Joyce Lowinson

Δ9-Tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis

This study examined the effects of acute administration of delta-9-tetrahydrocannabinol (Δ9-THC), the psychoactive ingredient in marijuana, on extracellular efflux of dopamine (DA) and its metabolites as measured by in vivo microdialysis in nucleus accumbens of conscious, freely-moving rats. Δ9-THC, at low doses (0.5–1.0 mg/kg), which significantly enhance brain stimulation reward (intracranial self-stimulation), significantly increased DA efflux in nucleus accumbens. Augmentation of DA efflux by Δ9-THC was abolished by removal of calcium (Ca++) ions from the perfusion fluid, indicating a Ca++-dependence of Δ9-THCs action. Augmentation of DA efflux by Δ9-THC was either totally blocked or significantly attenuated by doses of naloxone as low as 0.1 mg/kg. Given the postulated role of mesocorticolimbic DA circuits in mediating and/or modulating brain stimulation reward, the present data raise the possibility that marijuanas rewarding effects, and hence its euphorigenic effects and abuse potential, may be related to pharmacological augmentation of presynaptic DA mechanisms. Additionally, the DA mechanisms enhanced by marijuana appear to be modulated by an endogenous opioid peptide system.

Conditioned place preference induced by Δ9-tetrahydrocannabinol: comparison with cocaine, morphine, and food reward

The rewarding property of delta 9-tetrahydrocannabinol (THC), the psychoactive constituent of marijuana and hashish, was studied using the conditioned place preference paradigm, and compared to that of cocaine, morphine, and food reward. The results of Experiment 1 demonstrated that 2.0 and 4.0 mg/kg doses produced a reliable shift in preference for the THC-paired compartment. The THC place preference observed at 2.0 and 4.0 mg/kg was nearly equivalent to that produced by low doses of cocaine (5.0 mg/kg), morphine (4.0 mg/kg), and food in non food-deprived animals. The second experiment used a different conditioning procedure that included a washout period for THC. The results of Experiment 2 demonstrated that a THC place preference could be obtained using a lower dose of THC (1.0 mg/kg), and that this THC place preference was equivalent to that produced by 10 mg/kg cocaine. At higher doses (2.0 and 4.0 mg/kg), THC produced a dose-dependent place aversion. These results suggest that THCs action on brain reward substrates, previously demonstrated by electrical brain stimulation reward, in vivo brain microdialysis, and in vivo brain electrochemistry studies, reflects itself behaviorally in increased appetitive motivational value for environmental stimuli associated with ingestion of marijuana and hashish.

The narcotic-dependent mother: fetal and neonatal consequences.

During the years 1971--1974, 230 infants born to drug-dependent women and 33 infants born to ex-addicts were studied. Heroin abuse declined while methadone usage increased during those years. Compared to heroin abuse, methadone maintenance treatment during pregnancy was associated with more consistent prenatal care, more normal fetal growth and reduced fetal mortality. Meconium staining of amniotic fluid was increased in the heroin and heroin-methadone groups; this was not associated, however, with an increase in meconium aspiration or a reduction in Apgar scores. Of special note was the equally severe intrauterine growth retardation of infants of former heroin addicts who were free of narcotic use during pregnancy. Neonatal withdrawal from methadone appeared to be more severe than from heroin, as judged by amount of medication required to control symptoms and duration of treatment. In all groups, central nervous system signs were the most common manifestations of withdrawal. Severity of withdrawal did not correlate with late pregnancy maternal methadone dosage. Neonatal seizures occurred in 1.5% of the heroin group and 10% of the methadone group. Discharge of an infant to a parent rather than to an alternate care-taker was more likely if the mother was enrolled in a methadone treatment program. Methadone maintenance programs appear to offer significant therapeutic benefits, balancing the untoward effects of the drug on the newborn infant.

Δ9-Tetrahydroeannabinol enhances presynaptic dopamine efflux In medial prefrontal cortex

Abstract Acute administration of 1.0–2.0 mg/kg Δ 9 -tetrahydrocannabinoI Δ 9 -THC) increased presynaptic dopamine (DA) efflux in the medial prefrontal cortex of rats, as measured by intracerebral microdialysis in awake, behaving rats. These data are congruent with suggestions that (1) marijuanas euphorigenic effects and abuse potential may be related to augmentation of presynaptic DA mechanisms, and (2) the medial prefrontal cortex may be an important site of action for drugs of abuse in general and for Δ 9 -THC in particular.

Strain-specific facilitation of dopamine efflux by Δ9-tetrahydrocannabinol in the nucleus accumbens of rat: An in vivo microdialysis study

This study tests the hypothesis that delta 9-tetrahydrocannabinol (delta 9-THC) has a strain-specific facilitatory effect on dopamine (DA) efflux in rat nucleus accumbens, a crucial forebrain convergence of reward-relevant DA neural fibers that has been implicated as a focal brain locus mediating the euphorigenic properties of drugs of abuse. The dependent variable is presynaptic DA efflux measured by in vivo microdialysis in the nucleus accumbens. The independent variables are: (1) intraperitoneal injections of delta 9-THC at 0.0 (vehicle), 0.5 and 1.0 mg/kg; (2) Sprague-Dawley vs Lewis strain rat. Results show that delta 9-THC produces a dose-dependent, strain-specific enhancement of basal DA efflux in Lewis strain rats. These results suggest that genetic variation influences drug abuse vulnerability.

Drug craving and positive/negative hedonic brain substrates activated by addicting drugs

Self-administered electrical brain-stimulation reward is one of the most powerful reinforcers known, rivalled only by the most intensely addicting drugs (e.g. cocaine). In humans, such stimulation produces intense pleasure or euphoria. The brain systems subserving this reward apparently consist of synaptically interconnected neurons associated with the medial forebrain bundle (MFB). ‘First-stage’ neurons run caudally within the MFB, and synapse in the ventral tegmental area on ‘second-stage’ dopaminergic neurons running rostrally within the MFB, which are preferentially activated by habit-forming drugs, and which synapse in the nucleus accumbens on ‘third-stage’ endogenous opioid peptide neurons. Many other types of neurons synapse onto this reward circuit to regulate hedonic tone. Also, this reward circuit is strongly implicated in the pleasures produced by natural rewards (e.g. food, sex). It is widely assumed that crawing is mediated by these same circuits. Some theories posit that craving results from neurotransmitter (dopamine) depletion within the reward circuitry. Other theories posit that ‘opponent-process’ neural systems exist within the reward circuitry, mediating both positive and negative hedonic processes. In this view, craving results from functional dominance of neural systems mediating negative hedonic tone over those mediating positive hedonic tone. It is suggested that current neurophysiological, neurochemical, neuropharmacological and neuro-behavioral data appear to favor this latter view of the neurobiology of craving. It is further suggested that multiple craving states exist, with multiple neurotransmitter substrates. If true, such facts would imply that anti-drug-craving medication development programs predicated on a simple ‘hypo-dopaminergic’ concept of drug craving have little chance of success.

Methadone Treatment and Physical Complaints: A Clinical Analysis

In this study 102 male patients on the Harlem Hospital Methadone Maintenance Treatment Program were asked about physical complaints which they attributed to taking methadone. The most common complaints were sweating, constipation, drowsiness, sexual problems, and aches in bones and joints. There were no statistically significant differences between new patients and long-term patients, but long-term patients appear more likely to be bothered by sweating than new patients, and constipation occurs most frequently during the initial stages of treatment. Complaints were found, in general, to be minor and did not constitute a barrier to patient retention in treatment.

Detoxification of Long-Term Methadone Patients: Problems and Prospects

Various aspects of the detoxification of rehabilitated methadone patients are considered in the light of experience at the Albert Einstein College of Medicine-Bronx Psychiatric Center MMTP and the reports of others in the field. Patients studied met certain eligibility requirements which were thought to enhance the probability of successful detoxification. A total of 228 (10.4%) of 2,814 patients were included in the project. Sixty-three patients have completed detoxification. A follow-up on these patients indicates that 22.2% claim abstinence from all drugs and are reporting to the clinic, 47.6% claim abstinence but have not reported to the clinic, 14.3% returned to methadone maintenance, and 15.9% are lost to contact. This and other studies emphasize the importance of adequate counseling during detoxification.

Three Oral Formulations of Methadone A Clinical and Pharmacodynamic Comparison

This study was done to determine whether there were any differences in subjective symptoms of opiate withdrawal or methadone pharmacodynamics among patients as they were switched between three different oral formulations of methadone. Patients enrolled in a three-way double-blind crossover trial of three methadone formulations. Subjective symptoms and pharmacodynamic measures were assessed throughout the study period. Eighteen patients were enrolled the study. No statistically significant differences in any of the pharmacodynamic parameters studied were found among the three methadone preparations. There was no significant difference among preparations in the rate and extent of rise and fall in plasma methadone levels during a 24-hour intensive sampling period. Subjective symptoms also did not correlate with methadone formulation. Intolerance to changes in methadone formulation, often observed clinically, do not appear to have a pharmacodynamic basis. Our findings support the notion that such change intolerance reflects factors other than the pharmacologic properties of the different formulations of methadone.

Rehabilitation of the Puerto Rican Addict: A Cultural Perspective

Drug addiction has assumed major proportions in the Hispanic population. This paper questions whether treatment programs in Puerto Rican communities adequately relate their rehabilitative services to the realities of Hispanic culture. The experience of a clinic in the South Bronx is reviewed, and it is suggested that programs need to be aware of cultural differences, provide Hispanic staff to treat Hispanic patients, and build up acknowledged strengths, values, and folkways.