Drug-induced reinstatement to heroin and cocaine seeking: a rodent model of relapse in polydrug use

The authors investigated several features of polydrug use in rats. Heroin and cocaine were self-administered following responses on different levers, with only 1 drug and 1 lever available on alternate days of training. Four doses of each drug (heroin: 25, 50, 100, and 200 microg/kg/infusion; cocaine: 0.25, 0.5, 1, and 2 mg/kg/infusion) were tested, and each rat was exposed to a single dose combination. Rats readily developed drug-specific and dose-related responding. During extinction, rats displayed a significant bias for responding on the cocaine- associated lever. Priming injections of either cocaine (20 mg/kg) or heroin (0.25 mg/kg) reinstated responding that was selective for the lever previously associated with each drug. These results suggest that in this type of polydrug use, drugs have the capacity to activate drug-seeking behavior selectively oriented toward stimuli previously associated with their administration.     

Chronic morphine reduces pain-related disability in a rodent model of chronic, inflammatory pain.

Chronic pain is disabling, and the adverse effects of morphine are also disabling. The best way to assess the beneficial effects relative to the potential adverse effects of chronic morphine may be through the use of quantitative measures of functional disability in people and animals experiencing pain. If chronic morphine alleviates chronic pain and its beneficial analgesic effects outweigh whatever adverse effects it may produce, then it should reduce pain-related disability. Rats with adjuvant-induced arthritis were implanted with subcutaneous morphine pellets. Continuous morphine reduced pain-related disability in tasks motivated by food reward or shock avoidance throughout the 35 days of continuous administration--first, in tests that primarily assessed the function of the less severely affected forelimbs, and later, as the inflammation subsided, in tests more dependent on the function of the more severely affected hind limbs.     

Methadone maintenance and other factors associated with intraindividual temporal trends in injection-drug use

The objective of this study was to determine what sociodemographic, lifestyle, or drug-related characteristics predict temporal changes in self-reported drug injection frequencies among HIV-seronegative injection-drug users (IDUs) who were being given HIV testing and risk reduction counseling. The 277 subjects were given 4–11 quarterly interviews including a detailed history of drug use and other HIV risk factors, HIV risk reduction counseling, and venipuncture for HIV antibody testing. A regression slope of change over time in drug injection frequency was calculated for each subject, and categories were created of decreasing temporal slope, increasing slope, relapse (decrease initially, then increase), or no substantial change. Only 44% of subjects decreased their drug injection frequencies despite repetitive HIV testing and counseling. In multivariate logistic analyses, decreasing temporal trends were associated with consistent enrollment in methadone maintenance (p < .1), whereas increasing trends conversely were associated with inconsistent enrollment (p < .01) and also with an absence of crack use (p < .01). Relapses were significantly associated with needle sharing with multiple partners and a low frequency of smoking. The data suggest that methadone maintenance facilitates a positive response to HIV risk reduction counseling. However, the fact that only a minority of subjects displayed a decreasing temporal trend in drug injection frequencies emphasizes the need for improved therapeutic and counseling techniques.     

Review of evidence for a novel model of cocaine-induced cardiovascular toxicity.

Cocaine is known to produce life-threatening cardiovascular complications in some but not all individuals. This review considers the premise that an appropriate animal model for cocaine-induced cardiotoxicity should be characterized by varying sensitivity in the population to the deleterious effects of cocaine. We have studied such a model in which physiological, biochemical, and pathological sensitivity to cocaine varies in rats. Our studies have identified a subset of rats that respond to cocaine with a decrease in cardiac output and a substantial increase in systemic vascular resistance (named vascular responders). In contrast, another group, designated mixed responders, is characterized by a smaller increase in systemic vascular resistance and a small increase in cardiac output. We reported that vascular responders are more likely to develop hypertension and cardiomyopathies with repeated cocaine administration. Under chloralose anesthesia, vascular responders have more profound pressor responses to cocaine and an initial brief spike in renal sympathetic nerve activity not usually noted in mixed responders. Vascular responders have higher resting and cocaine-induced dopamine turnover in the striatum. In addition, vascular responders have higher alpha-adrenergic vasoconstrictor tone, whereas mixed responders have higher adrenergic cardiac tone. The difference in cardiac output and systemic vascular resistance responses to cocaine in these two subsets of the population can be prevented by L-type calcium channel, muscarinic, or alpha-adrenergic blockade. Similar hemodynamic response variability is noted with other psychoactive agents and with acute stress, suggesting that the response patterns are not unique to cocaine. We propose that individual hemodynamic response variability is dependent on differences in CNS responsiveness and correlated with the incidence of cardiovascular disease.     

Methadone maintenance in prison: evaluation of a pilot program in Puerto Rico

OBJECTIVES: To describe and evaluate a pilot methadone maintenance program for heroin-dependent inmates of Las Malvinas men's prison in San Juan, Puerto Rico. METHODS: Data from self-report of inmates' drug use before and during incarceration, attitudes about drug treatment in general and methadone maintenance in particular, and expectations about behaviors upon release from prison and from testing inmates' urine were analyzed comparing program patients (n=20) and inmates selected at random from the prison population (n=40). Qualitative data obtained by interviewing program staff, the correctional officers and superintendent, and commonwealth officials responsible for establishing and operating the program were analyzed to identify attitudes about methadone and program effectiveness. RESULTS: Heroin use among prisoners not in treatment was common; 58% reported any use while incarcerated and 38% reported use in past 30 days. All patients in the treatment program had used heroin in prison in the 30 days prior to enrolling in treatment. While in treatment, the percentage of patients not using heroin was reduced, according to both self-report and urine testing, to one in 18 (94% reduction) and one in 20 (95% reduction), respectively. Participation in treatment was associated with an increased acceptance of methadone maintenance. Prison personnel and commonwealth officials were supportive of the program. CONCLUSIONS: The program appears to be a success, and prison officials have begun an expansion from the current ceiling of 24 inmates to treat 300 or more inmates.     

Methadone distribution and excretion into breast milk of clients in a methadone maintenance programme

Aims Methadone is widely used in maintenance programs for opioid-dependent subjects. The aims of the study were to quantify the distribution and excretion of methadone in human milk during the early postnatal period and to investigate exposure of breast fed infants to the drug.
Methods Blood and milk samples were obtained from 12 breast feeding women who were taking methadone in daily doses ranging from 20–80  mg (0.3–1.14  mg  kg⁻¹ ). Blood was also obtained from eight of their infants. Methadone concentration in these samples was quantified by h.p.l.c. The infants were observed for withdrawal symptoms.
Results The mean (95% CI) milk/plasma ratio was 0.44 (0.24–0.64). Exposure of the infants, calculated assuming an average milk intake of 0.15  l  kg⁻¹  day⁻¹ and a bioavailability of 100% was 17.4 (10.8–24)  μg  kg⁻¹  day⁻¹. The mean infant dose expressed as a percentage of the maternal dose was 2.79 (2.07–3.51)%. Methadone concentrations in seven infants were below the limit of detection for the h.p.l.c. assay procedure, while one infant had a plasma methadone concentration of 6.5  μg  l⁻¹ . Infant exposure to methadone via human milk was insufficient to prevent the development of a neonatal abstinence syndrome which was seen in seven (64%) infants. No adverse effects attributable to methadone in milk were seen.
Conclusions We conclude that exposure of breast fed infants to methadone taken by their mothers is minimal and that women in methadone maintenance programs should not be discouraged from breast feeding because of this exposure.     

Methadone maintenance treatment (MMT): a review of historical and clinical issues

Methadone maintenance has been evaluated since its development in 1964 as a medical response to the post-World War II heroin epidemic in New York City. The findings of major early studies have been consistent. Methadone maintenance reduces and/or eliminates the use of heroin, reduces the death rates and criminality associated with heroin use, and allows patients to improve their health and social productivity. In addition, enrollment in methadone maintenance has the potential toreduce the transmission of infectious diseases associated with heroin injection, such as hepatitis and HIV. The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with heroin. A majority of patients require 80-120 mg/d of methadone, or more, to achieve these effects and require treatment for an indefinite period of time, since methadone maintenance is a corrective but not a curative treatment for heroin addiction. Lower doses may not be as effective or provide the blockade effect. Methadone maintenance has been found to be medically safe and nonsedating. It is also indicated for pregnant women addicted to heroin. Reviews issued by the Institute of Medicine and the National Institutes of Health have defined narcotic addiction as a chronic medical disorder and have claimed that methadone maintenance coupled with social services is the most effective treatment for this condition. These agencies recommend reducing governmental regulation to facilitate patients access to treatment. In addition, they recommend that the number of programs be expanded, and that new models of treatment be implemented,if the nationwide problem of addiction is to be brought under control. The National Institutes of Health also recommend that methadone maintenance be available to persons under legal supervision, such as probationers, parolees and the incarcerated. However, stigma and bias directed at the programs and the patients have hindered expansion and the effective delivery of services. Professional community leadership is necessary to educate the general public if these impediments are to be overcome.     

The utility of a rodent model in detecting pediatric drug-induced nephrotoxicity.

A multi-age rat model was used to identify potential age-related differences in renal injury following exposure to gentamicin (GM). In this study, 10-, 25-, 40-, and 80-day-old Sprague-Dawley rats were dosed with GM at 0, 50, or 100 mg kg(-1) body weight per day (mkd) sc for 6 or 14 days. Urine samples were collected up to 72 h after initial dosing. The maximum tolerated dose was lower in 10-day-old rats than for other ages (none survived 11 days of treatment). Eighty-day-old rats given the highest dose showed a diminished rate of growth and an increase in serum creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (Kim-1), and renal pathology. Ten- and 40-day-old rats given 100 mkd of GM for 6- or 14 days also had increased levels of serum BUN and Cr and renal pathology, whereas only mild renal alterations were found in 25-day-old rats. After 6 days of treatment with 100 mkd GM, significant increases in Havcr-1 (Kim-1) gene expression were detected only in 10- and 80-day-old rats. In urine samples, nuclear magnetic resonance and ultra performance liquid chromatography/mass spectrometry analysis detected changes related to GM efficacy (e.g., hippurate) and increases in metabolites related to antioxidant activity, which was greatest in the 80-day-old rats. The magnitude of the genomic, metabonomic, and serum chemistry changes appeared to correlate with the degree of nephropathy. These findings indicate that an experimental animal model that includes several developmental stages can detect age-related differences in drug-induced organ toxicities and may be a useful predictor of pediatric drug safety in preclinical studies.     

Multidose risperidone treatment evaluated in a rodent model of tardive dyskinesia.

Risperidone is a second-generation antipsychotic that lacks acute motor side effects at low doses (<6 mg/day), but above this level is associated with parkinsonism and akathesia. The literature suggests an association between acute motor side effects and tardive dyskinesia (TD); therefore, we hypothesized that low dose levels of risperidone will spare TD. As clinical studies of TD liability with fixed doses of risperidone are difficult to conduct, we tested low and high doses of risperidone in a rodent model of TD, vacuous chewing movements (VCMs) production. Low doses of risperidone (1.5 mg/kg/day) resulted in control levels of VCMs after 6 months of treatment, whereas high doses of risperidone (6 mg/kg/day) produced VCM in the same range as haloperidol. Plasma drug levels are reported. If this animal model predicts TD risk in humans, the TD liability with low-dose risperidone is at a placebo level, whereas higher doses show haloperidol-like TD risk, as predicted from the acute motor effects.     

Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics

Mildronate is a fatty acid oxidation inhibitor approved as an antianginal drug in parts of Europe. We carried out the first study to determine whether a 10-day course of mildronate could reduce myocardial infarct size (IS) during acute myocardial ischemia. Sprague Dawley rats received 200 mg/kg/d of mildronate (treated group, n = 16) or sterile water (control group, n = 14) subcutaneously for 10 days before ischemia-reperfusion. Rats were then subjected to 45 minutes of left coronary artery occlusion and 2 hours of reperfusion. The 2 groups had identical areas at risk: treated 38 +/- 3%; controls 38 +/- 2%. The amount of necrosis was smaller in the mildronate group at 16 +/- 2% of the left ventricle versus controls, 22 +/- 2% (P = 0.05); and for any amount of risk >25%, necrosis was smaller in the treated group (P = 0.0035). Myocardial IS (% of risk zone) was 43+/-3% in the mildronate-treated rats, and 57+/-4% in controls (P = 0.004). During occlusion, there were no differences between the 2 groups in heart rate (216 +/- 12 bpm, mildronate and 210 +/- 9 bpm, control), in mean arterial pressure (60 +/- 2 mm Hg, mildronate and 64 +/- 3 mm Hg, control) or in the frequency of arrhythmias. Our study for the first time demonstrated that a 10-day treatment with mildronate reduced myocardial IS in an experimental model of acute myocardial ischemia, without any effect on hemodynamics.     

The validity of the reinstatement model of craving and relapse to drug use

Rationale The reinstatement procedure has been used increasingly as a laboratory model of craving and relapse to drug abuse. With the number of reports involving this procedure growing, its validity as a model of relapse merits discussion. Objectives The present commentary addresses the validity of the reinstatement procedure in relation to the following three types of models: 1) formal equivalence models, which are assessed on the basis of how well they resemble some phenomenon outside the laboratory (i.e. face validity); 2) correlational models, which are assessed on the basis of how well they predict outcomes of various interventions (such as drug administration or environmental change) when effected outside the laboratory (i.e. predictive validity); and 3) functional equivalence models, which are assessed on the basis of whether the laboratory phenomenon is mechanistically identical or reasonably similar to the phenomenon outside the laboratory (i.e. content validity). Methods In order to evaluate the reinstatement model, we briefly examined its various forms and uses, and compared preclinical outcomes to what is known about relapse from the clinical literature. Results In its most general form, the reinstatement model has reasonable face validity; that is, there is a general agreement in appearance or form of the behavior in the model and the clinical target, relapse. This face validity is generally absent for the procedure when it is used as a model of craving. The predictive validity of the model has not been established. Evidence from studies of treatments for drug relapse have not supported the validity of the model, however from studies of the effects of the presentation of various types of stimuli (e.g. drug "priming") there is mixed evidence supporting predictive validity. With regard to functional equivalence, there is reasonable evidence supporting functional commonalities between drug self-administration in laboratory animals and human drug abusers, which lends support to the validity of the reinstatement model. However, there are several specific areas of departure between the methods and results using the model and clinical practices and observations about relapse, suggesting a lack of functional equivalence. Conclusions There is reasonable evidence to support the face validity of the model, but at this time, neither its predictive validity nor functional equivalence has been fully established, which underscores the need for caution in generalizing results from the model to the clinical condition.     

CGP 44532, a GABAB receptor agonist, is hedonically neutral and reduces cocaine-induced enhancement of reward

Drugs that alter the function of gamma-aminobutyric acid (GABA) neurotransmission seem to reduce cocaine reinforcement, and as such may be useful in pharmacologically treating cocaine addiction. In the present experiment, the anti-cocaine effects of CGP 44532, a phosphinic acid analogue of GABA, and a highly selective GABA(B) receptor agonist were examined in male Sprague-Dawley rats using brain stimulation reward (BSR) paradigm. In this method, the relationship between the rate of bar pressing and the frequency of stimulation pulses was analyzed in two measures: the maximum rate of responding (MAX) and the frequency necessary to sustain half maximal rate of responding known as the locus of rise (LOR). CGP 44532 was found to be hedonically neutral without producing any measurable effects on performance (MAX). It also dose-dependently reduced cocaine-induced BSR enhancement, in the order of 15-31%, as shown by progressive shifts in LOR towards baseline. Thus, in theory, administration of CGP 44532 might reduce cocaine's hedonic effects, while also maintaining patient compliance. Whether this agent would also be effective at curbing craving, a long-term consequence of drug abuse, remains to be determined.     

Opioid substitution treatment reduces substance use equivalently in patients with and without posttraumatic stress disorder

OBJECTIVE: The purpose of this study was to determine whether opioid-dependent patients with diagnosed posttraumatic stress disorder (PTSD) have poorer long-term outcomes in opioid substitution treatment than do patients without PTSD. METHOD: This prospective observational study examined outcomes of 255 opioid-dependent patients (men = 248) entering opioid substitution treatment at eight clinics in the Veterans Health Administration (VHA). Subjects were interviewed at treatment entry, 6 months, and 1 year about substance use and related problems, health status, treatment satisfaction, and non-VHA health care utilization. Medical records were reviewed to obtain toxicology results, health care utilization data, and diagnoses. Medical record review identified a diagnosis of PTSD in 71 (28%) patients. Substance-use and mental-health outcomes and health care utilization in the first year following treatment entry were compared between patients with and without a diagnosis of PTSD. RESULTS: Patients with and without PTSD had similar treatment responses. Although patients with PTSD had longer histories of drug use at intake, at 1-year follow-up they showed reductions in heroin, cocaine, and alcohol use, comparable to patients without the disorder. PTSD patients received higher doses of opiate medication, attended more psychosocial treatment sessions for substance-use disorder, and had better treatment retention. Psychiatric symptoms for patients with PTSD were more severe at intake and showed little improvement throughout treatment. CONCLUSIONS: Opioid substitution therapy is as effective at reducing substance use in PTSD patients as it is in patients without the disorder, but additional services are needed for treatment of psychological problems that are largely unchanged by treatment for addiction.     

Immunotoxicity of poly-drug use: abnormalities in the active and high-affinity CD2 antigen (E-rosette receptor) bearing T-lymphocytes.

The E-rosetting profiles of T-cells were studied in 47 subjects with a history of poly-drug and alcohol abuse, and compared with 15 normal controls. No change was evident in numbers of total rosette-forming cells (TRFC). However, there was reduction in active and high-affinity rosette-forming cells (ARFC and HARFC). These two subsets of CD2-antigen-bearing T-cells are considered as immunocompetent surveillance cells. Thus the abnormality associated with them could be due to the combined immunotoxic effects of substance abuse, modulating the immune status of drug users.     

Prefrontocortical dopamine loss in rats delays long-term extinction of contextual conditioned fear, and reduces social interaction without affecting short-term social interaction memory.

Prefrontal dopamine loss delays extinction of cued fear conditioning responses, but its role in contextual fear conditioning has not been explored. Medial prefrontal lesions also enhance social interaction in rats, but the role of prefrontal dopamine loss on social interaction memory is not known. Besides, a role for subcortical accumbal dopamine on mnesic changes after prefrontal dopamine manipulation has been proposed but not explored. The objective was to study the involvement of dopaminergic neurotransmission in the medial prefrontal cortex (mPFC) and nucleus accumbens in two mnesic tasks: contextual fear conditioning and social interaction memory. For contextual fear conditioning, short- and long-term freezing responses after an electric shock were studied, as well as extinction retention. Regarding social interaction memory, the recognition of a juvenile, a very sensitive short-term memory test, was used. Dopamine loss was carried out by injection of 6-hydroxydopamine, and postmortem catecholamine levels were analyzed by high-performance liquid chromatography. Prefrontocortical dopamine loss (>76%) led to a reactive enhancement of accumbal dopamine content (p<0.01), supporting the hypothesis that a hyperdopaminergic tone emerges in the nucleus accumbens after prefrontocortical dopamine loss. In lesioned rats, long-term extinction of contextual fear conditioning was significantly delayed and extinction retention was impaired without changes in acquisition and short-term contextual fear conditioning and, on the other hand, acquisition and short-term social interaction memory were not affected, although time spent on social interaction was significantly reduced. Added dopamine loss in the nucleus accumbens (>76%) did not alter these behavioral changes. In summary, the results of the present study indicate that the dopaminergic network in the mPFC (but not in the nucleus accumbens) coordinates the normal long-term extinction of contextual fear conditioning responses without affecting their acquisition, and it is involved in time spent on social interaction, but not acquisition and short-term social interaction memory.