to original sources

PubMed2003

Sex differences in response to oral amitriptyline in three animal models of depression in C57BL/6J mice.

RATIONALE: Knockout and transgenic mice provide a tool for assessing the mechanisms of action of antidepressants. The effectiveness of oral administration of the tricyclic antidepressant amitriptyline (AMI) was assessed in C57BL/6J (B6) mice, a common genetic background on which knockout and transgenic mice are maintained. OBJECTIVES: We determined whether oral AMI would have antidepressant-like effects in B6 mice and whether these effects varied according to sex, duration of treatment, and the depression model utilized. METHODS: Male and female B6 mice were administered AMI (200 microg/ml) in the drinking water as the sole source of fluid, along with 2% saccharin to increase palatability. Control mice were administered 2% saccharin alone. Mice were assessed for responsiveness to AMI in the tail suspension test (TST), the forced swim test (FST), and the learned helplessness (LH) paradigm. RESULTS: In the TST, AMI decreased immobility time regardless of sex or duration of treatment. AMI also decreased immobility time in the FST, but chronic treatment was necessary for full efficacy in both sexes. In the LH paradigm, both subchronic and chronic AMI treatment decreased escape latencies in female mice, but AMI was effective only after chronic treatment in males. The antidepressant-like effects of AMI could not be explained by differences in locomotor activity because activity levels were not altered by antidepressant treatment. CONCLUSIONS: Overall, oral AMI administration provides a valid model for behavioral assessment of antidepressant-like effects in knockout and transgenic mice maintained on a B6 background, but the effectiveness of oral AMI varies depending on sex, duration of treatment, and the depression model used.

Administration, Oral↗

PubMed2001

Maternal sertraline treatment and serotonin transport in breast-feeding mother-infant pairs.

OBJECTIVE: Pharmacological treatment of postpartum depression is frequently complicated by the mother's desire to breast-feed. Although breast milk levels of several selective serotonin reuptake inhibitors (SSRIs) have been reported to be relatively low, a critical question is whether SSRI exposure during nursing results in clinically significant blockade of serotonin (5-HT) reuptake in infants. This study determined the degree of transporter blockade in infants exposed to sertraline through maternal breast milk. METHOD: The extent of maternal and infant transporter blockade was assessed by measurement of platelet levels of 5-HT in 14 breast-feeding mother-infant pairs before and after 6-16 weeks of maternal treatment with sertraline for major depression with postpartum onset. Plasma sertraline and desmethylsertraline levels were obtained in 13 of these mothers and 11 of their infants. RESULTS: Marked declines in platelet 5-HT levels of 70%-96% were observed in mothers after sertraline treatment, 25-200 mg/day. In contrast, infants showed little or no change in platelet 5-HT levels after exposure through breast-feeding. Mean levels of maternal plasma sertraline and its major metabolite, desmethylsertraline, were 30.7 ng/ml and 45.3 ng/ml, respectively. Drug and drug metabolite concentrations in the infants were at or below the lower limit of quantitation. CONCLUSIONS: The data indicate that while mothers receiving clinical doses of sertraline experience substantial blockade of the platelet 5-HT transporter, platelet 5-HT uptake in nursing infants of treated mothers is unaltered. The observations suggest that mothers taking sertraline can breast-feed without appreciably affecting peripheral or central 5-HT transport in their infants.

Blood Platelets↗

PubMed2001

Effect of opioid dependence pharmacotherapies on zidovudine disposition.

Injection drug users are frequently infected with human immunodeficiency virus (HIV) and receive opioid dependence pharmacotherapies and zidovudine (ZDV), the latter as a component of highly active antiretroviral therapy. We previously reported that methadone substantially increases ZDV concentrations. We now report on oral ZDV pharmacokinetics in 52 subjects receiving the opioid dependence pharmacotherapies l-alpha-acetylmethadol LAAM, buprenorphine, or naltrexone, and 17 non-opioid-treated controls. Relative to the area under the time-concentration curve (AUC) of ZDV in control subjects, no statistically significant differences in ZDV AUC were observed in participants treated with LAAM (p = .75), buprenorphine (p = .37), or naltrexone (p = .34). While methadone maintenance may result in ZDV toxicity and possibly require dose adjustments, other opioid pharmacotherapies should not produce ZDV toxicity.

Anti-HIV Agents↗

PubMed2000

Prevalence of multiple dideoxynucleoside analogue resistance (MddNR) in a multicenter cohort of HIV-1-infected Italian patients with virologic failure.

We evaluated the prevalence of both Q151M and 6-bp insert at position 69 of RT region responsible for multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 variants in 177 patients who failed to respond to combination therapy. Patients had received protease inhibitors (PI) and/or nonnucleoside reverse transcriptase inhibitors (NNRTIs) after a long-term experience with nucleoside reverse transcriptase inhibitors (NRTIs) (including zidovudine monotherapy). Two of 177 patients (1.1%) showed the specific complex of Q151M mutation, while 4 (2.3%) had the 69 6-bp insert. Mutations that belong to the 151 set in the absence of the pivotal Q151M substitution were detected in as many as 3.9% of the patients. One patient exhibited a 69S [VG] insert that has not been previously phenotypically characterized. This HIV-1 isolate had high levels of resistance to all NRTIs except stavudine. MddNR is an emerging problem after sequential therapy with this class of compounds among HIV-1-infected patients. Either didanosine (ddI) or zidovudine (ZDV) monotherapy allowed the emergence of MddNR variants containing Q151M complex. Monotherapy with ZDV and ddI or subsequent treatments with various NRTI combinations were the common background in the patients with the 69 insert. The overall prevalence of MddNR (3.4%) in Italy is comparable with that observed in several other European countries (3.4%-6.5%). These data suggest that patients failed by NRTI regimens should be analyzed for the presence of both patterns of MddNR.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Impact of self-administered cocaine and cocaine cues on extracellular dopamine in mesolimbic and sensorimotor striatum in rhesus monkeys.

Studies were conducted to determine the impact of self-administered cocaine on extracellular striatal dopamine in four rhesus monkeys. The extent to which external cue conditioning contributed to the effects of cocaine and whether there is activation of striatal dopaminergic neurotransmission during drug-seeking behavior was also examined. Microdialysis measurements were made at 2 min intervals in sensorimotor (dorsolateral) and mesolimbic (central and ventromedial) striatum. A fixed-ratio schedule of reinforcement was used, with cocaine availability signaled by a visual cue. Studies examined the effects of cocaine or cocaine cues against a drug-free baseline. Large (fivefold to eightfold) increases in extracellular dopamine after a self-administered infusion of 0.5 mg/kg cocaine were quite rapid and matched the time course of reported subjective effects in human laboratory studies. To determine if conditioning to external cues contributed to the cocaine-induced increases, saline was substituted for cocaine in the infusion, leaving all other visual and auditory stimuli unchanged. No increase in extracellular dopamine in either sensorimotor or mesolimbic striatal subdivisions was observed. Extracellular dopamine during extended periods of drug-seeking behavior triggered by a visual cue was determined in both central and ventromedial striatum. This procedure also did not result in any measurable changes in extracellular dopamine. These studies demonstrate rapid and pronounced pharmacological actions of self-administered cocaine. No apparent conditioned component of those actions was associated with external environmental cues, suggesting that cues that trigger drug-seeking behavior in nonhuman primates do not cause conditioned increases in mesolimbic striatal dopamine.

Animals↗

PubMed2000

Significant interaction between clozapine and cocaine in cocaine addicts.

Because clozapine may be prescribed to cocaine abusing patients with schizophrenia, we studied cocaine-clozapine interactions in a controlled setting. Eight male cocaine addicts underwent four oral challenges with ascending doses of clozapine (12.5, 25 and 50 mg) and placebo followed 2 h later by a 2-mg/kg dose of intranasal cocaine. Subjective and physiological responses, and serum cocaine levels were measured over a total 4-h period. Clozapine pretreatment increased cocaine levels during the study and significantly increased the peak serum cocaine levels in a dose dependent manner. In spite of this elevation in blood levels, clozapine pretreatment had a significant diminishing effect upon subjective responses to cocaine, including 'expected high', 'high' and 'rush', notably at the 50 mg dose. There was also a significant effect upon 'sleepiness', 'paranoia' and 'nervous'. Clozapine caused a significant near-syncopal episode in one subject in the study, requiring his removal from the study. Clozapine had no significant effect on baseline pulse rate and systolic blood pressure, but it attenuated the significant pressor effects of the single dose of intranasal cocaine. These data suggested a possible therapeutic role for clozapine in the treatment of cocaine addiction in humans, but also suggests caution due to the near-syncopal event and the increase in serum cocaine levels.

Adult↗

PubMed2000

Comparison of intravenous cocaethylene and cocaine in humans.

RATIONALE: Cocaethylene is a pharmacologically active homolog and metabolite of cocaine, formed by transesterification of cocaine in the presence of ethanol. Here we relate findings from a randomized, placebo-controlled, double-blind study in which we examined the physiological and subjective effects and pharmacokinetics of i.v. administered cocaethylene in human volunteers using cocaine as a comparator. METHODS: Cocaine-dependent participants randomly received one study drug, cocaethylene (0.25 or 0.5 mg/kg), cocaine (0.25 or 0.5 mg/kg), or placebo, during each experimental session which occurred on separate days. RESULTS: Cocaethylene was less potent in elevating heart rate than equivalent doses of cocaine. Similar differences between cocaine and cocaethylene were found for subjective measures ("Cocaine High", "Rush", "Stimulated" and "Good Drug Effects"). All active drug conditions produced significant increases in systolic blood pressure relative to placebo, but no significant effect on diastolic blood pressure was observed. Cocaethylene demonstrated a slower clearance, larger volume of distribution and correspondingly longer elimination half-life than cocaine. CONCLUSION: The findings from this study confirm those of previous studies that show that cocaethylene has pharmacological properties in common with cocaine, but is less potent.

Adult↗

PubMed1999

Rapid induction of behavioral and neurochemical tolerance to cocaethylene, a model compound for agonist therapy of cocaine dependence.

RATIONALE: Tolerance to abused drugs may impact on patterns of abuse, and in the case of agonist therapies, may be beneficial in that it reduces the reward value of a given dose of abused drug. Cocaethylene, a psychoactive metabolite resulting from concurrent alcohol and cocaine consumption, was examined because of its use in human research studies of drug reward mechanisms, and its potential as a model compound for an agonist based therapy for cocaine dependence. OBJECTIVE: Comparisons were made between cocaine and cocaethylene in the acute development of tolerance to the neurochemical and behavioral effects of cocaine. With chronic exposure, tolerance to the behavioral effects of cocaine was examined. METHODS: In awake rats with a microdialysis probe in the nucleus accumbens and a jugular catheter, an IV bolus/3-h infusion of cocaine or cocaethylene and a subsequent cocaine challenge was administered while extracellular dopamine and locomotion were monitored. Chronic IV treatment with cocaine, cocaethylene, and a water control was accomplished for 7 days using osmotic minipumps attached to jugular catheters. Animals were then challenged with an IV bolus of cocaine. RESULTS: With acute treatment, the IV bolus of cocaethylene at the beginning of the infusion period resulted in an initial behavioral activation equivalent to that caused by cocaine, after which there was a striking difference in that the cocaethylene group displayed a return to predrug levels of activity, while the cocaine group showed high levels of activity throughout the 3-h period. Both cocaethylene and cocaine resulted in an initial increase in the extracellular concentration of dopamine. However, after that initial increase, levels of dopamine dropped in the cocaethylene group while the cocaine group levels remained elevated. A 1-week infusion of cocaine or cocaethylene resulted in tolerance to the behavioral activating effects of a subsequent cocaine challenge. CONCLUSIONS: These results demonstrate a rapid induction of tolerance to the behavioral and neurochemical properties of cocaethylene, resulting in a diminished behavioral response to a cocaine challenge both acutely, and after 7 days. The relevance of these data for the use of cocaethylene as a model compound for an agonist approach to therapy for cocaine dependence is discussed.

Animals↗

PubMed1999

Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs methadone.

BACKGROUND: Cocaine abuse occurs in 40% to 60% of patients entering opioid maintenance treatment, and effective pharmacotherapies are needed for this combined dependence. METHODS: This 13-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of desipramine hydrochloride (0 or 150 mg/d) plus buprenorphine hydrochloride (12 mg/d) or methadone hydrochloride (65 mg/d) in 180 opioid-dependent cocaine abusers (124 men, 56 women). Supervised urine samples were obtained thrice weekly, and self-reported cocaine and heroin use was reported once weekly. Desipramine plasma levels were determined at weeks 4 and 10. RESULTS: In men, opioid abstinence was increased more rapidly over time when treated with methadone than with buprenorphine, whereas cocaine abstinence was increased more with buprenorphine than with methadone. In women, opioid abstinence was increased the least rapidly when treated with buprenorphine plus placebo, while cocaine abstinence was increased more rapidly over time when treated with methadone than with buprenorphine. Regardless of sex or opioid medication, desipramine increased opioid and cocaine abstinence more rapidly over time than placebo. Self-reported opioid use confirmed these findings. Desipramine plasma levels were higher in women than in men, particularly those on buprenorphine maintenance. Higher desipramine plasma levels were associated with greater opioid, but not cocaine, abstinence. CONCLUSIONS: Desipramine may be a useful adjunctive medication in facilitating opioid and cocaine abstinence in opioid-maintained patients. The efficacy of opioid medications to treat opioid or cocaine dependence may differ by sex. These findings highlight the importance of including sex as a factor when examining treatment outcome in these types of trials.

Adult↗

PubMed1999

Dark Agouti and Fischer 344 rats: differential behavioral responses to morphine and biochemical differences in the ventral tegmental area.

We sought to identify behavioral and biochemical differences between Dark Agouti and Fischer 344 inbred rat strains to assess whether they could serve as a model of genetically determined differences in sensitivity to drugs of abuse. We compared the strains for the following traits: morphine-induced locomotor activity and sensitization; circadian variation in plasma levels of corticosterone, a hormone reported to affect sensitivity to drugs of abuse; and several biochemical parameters in the ventral tegmental area and nucleus accumbens, brain regions implicated in the locomotor activating and reinforcing actions of drugs of abuse. Fischer 344 rats exhibited greater initial locomotor responses to morphine but, unlike Dark Agouti rats, did not develop sensitization to a second morphine exposure. Fischer 344 rats displayed a marked rise in basal plasma corticosterone levels in the late light phase and early dark phase, whereas Dark Agouti rats showed no significant circadian variation in corticosterone levels. Relative to drug-naive Fischer 344 rats, drug-naive Dark Agouti rats showed higher levels of tyrosine hydroxylase and glial fibrillary acidic protein, and lower levels of neurofilament proteins, in the ventral tegmental area. In contrast, no strain differences were found in levels of tyrosine hydroxylase, specific G protein subunits or protein kinase A in the nucleus accumbens. Together, these results demonstrate that Dark Agouti rats and Fischer 344 rats exhibit differences in specific behavioral, endocrine and biochemical parameters related to sensitivity to drugs of abuse.

Animals↗

PubMed1999

Naltrexone and morphine alter the discrimination and plasma levels of ethanol.

The opioid antagonist, naltrexone, reduces intake of, and operant responding for, ethanol, but reports of how the opioid agonist morphine alters these effects are conflicting. We examined the discrimination and plasma levels of ethanol with naltrexone and morphine pretreatments. Rats were trained to discriminate ethanol (1.5 g/kg; i.g.) from water, under a two-lever, food-reinforced procedure. Ethanol and pentobarbital, but not amphetamine, substituted for ethanol in a dose-related manner. Naltrexone reduced ethanol-induced, ethanol-appropriate responding to about 35%, but the peripherally-acting antagonist, naltrexone methobromide, was without effect. Morphine neither substituted for nor enhanced ethanol-appropriate responding. Rather, ethanol-induced, ethanol-appropriate responding was attenuated in a dose-related manner by morphine administration. Neither naltrexone nor morphine altered ethanol-appropriate responding to the substitution with pentobarbital. In another group of rats, both naltrexone and morphine decreased plasma ethanol levels, and delayed the time of peak concentrations, suggesting that opiates alter the behavioral effects of ethanol through both pharmacokinetic and pharmacodynamic mechanisms. The similarities between an opioid agonist and an antagonist suggest that either naltrexone has opioid agonist-like effects, or that these effects occur through non-opioidergic mechanisms.

Animals↗

PubMed1998

Disulfiram effects on acute cocaine administration.

Disulfiram (Antabuse) is being used in outpatient clinical trials to determine its efficacy as a treatment for cocaine dependence. This inpatient randomized, double-blind, placebo-controlled, within-subjects study was conducted to determine whether disulfiram (placebo, 250 or 500 mg/day) alters responses to acute intranasal cocaine (placebo, 1 or 2 mg/kg) administration. Effects of disulfiram on cocaine pharmacokinetics, physiological, and behavioral responses were determined. Disulfiram treatment increased plasma cocaine concentrations three to six times and significantly increased cocaine-associated cardiovascular responses, but did not significantly alter behavioral responses to cocaine. These interactions should be considered in the decision regarding disulfiram treatment in cocaine dependent patients.

Acute Disease↗

PubMed1998

Concurrent use of cocaine and alcohol is more potent and potentially more toxic than use of either alone--a multiple-dose study.

BACKGROUND: Simultaneous abuse of cocaine and alcohol is widespread and increasingly detected in patients seeking emergent care. This double-blind, randomized, within-subjects study used a paradigm more closely approximating practices of drug abusers to better understand the pathogenesis of cocaine-alcohol abuse. METHODS: Subjects meeting DSM-IV criteria for cocaine dependence and alcohol abuse participated in three drug administration sessions: four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg) administered following the initial cocaine dose and a second dose (120 mg/kg) at 60 min calculated to maintain plasma alcohol concentration at approximately 100 mg/dL during cocaine administration; four doses of cocaine/placebo alcohol; four doses of cocaine placebo/alcohol. Pharmacokinetic, physiological, and behavioral effects were followed over 8 hours. RESULTS: Cocaine-alcohol produced greater euphoria and increased perception of well-being relative to cocaine. Heart rate significantly increased following cocaine-alcohol administration relative to either drug alone. Cocaine concentrations were greater following cocaine-alcohol administration. Cocaethylene had a longer halflife with increasing concentrations relative to cocaine at later time points. CONCLUSIONS: Enhanced psychological effects during cocaine-alcohol abuse may encourage ingestion of larger amounts of these substances over time placing users at heightened risk for greater toxicity than with either drug alone.

Adult↗

PubMed1998

Methadone effects on zidovudine disposition (AIDS Clinical Trials Group 262).

Large numbers of injection drug users (IDUs) are infected with HIV and receive both methadone and zidovudine (ZDV) therapy. Pharmacokinetic interactions between these agents may effect drug efficacy, toxicity, and compliance. To confirm and expand previous studies that identified a potential interaction between ZDV and methadone, we performed a within-subject study to determine oral and intravenous ZDV pharmacokinetics in 8 recently detoxified, heroin-addicted patients with HIV disease before and after initiation of methadone treatment. Acute methadone treatment increased oral ZDV in the area under the curve (AUC) by 41% (p = .03) and intravenous ZDV AUC by 19% (p = .06). Clearance was reduced by 21% (p = .007) and 19% (p = .04), respectively. Chronic methadone treatment increased oral ZDV AUC by 29% (p = .15) and intravenous ZDV AUC by 41% (p = .05). Clearance was decreased by 26% for both routes (p = .02). Methadone levels remained in the therapeutic range during ZDV treatment. These effects resulted primarily from inhibition of ZDV glucuronidation, but also from decreased renal clearance of ZDV. This study confirms that methadone-maintained patients receiving standard ZDV doses experience greater ZDV exposure and may be at increased risk for ZDV side effects and toxicity. Increased toxicity surveillance and possibly reduction in ZDV dose are indicated when these two agents are given concomitantly.

Administration, Oral↗

PubMed1998

Chronic disulfiram treatment effects on intranasal cocaine administration: initial results.

BACKGROUND: Simultaneous abuse of cocaine and alcohol is common. Alcohol decreases negative stimulant effects and potentiates "high." Disulfiram (Antabuse) is being studied in outpatient trials as a cocaine pharmacotherapy with the rationale that inability to modulate cocaine effects with alcohol may decrease cocaine use. METHODS: We examined the interaction of disulfiram and cocaine in a randomized, double-blind, placebo-controlled study where subjects were chronically treated with disulfiram and then participated in intranasal cocaine administration studies. RESULTS: Disulfiram 250 mg/day treatment significantly increased plasma cocaine concentrations (p = .013), heart rate (cocaine 1 mg/kg, p = .046), and systolic (cocaine 2 mg/kg p = .003) and diastolic (cocaine 2 mg/kg, p = .022) blood pressure. "High" and "nervous" ratings were nonsignificantly increased. CONCLUSIONS: The combination of "high" with increased anxiety in the context of inability to lessen negative effects with alcohol may be an effective treatment in selected patients. The significant pharmacokinetic interaction must be considered in the decision regarding use of disulfiram.

Administration, Intranasal↗

PubMed1998

Lithium and desipramine versus desipramine alone in the treatment of severe major depression: a preliminary study.

Improvement following lithium augmentation is well-documented in depressed patients resistant to tricyclic antidepressants. However, response latency to lithium augmentation is extremely variable, suggesting other mechanisms may be involved. To evaluate whether long-term tricyclic treatment is necessary for lithium augmentation's effect, the rapidity and magnitude of response to lithium combined with desipramine from the start of treatment was compared to desipramine alone in severely depressed patients. Patients with DSM-III-R major depression were randomized to double-blind, placebo-controlled treatment with either lithium + desipramine or placebo + desipramine for 4 weeks. Response criteria were based on Hamilton Depression Rating Scale scores and global improvement. Analysis of covariance of Hamilton scores demonstrated that lithium + desipramine was superior to placebo + desipramine at week 1 (P < 0.009), week 2 (P < 0.028), and week 3 (P < 0.07), although not at week 4. There were more responders to the combination than to monotherapy (P < 0.042). These preliminary data suggest that lithium + desipramine may have some efficacy in severely depressed patients. Further studies with larger samples are needed to confirm these findings.

Adult↗

PubMed1998

Incidence of passive exposure to crack/cocaine and clinical findings in infants seen in an outpatient service.

OBJECTIVES: Passive exposure to crack/cocaine and the associated clinical symptoms may present a significant health risk to very young infants and children. This study was designed to determine the incidence of cocaine exposure, presumed to be passive, in ill infants younger than 1 year of age, using a threshold of detection for cocaine and/or its major metabolite, benzoylecognine (BE), that is lower than the current National Institute on Drug Abuse standard. The study also investigates the morbidity associated with passive cocaine exposure in this population. METHODS: We prospectively obtained 124 samples of urine from 122 children younger than 1 year of age for routine clinical indications from the emergency department at Yale-New Haven Hospital. Samples were analyzed by radioimmunoassay (RIA) for cocaine, with cross-reactivity for BE. The presence of BE in a portion of the RIA-positive samples also was detected in additional analyses by enzyme-multiplied immunoassay technique or by gas chromatography-mass spectrometry. A chart review was conducted on all 122 patients by reviewers blind to the urine toxicology results. Presenting complaints, symptoms, vital signs, and diagnosis were obtained for all visits before the first birthday. Birth history, including maternal drug history and birth weight, demographics, and number of medical visits in the first year, were recorded as well. RESULTS: Of the 124 samples, 45 (36.3%) were positive (>/=50 ng/mL of BE equivalents) for cocaine and/or cocaine metabolite by RIA testing. The positive results, determined by RIA, were highly correlated with patients who had lower and upper respiratory symptoms and sought medical care more often. CONCLUSIONS: The incidence of unsuspected, passive cocaine exposure in ill infants seeking medical care primarily through an emergency service may be as high as 1 in 3 to 6 infants from our predominantly inner city population. Current immunoassay methods, specific for BE, and their routine threshold of detection (200 to 300 ng/mL) may not be sensitive enough to detect cocaine and BE in the urine samples of children younger than 1 year of age who are exposed passively. The development of upper and lower respiratory symptoms is correlated significantly with positive urine results in this study. The increased use of health care resources correlated with passive cocaine exposure in this sample may serve as an indirect marker for the increased medical needs of these infants.

Cocaine↗

PubMed1997

Imaging D2 receptor occupancy by endogenous dopamine in humans.

The impact of endogenous dopamine on in vivo measurement of D2 receptors in humans was evaluated with single photon emission computerized tomography (SPECT) by comparing the binding potential (BP) of the selective D2 radiotracer [123I]IBZM before and after acute dopamine depletion. Dopamine depletion was achieved by administration of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT), given orally at a dose of 1 g every six hours for two days. AMPT increased [123I]IBZM BP by 28 +/- 16% (+/- SD, n = 9). Experiments in rodents suggested that this effect was due to removal of endogenous dopamine rather than D2 receptor upregulation. Synaptic dopamine concentration was estimated as 45 +/- 25 nM, in agreement with values reported in rodents. The amplitude and the variability of the AMPT effect suggested that competition by endogenous dopamine introduces a significant error in measurement of D2 receptors in vivo with positron emission tomography (PET) or SPECT. However, these results also imply that D2 receptor imaging coupled with acute dopamine depletion might provide estimates of synaptic dopamine concentration in the living human brain.

Adult↗