Chronic Heroin Research Articles

Outcome of long‐term heroin‐assisted treatment offered to chronic, treatment‐resistant heroin addicts in the Netherlands

To describe 4-year treatment retention and treatment response among chronic, treatment-resistant heroin-dependent patients offered long-term heroin-assisted treatment (HAT) in the Netherlands. Observational cohort study. Out-patient treatment in specialized heroin treatment centres in six cities in the Netherlands, with methadone plus injectable or inhalable heroin offered 7 days per week, three times per day. Prescription of methadone plus heroin was supplemented with individually tailored psychosocial and medical support. Heroin-dependent patients who had responded positively to HAT in two randomized controlled trials and were eligible for long-term heroin-assisted treatment (n = 149). Primary outcome measures were treatment retention after 4 years and treatment response on a dichotomous, multi-domain response index, comprising physical, mental and social health and illicit substance use. Four-year retention was 55.7% [95% confidence interval (CI): 47.6-63.8%]. Response was significantly better for patients continuing 4 years of HAT compared to patients who discontinued treatment: 90.4% versus 21.2% [difference 69.2%; odds ratio (OR) = 48.4, 95% CI: 17.6-159.1]. Continued HAT treatment was also associated with an increasing proportion of patients without health problems and who had stopped illicit drug and excessive alcohol use: from 12% after the first year to 25% after 4 years of HAT. Long-term HAT is an effective treatment for chronic heroin addicts who have failed to benefit from methadone maintenance treatment. Four years of HAT is associated with stable physical, mental and social health and with absence of illicit heroin use and substantial reductions in cocaine use. HAT should be continued as long as there is no compelling reason to stop treatment.

Isoprostane as a Marker of Oxidative Stress in Chronic Heroin Users: Correlation with Duration of Heroin Use or Concomitant Hepatitis C Infection

Background: Although chronic heroin abuse has been extensively linked to oxidative stress, and while plasma 15-F2t-IsoP is considered a good indicator of oxidative stress, there remain few references in the literature about the plasma concentration of this marker in heroin dependent subjects. Objectives: To determine plasma 15-F2t-IsoP, as a marker of oxidative stress, in chronic heroin users, and to examine whether the values of this marker correlate with the duration of heroin use or with the presence of anti-HCV antibodies. Methods: Forty-two chronic heroin users and twenty two healthy control subjects were recruited for this study. An enzyme-immunoassay method was used for the determination of 15-F2t-IsoP in plasma. Results: Plasma 15-F2t-IsoP values were significantly higher in chronic heroin users compared to healthy controls. No correlation was found between the values of plasma 15-F2t-IsoP and the duration of heroin use. Heroin dependent subjects positive for anti-HCV antibodies had significantly lower values of plasma 15-F2t-IsoP as compared to those without a history of HCV infection. Conclusions: The elevated plasma 15-F2t-IsoP values in heroin dependent subjects, compared to healthy individuals, indicate a shift of the balance between oxidants and antioxidants towards the former and suggest that heroin dependent subjects could benefit from an antioxidant therapy.

Renal amyloidosis in intravenous heroin addicts with nephrotic syndrome and renal failure

Renal amyloidosis has emerged as an important differential diagnosis when heroin addicts are admitted to renal clinics with proteinuria and nephrotic syndrome. We present nine heroin addicts with renal AA amyloidosis, a condition previously not encountered in Norway, who were admitted to our renal clinic during the last 3.5 years. In the same time period a total of 209 patients were biopsied from native kidneys. Heroin abuse was associated with 70% of all biopsy-verified renal AA amyloidosis during this time period. Renal amyloidosis was found in 9 of the 12 heroin addicts that were biopsied. 6 of the 9 heroin addicts with amyloidosis required dialysis within 13 months after admission. Renal AA amyloidosis among heroin addicts seems to be associated with chronic suppurative skin infections. AA amyloidosis should always be considered in chronic heroin addicts presenting with proteinuria and renal impairment.

Addiction related alteration in resting-state brain connectivity

It is widely accepted that addictive drug use is related to abnormal functional organization in the user's brain. The present study aimed to identify this type of abnormality within the brain networks implicated in addiction by resting-state functional connectivity measured with functional magnetic resonance imaging (fMRI). With fMRI data acquired during resting state from 14 chronic heroin users (12 of whom were being treated with methadone) and 13 non-addicted controls, we investigated the addiction related alteration in functional connectivity between the regions in the circuits implicated in addiction with seed-based correlation analysis. Compared with controls, chronic heroin users showed increased functional connectivity between nucleus accumbens and ventral/rostral anterior cingulate cortex (ACC), between nucleus accumbens and orbital frontal cortex (OFC), and between amygdala and OFC and reduced functional connectivity between prefrontal cortex and OFC and between prefrontal cortex and ACC. These observations of altered resting-state functional connectivity suggested abnormal functional organization in the addicted brain and may provide additional evidence supporting the theory of addiction that emphasizes enhanced salience value of a drug and its related cues but weakened cognitive control in the addictive state.

Event-related potentials in a Go/Nogo task of abnormal response inhibition in heroin addicts

Inhibitory control dysfunction is regarded as a core feature in addicts. The major objective of this study was to explore the time course of response inhibition in chronic heroin addicts and provide the neurophysiological evidence of their inhibitory control dysfunction. The amplitudes and latencies of ERP components were studied in fourteen heroin addicts (mean duration of heroin use being (13.54+/-5.71) years (Mean+/-SD), average abstinence being ((4.67+/-6.44) months)) and fourteen matched healthy controls with a visual Go/Nogo task. Our results showed that heroin addicts demonstrated significantly larger Go-N2 amplitudes which results in a decreased N2 Go/Nogo effect, but no statistically significant differences were found between heroin addicts and controls in P3. The ERP data suggest that fronto-central areas of heroin addicts were impaired during the inhibition process (200-300 ms) and over-activated to targets. The impaired early process might reflect an abnormal conflict monitoring process in heroin addicts. These results consolidate the inhibitory control dysfunction hypothesis in chronic heroin users.

Dysfunctional connectivity patterns in chronic heroin users: An fMRI study

Recent functional neuroimaging studies have examined cognitive inhibitory control, decision-making and stress regulation in heroin addiction using a cue-reactivity paradigm. Few studies have considered impairments in heroin users from an integrated perspective for evaluation of their brain functions. We hypothesized that the brain regions that are dysregulated in the chronic heroin users during cue-reactivity studies may also show dysfunctional connectivity in memory, inhibition and motivation-related dysfunctions during a resting state free of cues. The present study used resting functional magnetic resonance imaging (fMRI) to compare the interaction of brain regions between 12 chronic heroin users and 12 controls by employing a novel graph theory analysis (GTA) method. As a data-driven approach, GTA has the advantage of evaluating the strength as well as the temporal and spatial patterns of interactions among the brain regions. Abnormal topological properties were explored in the brain of chronic heroin users, such as the dysfunctional connectivity in the prefrontal cortex, ACC, SMA, ventral striatum, insula, amygdala and hippocampus. Our results suggest that GTA is a useful tool in defining dysregulated neural networks even during rest. This dysfunctional brain connectivity may contribute to decrease self-control, impaired inhibitory function as well deficits in stress regulation in chronic heroin users.

Heroin-Assisted Treatment Helps Some Patients

Heroin-Assisted Treatment Helps Some Patients

An Economic Analysis of Income and Expenditures by Heroin-Using Research Volunteers

At a Detroit research program from 2004 to 2005, out-of-treatment chronic daily heroin users (N = 100) were interviewed to evaluate relationships between past 30-day income and factors influencing heroin price, expenditures, and consumption. Weekly heroin purchasing frequency was positively related to income and number of suppliers, and negatively related to time cost (min) from primary supplier. Daily heroin consumption was positively related to income and injection heroin use, and negatively related to unit cost of heroin. Implications and limitations are noted. Simulations are underway to assess within-subject changes in drug demand. Supported by NIH/NIDA R01 DA15462 and Joe Young, Sr. Funds (State of Michigan).

Phosphorylation of GluR1, ERK, and CREB during spontaneous withdrawal from chronic heroin self‐administration

Negative motivational symptoms are observed soon after withdrawal from chronic opiate administration, and are thought to mediate dependence. Examination of brain region-specific signaling changes that accompany early withdrawal may shed light on neural mechanisms underlying negative reinforcement and dependence. Thus, we measured alterations in protein phosphorylation in multiple limbic brain regions in rats undergoing 24 h spontaneous or naltrexone-precipitated withdrawal from chronic (6 h/day) i.v. heroin self-administration. Region-specific increases in cyclic AMP-dependent GluR(1) (S845) phosphorylation were found in the nucleus accumbens shell, basolateral amygdala, hippocampal CA1 and CA3 subregions, and premotor cortex from 12 to 24 h of spontaneous withdrawal, and there were no changes in prefrontal cortex, nucleus accumbens core or caudate-putamen. Increased GluR(1) (S845) phosphorylation was detected earlier (12 h withdrawal) in the central amygdala and ventral tegmental area. In contrast, prominent increases in extracellular signal-regulated kinase phosphorylation were found in both prefrontal and premotor cortex, and CA1 and CA3 between 12 and 24 h withdrawal. Phosphorylation of striatal cyclic AMP response element binding protein increased in the caudate-putamen but not in the nucleus accumbens. Naltrexone administration after 24 h withdrawal increased extracellular signal-regulated kinase phosphorylation in the central amygdala, and nucleus accumbens core and shell. Thus, spontaneous withdrawal from heroin self-administration produces region- and time-dependent changes in cyclic AMP and extracellular signal-regulated kinase activity that could contribute to the behavioral manifestation of opiate dependence.

Adulterant profile of illicit street heroin and reduction of its precipitated physical dependence withdrawal syndrome by extracts of St John's wort (Hypericum perforatum)

The study evaluated the adulterants in a specimen of illicit street heroin supplied under strict control by the Pakistan Anti-Narcotic Force. It also examined the effects of Hypericum perforatum L. extracts on the naloxone-induced heroin withdrawal syndrome. The GC-MS analysis of the specimen showed that in addition to heroin (37.8%), the sample also contained caffeine (8.4%), phenobarbitone (12.7%), 6-acetyl codeine (5.3%), 6-acetyl morphine (10.9%) and noscapine (15.8%). Administration of the heroin to rats for 8 days induced physical withdrawal signs of abdominal constriction, diarrhoea and vocalization on touch after naloxone treatment. Aqueous Hypericum perforatum extracts (20 mg/kg twice daily chronically or as a single acute dose 90 min before naloxone) given orally to the heroin dependent rats attenuated abdominal constrictions both acutely and chronically while the hydroethanol and ethanol extracts were only effective in acutely treated animals. Diarrhoea was ameliorated by the hydroethanol and ethanol extracts following acute or chronic heroin treatment while the aqueous extract failed to show any effect. Vocalization on touch during withdrawal was reduced by all the extracts either chronically or acutely with the exception of chronic treatment with hydroethanol extracts. The findings suggest that Hypericum perforatum is capable of reducing the physical signs of opiate withdrawal.

Repeated heroin in rats produces locomotor sensitization and enhances appetitive Pavlovian and instrumental learning involving food reward

We tested the hypothesis that sensitization to heroin enhances appetitive motivational processes involving food reward. In Experiment 1, sixteen rats were exposed to positive pairings of a light stimulus and food for 4 consecutive daily sessions. Then, the rats received either saline or heroin (2 mg/kg) injections before placement in activity monitors for 9 consecutive daily sessions. Rats were then tested in operant conditioning chambers where one lever produced the light stimulus previously paired with food and another lever produced a tone stimulus not paired with anything. Heroin produced both significant progressive increases in locomotor activity (sensitization) and significantly enhanced conditioned reinforcement of instrumental lever pressing by the food-associated stimulus. In Experiment 2, thirty-two rats were given Pavlovian discrimination training in a conditioned magazine approach task where one stimulus was associated with food and a second unpaired with food. Rats then received repeated saline or heroin injections as in Experiment 1, before being tested under extinction conditions with the two stimuli without the drug. Chronic heroin had no effect on performance in this test, but it facilitated learning of the reversed discrimination in a subsequent phase. These data suggest that sensitization to heroin enhances appetitive motivational processes involving food reward.

A survey of acute and chronic heroin dependence in ten inbred mouse strains: Evidence of genetic correlation with morphine dependence

Heroin and morphine exposure can cause physical dependence, with symptoms manifesting during their withdrawal. Inter-individual differences in symptom frequency during morphine withdrawal are a common finding that, in rodents, is demonstrably attributable to genotype. However, it is not known whether inter-individual differences characterize heroin withdrawal, and whether such variation can be similarly influenced by genotype. Therefore, we injected mice of ten inbred strains with acute and chronic heroin doses and compared their jumping frequencies, a common index of withdrawal magnitude, during naloxone-precipitated withdrawal. The data revealed significant strain frequency differences (range after acute and chronic heroin injection: 0–104 and 0–142 jumps, respectively) and substantial heritability ( h 2 = 0.94 to 0.96), indicating that genetic variance is associated with heroin withdrawal. The rank order of strain sensitivity for acute and chronic heroin withdrawal jumping, and for the current heroin and previous morphine strain data, were significantly correlated ( r = 0.75–0.94), indicating their genetic and, ultimately, physiological commonality. These data suggest that the genetic liability to heroin dependence remains constant across a period of heroin intake, and that heroin and morphine dependence may benefit from common treatment strategies.

Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor

Chronic cocaine and heroin users display a variety of central nervous system (CNS) dysfunctions including impaired attention, learning, memory, reaction time, cognitive flexibility, impulse control and selective processing. These findings suggest that these drugs alter normal brain functions and possibly cause neurotoxicity. Neurotrophins are a class of proteins that serve as survival factors for CNS neurons. In particular, nerve growth factor (NGF) plays an important role in the survival and function of cholinergic neurons while brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity and in the maintenance of midbrain dopaminergic and cholinergic neurons.Our goal was to identify possible change in serum neurotrophins in heroin and cocaine users.In the present study, we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF levels in serum of three groups of subjects: heroin-dependent patients, cocaine-dependent patients and healthy volunteers.BDNF was decreased in heroin users whereas NGF was decreased in both heroin and cocaine users (1).These findings indicate that NGF and BDNF may play a role in the neurotoxicity and addiction induced by these drugs. In view of the neurotrophin hypothesis of schizophrenia the data also suggest that reduced level of neurotrophins may increase the risk of developing psychosis in drug users.1) Angelucci F, Ricci V, Pomponi M, Conte G, Mathe AA, Tonali P, Bria P. Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor. J Psychopharmacol. 2007 Aug 22

Acute and chronic heroin dependence in mice: Contribution of opioid and excitatory amino acid receptors

Opioid and excitatory amino acid receptors contribute to morphine dependence, but there are no studies of their role in heroin dependence. Thus, mice injected with acute or chronic heroin doses in the present study were pretreated with one of the following selective antagonists: 7-benzylidenenaltrexone (BNTX), naltriben (NTB), nor-binaltorphimine (nor-BNI; δ 1, δ 2, and κ opioid receptors, respectively), MK-801, or LY293558 (NMDA and AMPA excitatory amino acid receptors, respectively). Naloxone-precipitated withdrawal jumping frequency, shown here to be a reliable index of heroin dependence magnitude, was reduced by BNTX or NTB in mice injected with both acute and chronic heroin doses. In contrast, nor-BNI did not alter jumping frequencies in mice injected with an acute heroin dose but significantly increased them in mice receiving chronic heroin injections. Continuous MK-801 or LY293558 infusion, but not injection, reduced jumping frequencies during withdrawal from acute heroin treatment. Their delivery by injection was nonetheless effective against chronic heroin dependence, suggesting mechanisms not simply attributable to NMDA or AMPA blockade. These data indicate that whereas δ 1, δ 2, NMDA, and AMPA receptors enable acute and chronic heroin dependence, κ receptor activity limits the dependence liability of chronic heroin. With the exception of δ 1 receptors, the apparent role of these receptors to heroin dependence is consistent with their contribution to morphine dependence, indicating that there is substantial physiological commonality underlying dependence to both heroin and morphine. The ability of κ receptor blockade to differentially alter acute and chronic dependence supports previous assertions from studies with other opioids that acute and chronic opioid dependence are, at least in part, mechanistically distinct. Elucidating the substrates contributing to heroin dependence, and identifying their similarities and differences with those of other opioids such as morphine, may yield effective treatment strategies to the problem of heroin dependency.

Hemorheological changes and characteristic parameters derived from whole blood viscometry in chronic heroin addicts

A group of 15 chronic opioid addicts (DA) with mean age 26.5+/-7.3 years was studied by means of a rotational Contraves Low Shear 30 viscometer and the results have been compared with a control group of 19 healthy subjects. It was found that the mean whole blood viscosity values of the investigated group of heroin abusers (n=15) were elevated compared to that of healthy persons (n=19) over the whole shear rate range and fell by more than ten orders of magnitude (Savov et al., 2006). The present investigation uses the coefficients of the models of Ostwald-de-Walle (power law) and Herschel-Bulkley law, which describe whole blood flow curves (tau-gamma) within the shear rates range from 10(-2) to 10(2) s(-1) and itself incorporate whole blood viscosity data in the entire shear rate range. A significant difference in the mean yield shear stress tau(0) values of the drug abusers' group compared to the controls was found. A strong positive linear correlation was determined between the parameters of RBC aggregation in the group of heroin addicts confirming our previous results (Ivanov and Antonova, 2005; Savov, Zvetkova et al., 2007; Savov, Antonova et al., 2007) for intensive RBC and platelet aggregation and morphological changes in DA group.

Chronic administration of heroin to mice produces up-regulation of brain apoptosis-related proteins and impairs spatial learning and memory

Several studies open up the possibility that chronic exposure to opioid drugs in the CNS would interfere with learning and memory through a neurotoxic effect related to activation of apoptotic pathways. Here, we have analyzed the effects of prolonged heroin administration on sensorimotor and cognitive performance in mice, as well as the associated changes in brain expression of proteins regulating the extrinsic (FasL and Fas) and the mitochondrial (Bcl-2, Bcl-X L, Bad and Bax) apoptotic pathways. Our findings indicate that chronic heroin did not interfere with mice performance in a battery of sensorimotor tests. On the other hand, cognitive ability in the Morris water maze and cognitive flexibility-related performance were strongly impaired by chronic heroin. These effects were associated with up-regulation of pro-apoptotic proteins such as Fas, FasL and Bad, in the cortex and hippocampus, indicating the activation of both the death receptor and the mitochondrial apoptotic pathways. Another indicator of apoptosis was the presence of TUNEL (TdT-mediated dUTP nick-end labeling) positive cells scattered throughout the brain.

Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor

Chronic cocaine and heroin users display a variety of central nervous system (CNS) dysfunctions including impaired attention, learning, memory, reaction time, cognitive flexibility, impulse control and selective processing. These findings suggest that these drugs may alter normal brain functions and possibly cause neurotoxicity. Neurotrophins are a class of proteins that serve as survival factors for CNS neurons. In particular, nerve growth factor (NGF) plays an important role in the survival and function of cholinergic neurons while brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity and in the maintenance of midbrain dopaminergic and cholinergic neurons. In the present study, we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF levels in serum of three groups of subjects: heroin-dependent patients, cocaine-dependent patients and healthy volunteers. Our goal was to identify possible change in serum neurotrophins in heroin and cocaine users. BDNF was decreased in heroin users whereas NGF was decreased in both heroin and cocaine users. These findings indicate that NGF and BDNF may play a role in the neurotoxicity and addiction induced by these drugs. In view of the neurotrophin hypothesis of schizophrenia the data also suggest that reduced level of neurotrophins may increase the risk of developing psychosis in drug users.

Factors associated with nonmedical use of prescription opioids among heroin-abusing research volunteers.

This retrospective study examined factors associated with nonmedical opioid use among 208 heroin-abusing research volunteers in the metropolitan Detroit area. Drug and medical history data were obtained from structured questionnaires administered during screening for behavioral pharmacology research studies. Analyses included demographic data (gender and race), history of drug use (prescribed, nonmedical, and route of use), and potentially relevant medical conditions (e.g., pain). All volunteers (mean age=43 years) reported chronic heroin use (mean duration=21 years), with 66% currently injecting heroin. Two multiple logistic regression analyses were used to identify factors related to lifetime and current nonmedical opioid use (predicted variables). Odds ratios (ORs) from logistic regression--which predicted membership in lifetime heroin use only (n=52) versus heroin plus nonmedical opioid use (n=156) groups--indicated that nonmedical opioid use was significantly associated with legitimate prescription opioid use (OR=10.5), having ever sought treatment for heroin use (OR=4.21), and a history of lung problems (OR=3.66) and dental pain (OR=2.58). The finding of a significant positive association (R(2)=.83) between lifetime rates of medical and nonmedical use of specific opioids in this study is consistent with previous observations that prescription opioid use or availability is a prominent risk factor for nonmedical opioid use. A limitation of this study is that age-of-onset data were not originally collected; thus, the relative (predictive) order of pain conditions, medical use, and nonmedical use of opioids cannot be determined retrospectively.

Peripheral retinal neovascularization in talc retinopathy

Background Neovascularization of the peripheral retina can be present in a number of systemic and ocular diseases. Very rarely, peripheral retinal neovascularization can also be manifested in intravenous drug abusers. In addition to ocular complications, intravenous drug abusers are at high risk for contracting various infections and the development of pulmonary and cardiovascular diseases. We present a case of a chronic heroin and cocaine abuser with bilateral peripheral retinal neovascularization, pulmonary complications, and a history of endocarditis. Case report A patient with a 20-year history of heroin and cocaine abuse initially presented for a routine eye examination. Fundus examination revealed pinpoint white deposits centered in both maculas, engorged vascular fronds with a patch of intraretinal hemorrhage in the peripheral retinal of the right eye and neovascularization of the disc as well as exudation with adjacent focal preretinal hemorrhage in the left eye. The patient underwent fluorescein angiography and was screened for diabetes, sarcoidosis, and sickle cell disease. When no systemic disease could be discovered, it was concluded that the peripheral retinal neovascularization developed as a result of vascular occlusion from heroin and cocaine abuse. Discussion It is important to investigate the cause of neovascularization in the peripheral retina. Retinal vascular emboli such as talc are common in drug abusers, but in most cases, the retinal deposits pose only a minimal threat to vision. However, this case shows that careful retinal examination is warranted in drug abusers to rule out neovascularization of the retina. Other causes of peripheral retinal neovascularization should be ruled out as well. These conditions include sickle cell retinopathy, sarcoidosis, diabetic retinopathy, blood dyscrasias, retinal vascular occlusion, Eales’ disease, and other systemic conditions, so that appropriate ocular and systemic treatment can be provided. Peripheral retinal neovascularization is best treated by pan-retinal photocoagulation.

Reciprocal effects of response contingent and noncontingent intravenous heroin on in vivo nucleus accumbens shell versus core dopamine in the rat: a repeated sampling microdialysis study

Although passive administration of heroin to drug-naive rats increases extracellular dopamine (DA) in the nucleus accumbens (NAc), its ability to do so also after active drug exposure (self-administration) is debated. This study investigated by repeated microdialysis sampling the inter- and intrasession changes in the responsiveness of the NAc shell and core DA and the behavioral effects of active and passive heroin exposure in the intravenous self-administration/yoked paradigm. Rats were implanted with jugular catheters and bilateral intracerebral chronic guide cannulae. Nose poking in the active hole by master rats resulted in heroin administration to the same subjects and to their yoked mates. Concentric microdialysis probes were inserted daily in the guide cannulae, and changes in dialysate DA in response to heroin exposure (0.05 mg/kg) were monitored in the same subject for 90 min for 4 weeks. Behavior associated with heroin exposure, distinguished into nonstereotyped and stereotyped, was also recorded. Dialysate DA increased preferentially in the shell of master rats from the first session (+112%) and throughout the 4 weeks of self-administration (+130-140%). In yoked rats, a preferential but lesser increase in DA in the shell was observed only on the first session (+60%), as the DA response in the NAc core increased progressively (+25-118%), so that within a week, the shell/core ratio was reversed, and this pattern was maintained for the following 2 weeks. Yoked rats showed a progressive and larger increase in stereotyped behaviors than master rats. Chronic heroin self-administration increases extracellular DA preferentially in the NAc shell. Response-noncontingent heroin administration is particularly prone, compared to response-contingent administration, to induce behavioral and biochemical sensitization.