Opiate Dependence Research Articles

A ‘MIRACLE CURE’ MISUNDERSTOOD

Keith Humphreys' inclusion of ‘ultra-rapid opiate detoxification’[1], among discredited ‘miracle cures’ for addiction, needs several important qualifications. The basic theory (using opiate antagonists to make withdrawal shorter, more successful and less unpleasant) was validated in several randomized controlled trials (RCTs) by respected academics in the 1970s and 1980s, all using oral sedation as well as specific antiwithdrawal drugs such as clonidine, to reduce discomfort. Using general anaesthesia (GA) or intravenous sedation (IVS) was a logical development, especially for patients who were difficult to sedate orally. Loimer and his entirely academic colleagues in Vienna were the first to use anaesthesia and regarded the procedure as merely making planned opiate withdrawal easier and more certain. Antagonist-precipitated withdrawal is now combined invariably with initiating oral or implanted naltrexone (NTX). RCTs show that supervised NTX is an effective adjunct to abstinence-based programmes [2] (as supervised disulfiram is in alcoholism), and that NTX implants/depot-injections are more effective than oral NTX or placebo implants. A ‘rapid’ opiate detoxification (ROD) is simply one in which a full dose of NTX (or an implant) is given within 24 hours of starting [3] and can be performed under oral sedation, IVS or GA. ‘Ultra-rapid opiate detox’ (UROD) is no quicker than other rapid methods but was trademarked by the CITA company, who promoted UROD irresponsibly as a miracle cure [4]. They also criticized agonist maintenance. In Britain, ROD acquired a bad reputation when a UROD patient died in unsupervised and thus still mysterious circumstances in a CITA clinic. However, in several other centres, using a variety of rapid or accelerated techniques, hundreds or even thousands of patients have had ROD followed by depot NTX with little detoxification morbidity, no deaths and 3-year outcomes that can compare with agonist maintenance. The Stapleford Centre is a private clinic and provides both agonist- and antagonist-based treatments for opiate dependence. It does not currently conduct rapid detoxifications.

Association of Nerve Growth Factor and Vascular Endothelial Growth Factor A with Psychometric Measurements of Opiate Dependence: Results of a Pilot Study in Patients Participating in a Structured Diamorphine Maintenance Program

Preclinical study results suggest that neurotrophic peptides like nerve growth factor (NGF) and vascular endothelial growth factor A (VEGF-A) may be associated with symptoms of addictive behavior like withdrawal symptoms and rewarding effects. We investigated alterations in NGF and VEGF-A serum levels in opiate-dependent patients (25 male patients), who received diamorphine (DAM, heroin) treatment within a structured opiate maintenance program, and compared the results with the NGF and VEGF-A serum levels of healthy controls (23 male controls). NGF and VEGF-A serum levels were assessed before and after DAM administration twice a day (in the morning (16 h after last application – t1) and in the afternoon (7 h after last application – t3)) in order to detect a possible immediate or summative (in the afternoon) heroin effect on these two neuropeptides. Moreover, we investigated possible associations between the serum levels of these neurotrophic growth factors and psychometric dimensions of addictive behavior, e.g. craving, withdrawal, depression. Whereas there was no direct effect of DAM application on the serum levels of both neurotrophic growth factors neither in the morning nor in the afternoon, the NGF serum levels of the patient group were found to be significantly increased at all four time points of investigation compared with the healthy controls. In contrast, VEGF-A serum levels did not differ significantly in the patient and control groups. We found a significant positive association between the NGF serum levels and several items of the short opiate withdrawal scale as well as a negative association between self-reported mood (measured by visual analogue scale) and mood before heroin application (in the morning as in the afternoon). Moreover, we found a significant positive association between the NGF serum levels (t1 and t3) and the self-reported craving for methadone. In contrast, we found a negative association between the VEGF-A serum levels and avoidance, anxiety, suicide intentions of the SCL-90 as well as a positive association between the VEGF-A serum levels and the subscales of the heroin craving questionnaire measuring the rewarding effects of heroin. In conclusion, the results of this pilot study show that there might be an association between symptoms of opiate dependence and withdrawal and serum levels of VEGF-A and NGF.

GRK2 Protein-mediated Transphosphorylation Contributes to Loss of Function of μ-Opioid Receptors Induced by Neuropeptide FF (NPFF2) Receptors

Neuropeptide FF (NPFF) interacts with specific receptors to modulate opioid functions in the central nervous system. On dissociated neurons and neuroblastoma cells (SH-SY5Y) transfected with NPFF receptors, NPFF acts as a functional antagonist of μ-opioid (MOP) receptors by attenuating the opioid-induced inhibition of calcium conductance. In the SH-SY5Y model, MOP and NPFF(2) receptors have been shown to heteromerize. To understand the molecular mechanism involved in the anti-opioid activity of NPFF, we have investigated the phosphorylation status of the MOP receptor using phospho-specific antibody and mass spectrometry. Similarly to direct opioid receptor stimulation, activation of the NPFF(2) receptor by [D-Tyr-1-(NMe)Phe-3]NPFF (1DMe), an analog of NPFF, induced the phosphorylation of Ser-377 of the human MOP receptor. This heterologous phosphorylation was unaffected by inhibition of second messenger-dependent kinases and, contrarily to homologous phosphorylation, was prevented by inactivation of G(i/o) proteins by pertussis toxin. Using siRNA knockdown we could demonstrate that 1DMe-induced Ser-377 cross-phosphorylation and MOP receptor loss of function were mediated by the G protein receptor kinase GRK2. In addition, mass spectrometric analysis revealed that the phosphorylation pattern of MOP receptors was qualitatively similar after treatment with the MOP agonist Tyr-D-Ala-Gly (NMe)-Phe-Gly-ol (DAMGO) or after treatment with the NPFF agonist 1DMe, but the level of multiple phosphorylation was more intense after DAMGO. Finally, NPFF(2) receptor activation was sufficient to recruit β-arrestin2 to the MOP receptor but not to induce its internalization. These data show that NPFF-induced heterologous desensitization of MOP receptor signaling is mediated by GRK2 and could involve transphosphorylation within the heteromeric receptor complex.

A personal view from a long-lasting collaborator on the research strategies of Marshall Nirenberg

In this review, I summarized transition in Dr. Marshall Nirenberg’s research interests during 1970s, from a view of a long-lasting collaborator. Nirenberg switched his research filed to neurobiology after his success in deciphering genetic code and being honored with the Nobel Prize in Physiology or Medicine in 1968. His targets were to obtain genetically pure population of neurons, i.e. neuroblastoma clones, to make somatic hydrid cells, to culture neuronal and muscle cells, and to produce monoclonal antibodies against whole retinal or neuroblastoma cells. He studied neurotransmitters, receptors, cyclic nucleotides, cell differentiation, secretion, synapse formation, and chemical recognition. Especially he liked his hypothesis for opiate tolerance and dependency as a model of cellular memory. Through these studies, he seemed to devote all his time of about 50 years from 1960s to decoding brain memory processes.

Relative and Age-dependent Stimulation of Soluble and Cellular Immunity in Opiate Dependence

There is considerable recent interest in immunostimulation caused by opiates, but, although there is intense interest in this process within the central nervous system particularly in connection with the pathways underlying chronic pain, few studies set out to define the course of clinical markers of this process in the systemic circulation or over the temporal span of the life course. For this reason, we have compared clinical pathology results from 1747 opiate substance use disorder with 6450 non-substance use disorder patients taken from our clinical pathology database. All continuous data were transformed to their natural logarithm to improve normality assumptions. Globulins, erythrocyte sedimentation rate, white cell count, lymphocytes, monocytes, and platelets were all high in substance use disorder (P ≤ 0.01). These variables, C-reactive protein, high-sensitivity C-reactive protein, and neutrophils were all high at multiple regression when corrected for age (P < 0.0001) in both sexes (P ≤ 0.01). There were significant interactions between age and addictive status for C-reactive protein, high-sensitivity C-reactive protein, erythrocyte sedimentation rate, globulins, white cell count, and lymphocytes and monocytes (P < 0.01). These results are consistent with immunostimulation affecting soluble and cellular elements of the blood both in relative terms and after correction for age. They are consistent with other data showing diffuse and generalized immunostimulation like the high-risk polyclonal immunosenescent gammopathy seen in the very elderly known as "inflamm-aging" that carries an uncommonly poor prognosis for longevity. As such, it merits further detailed investigation.

Manifold implications of forgotten hyperglycemia in clinical opiate dependence

Both chronic opiate dependence and diabetes are widespread public health problems. The historically causal relationship between opiate pharmacology and hyperglycemia would appear to have fallen from curent medical knowledge. The aims of this study were to assess the severity of hyperglycemia in our opiate substance use disorder (SUD) patient population and review its pathophysiological basis. A review was undertaken of our clinical pathology database, comparing SUD patients and general medical controls (NSUD). A total of 1,602 SUD patients were compared with 2,858 NSUD patients 15–50 years of age. Mean ages were 31.29 ± 7.40 and 31.55 ± 9.17 years, respectively (P = 0.42) and were 68.60 and 52.76% male (P < 0.0001). The glycosylated hemoglobin (HbA1c) level in diabetics was 8.14 ± 2.76 and 6.29 ± 1.88 (P = 0.0032). In a nested case-control subset, random glucose, HbA1c, and fructosamine levels were all significantly elevated (P < 0.05). Adjusted for age, the HbA1c level was elevated among the SUD group (P < 0.0001) the age at addiction interaction was also significant (P < 0.0001). Serum glucose, HbA1c, fructosamine, and microalbumin levels were shown to be biomarkers of age. At multiple regression analysis, interactions between age, addictive status, glycemia, and the inflammatory markers, ethrocyte sedimentation rate and C-reactive protein, were significant (P < 0.05). At age 50, diabetic SUD patients had a HbA1c of 8.31%, which was equivalent to that of NSUD patients at age 140.54 years, a 181.07% elevation. These results confirm that hyperglycemia is higher in both an absolute and an age-dependent sense among diabetic SUD patients. These results are consistent with an acceleration of age-related and degenerative pathologies in many tissues and therefore carry far-reaching implications for the safety of indefinite opiate maintenance.

High-Sensitivity CRP in Opiate Addiction: Relative and Age-Dependent Elevations

High-sensitivity C-reactive protein (hs-CRP) has been shown to be linked with immune stimulation, but is not well studied over the lifetime in opiate addiction. hs-CRP was measured by standard laboratory methods in substance use disorder (SUD) patients and non-SUD (NSUD) aged 18-48 years. Data were log transformed to improve normality. 1231 SUD were compared with 326 NSUD patients of comparable ages. hs-CRP was 7.46 ± 14.24 versus 4.75 ± 13.40 mg/l (mean ± SD) significantly higher in the SUD group (P < 0.0001), a difference which persisted after exclusion of acutely elevated hs-CRP values (P < 0.0001). In multiple regression with age, addictive status was significant both by itself (P < 0.0001) and in interaction with age (P < 0.0001). At age 40 years, the SUD group had a mean hs-CRP of 3.68 which the NSUD group did not achieve till a modelled age of 157.09 years. In an interactive multivariate regression, interactions between age, addictive status, ALT and AST were significant. These data show that hs-CRP is elevated in opiate dependence both per se, and when controlled for age. Furthermore, they suggest that hs-CRP and immune stimulation seen in opiate addiction may underlie the acceleration of age-related multi-system chronic and coronary atherosclerotic disease well described in opiate dependence.

Differing age related trajectories of dysfunction in several organ systems in opiate dependence

Differing age related trajectories of dysfunction in several organ systems in opiate dependence

Self-efficacy and perceived benefits / barriers on the AIDs preventive behaviors

Background: Drug users (opiate dependency) account for about 65% of all AIDS cases in Iran. Drug injection has been identified as the most common way of HIV transmission in these patients. This study aimed to determine self-efficacy, and perceived benefits / barriers of AIDs preventive behaviors in opiate dependency. Methods: A cross-sectional study was conducted in 2009.The study population was 86 drug user men at Re-birth association in Zarandieh city. The data were collected using self-administered questionnaires includeing demographic characteristics, perceived benefits/barriers of self-efficacy and AIDS preventive behaviors. Data was analyzed with ANOVA, regression and correlation coefficients and descriptive statistical methods. Results: Regression analysis showed that age, education level, knowledge and perceived benefits/barriers, self-efficacy, all together explain 28% of AIDS preventive behaviors variance. Perceived barriers and self- efficacy were the most important predicting factor. 63% of the samples believed that they have ability of HIV-preventive behaviors. Conclusion: The study showed the relationship of perceived benefits/barriers, self- efficacy with AIDS preventive behaviors. It is suggested that the findings of this study may be used as a basis for designing interventions to improve better performance in the concerned area.

Restoring the double disconnect: towards a conceptual reinstatement of opiate addiction as a high risk behaviour.

Restoring the double disconnect: towards a conceptual reinstatement of opiate addiction as a high risk behaviour.

KPNA3 variation is associated with schizophrenia, major depression, opiate dependence and alcohol dependence.

KPNA3 is a gene that has been linked to schizophrenia susceptibility. In this study we investigated the possible association between KPNA3 variation and schizophrenia. To investigate a wider role of KPNA3 across psychiatric disorders we also analysed major depression, PTSD, nicotine dependent, alcohol dependent and opiate dependent cohorts. Using a haplotype block-based gene-tagging approach we genotyped six KPNA3 single nucleotide polymorphisms (SNPs) in 157 schizophrenia patients, 121 post-traumatic stress disorder patients, 120 opiate dependent patients, 231 alcohol dependent patients, 147 nicotine dependent patients and 266 major depression patients. One SNP rs2273816 was found to be significantly associated with schizophrenia, opiate dependence and alcohol dependence at the genotype and allele level. Major depression was also associated with rs2273816 but only at the allele level. Our study suggests that KPNA3 may contribute to the genetic susceptibility to schizophrenia as well as other psychiatric disorders.

P-36 - Medical assisted treatment of opiate dependence with Buprenorphine/Naloxon (Suboxone) of heroin addicts in prison who are aging penalties

Introduction The substitution treatment of opiate dependants with Buprenorphine/Naloxone (Suboxone) may be implemented in prisons’ environment for heroin addicts who must aging penalties during the treatment started. Aim To describe the treatment of opiate dependant individuals who have to spent certain period in prison, who were previously introduced in outpatient administering of substitution medicament Suboxone in Bosnia-Herzegovina. Methodology With presentation of clinical vignettes, authors described how opiate dependants with criminal past imprisoned in jail because of aging penalties avoided discontinuation of treatment after they were included in the Suboxone maintenance treatment program. This practice has been implemented in cooperation of Department of Psychiatry in Tuzla and Tuzla prison from 27 July 2009. We assessed 10 male opiate addicts (five married) aged 24.8 ± 4.7 years. Results All exemplars described with clinical vignettes showed that opiate dependants previously had open doubts in efficacy of this particular treatment during imprisonment, and after implementation of continual treatment in prison in cooperation with jail officers (nurse and guards) they surprised with positive effects on overall outcomes of Suboxone. Also they were very satisfied with life quality during treatment in prison. Also jail officers, family members of dependant person showed satisfaction with achieved efficacy of Suboxone eider during aging penalties. Conclusion Medically assisted treatment of opiate dependence with Suboxone for imprisoned addicts implemented as outpatient treatment with involvement of jail officers who were instructed in Suboxone daily administration, improved quality of life of treated opiate dependants, and quality of their relations in prison with others.

KPNA3Variation Is Associated with Schizophrenia, Major Depression, Opiate Dependence and Alcohol Dependence

KPNA3is a gene that has been linked to schizophrenia susceptibility. In this study we investigated the possible association betweenKPNA3variation and schizophrenia. To investigate a wider role ofKPNA3across psychiatric disorders we also analysed major depression, PTSD, nicotine dependent, alcohol dependent and opiate dependent cohorts. Using a haplotype block-based gene-tagging approach we genotyped sixKPNA3single nucleotide polymorphisms (SNPs) in 157 schizophrenia patients, 121 post-traumatic stress disorder patients, 120 opiate dependent patients, 231 alcohol dependent patients, 147 nicotine dependent patients and 266 major depression patients. One SNP rs2273816 was found to be significantly associated with schizophrenia, opiate dependence and alcohol dependence at the genotype and allele level. Major depression was also associated with rs2273816 but only at the allele level. Our study suggests that KPNA3 may contribute to the genetic susceptibility to schizophrenia as well as other psychiatric disorders.

P-34 - Quality of life of heroin addicts and their family members improved during medical assisted treatment of opiate dependence with buprenorphine/naloxon (suboxone)

Introduction The most modern medically assisted method of substitution treatment of opiate dependants with Buprenorphine/Naloxone (Suboxone) has been implemented in Department of Psychiatry in Tuzla from 27 July 2009. The treatment may improve quality of life (QoL) of treated opiate addicts and of their family members. Aim To assess QoL of treated opiate dependant individuals and their family members who signed contract to be partners in outpatient administering of substitution medicament Suboxone in Bosnia and Herzegovina. Methodology The study was carried out in northeast part of Bosnia and Herzegovina, in August 2009-October 2011. We assessed 40 (six females) opiate addicts aged 27.5 ± 5.3 years who were in medically assisted treatment with Suboxone. The first testing realized during psychological assessment in the beginning of treatment and retest realized two years after treatment initiated; also we tested and 40 family members of treated addicts for QoL. We used Manchester Short Assessment of Quality of Life (MANSA). Results During the first and second measuring of QoL there were no significant differences between opiate dependant individuals and their family members (p > 0.05). After second measuring, QoL of treated individuals increased from (mean±standard deviation=39.4 ± 9.3) to (65.1 ± 9.3)(t = −8.277, P Conclusion Medically assisted treatment of opiate dependence with Suboxone implemented as outpatient treatment with involvement of close family members who are not drug dependant, improved quality of life of treated opiate dependants and their family members.

P-114 - Characteristics of the onset of opioid dependence influence the process of dependence

Introduction and objectives In alcohol dependence are distinguished two types of course of illness in relation to age of onset of dependence. Aims An assessment of differences between opiate addicts with early and late age of onset of dependence. Methods 242 opiate dependent patients, treated with methadone, were asked about: length of dependence, dosage of methadone, HIV infection, effects of methadone on interviewed subjects and the age of onset of opiate dependence. Results In our sample 140 (58%) subjects developed opiate dependence below the age of 19, and 102 (42%) subjects developed dependence above the age of 18. Comparison of the patients with the onset of opiate dependence above the age of 18 with the patients with the onset of opiate dependence blow the age of 19 revealed that in the group with younger age of onset of opiate dependence there were statistically significant more women (40 vs. 23%), the patients were younger (35 vs. 38 years old), had longer time of dependence (19 vs. 16 years), had shorter time of well-being after taking a dose of methadone (12 vs. 15 hours). Conclusion Our research may suggest, in accordance with findings in alcohol dependence that subjects with early age of onset of opiate dependence differ in the course of dependence with the patients with late age of onset of opiate dependence.

P-35 - Some edemiological characteristics of opiate addicts with hepatitis c who are in substitution maintainance therapy with Buprenorphine/Naloxone (Suboxone) in bosnia-herzegovina

The most modern method of substitution treatment of opiate dependants with Buprenorphine/Naloxone (Suboxone) has been implemented in Department of Psychiatry in Tuzla from 27 July 2009. The treatment helps in discovering of hepatitis C infected intravenous users (IVUs), who are included in treatment of chronic hepatitis C (HCV) with Pegylated interferon-alpha-2a or Pegylated interferon-alpha-2b and the antiviral drug Ribavarin for a period of 24 or 48 weeks, depending on hepatitis C virus genotype. To assess epidemiological characteristics of treated opiate dependant IVUs infected with HCV in outpatient administering of substitution medicament Suboxone in Bosnia-Herzegovina. The study was carried out in northeast part of Bosnia and Herzegovina, in August 2009-October 2011. We assessed 112 (eleven females) opiate addicts aged 27.2 ± 4.9 years who were in medically assisted treatment with Suboxone. In the sample we found 29 (25.9) of 112, (four females) who were HCV infected. There were 61 (54.5%) of 112 who were IVUs. HCV infected and non-infected opiate addicts did not differ regarding age, age of the first drug intake, age of the first IV use, level of retention in Suboxone treatment and daily dose of Suboxone (P > 0.05). HCV positive drug users significantly more often did intake heroin intravenously inside one month before Suboxone treatment (p < 0.001). Medically assisted outpatient treatment of opiate dependence with Suboxone helps in discovering of HCV infected individuals and helps in recovery of both: opiate dependency and HCV infected with simultaneous treatment of chronic (HCV) with Pegylated interferon 2a/b with Ribavarin.

P-690 - Clinical gender differences in alcohol dependent patients

Introduction Alcohol dependence disorder has been widely described. However, differences due to gender remain unknown. Aim To compare clinical gender differences in an alcohol dependent outpatient sample. Methods Alcohol dependent outpatients from the centre for addiction treatment of the Vall d’Hebron University Hospital following treatment during 2005 to 2011 were evaluated. We included patients with an alcohol dependence following DSM-IV criteria. Sociodemographic and clinical variables were collected. Simple descriptive statistics were carried out for demographic and clinical data. Bivariate analysis was made to compare the main variables by sex using SPSSvs15.0. Results 149 patients were included, 83.2% were men. No gender differences were found in the mean age of the sample. Time of first alcohol use to regular consumption was significantly shorter in men (7.9 ± 6.9 year vs 13.95 ± 8.9 years). Significantly more women (68%) compared with men (44.4%) had comorbid psychiatric disorders. 52% of women and 28.2% of men had depressive symptoms. No gender differences were observed for psychotic, anxiety neither personality disorders. Comorbidity with nicotine dependence was high in men and in women (75.4% vs 73.9%). Significantly more women had sedatives dependence (16% vs 5.3%) and opiate dependence (8.3% vs 3.5%) without observing gender differences in the other drugs. The 71.4% of women consume alone compared with the 38.7% of men. Conclusions Alcoholic women tend to consume alone. They have more comorbid mental disorders, being depression the most prevalent. Besides alcohol dependence, women also had more sedatives and opiate dependence than men.

P-30 - Clinical correlations HIV infection in patients maintaining substitution treatment with methadone

Opiate dependence is a significant risk factor for HIV infection. An assessment of differences between opiate addicts with and without HIV infection. 171 opiate dependent patients treated with methadone were asked about: length of dependence, age of onset of opiate dependence, dosage of methadone, effects of methadone on interviewed subjects and HIV infection. In our sample 72 (42%) subjects had HIV infection (HIV+) and 99 (58%) subjects had not HIV infection (HIV-). Comparison of 99 HIV (-) patients with 72 HIV (+) patients revealed that in HIV (+) group there were statistically significantly more women (40 vs. 25%), patients were older (39 vs. 36 years old), had longer length of dependence (22 vs. 16 years), had longer time of maintained methadone treatment (63 vs. 26 months). It was also found that HIV (+) patients had earlier age of onset of opiate dependence than the patients in HIV (-) group (18 vs. 19 years old, p = 0,058). Our research may suggest that HIV infection had correlation with the course of methadone substitution treatment of opiate dependence.

P-113 - Five-year follow-up of a chinese patient with opiate drug psychological dependence after treatments with deep brain stimulation: case report

Opiate drug psychological dependence is acknowledged as a difficult problem in the world. Several studies have shown the short-term efficacy of deep brain stimulation (DBS) in reducing opiate addiction. In this case report, we report on long-term results up to five years in an opiate addiction patient. A 24-year-old man with three-year history of opiate addiction presented with several withdraw syndromes and more than three-time failures in detoxification. The patient was treated with bilateral DBS of the nucleus accumbens (NAc) for opiate psychological dependence. No relapse was found during the follow-up periods. This study suggests that DBS of the NAC could be an effective treatment of patients in reducing psychological dependence with a good recovery in psychological dysfunction.

Inputs from the basolateral amygdala to the nucleus accumbens shell control opiate reward magnitude via differential dopamine D1 or D2 receptor transmission

The basolateral amygdala (BLA), ventral tegmental area and nucleus accumbens (NAc) form a functionally connected neural circuit involved in the processing of opiate-related reward and memory. Dopamine (DA) projections from the ventral tegmental area to the BLA modulate associative plasticity mechanisms within the BLA. However, the role of DA receptor signaling in the BLA and its functional outputs to the NAc during opiate reward processing is not currently understood. Using an unbiased place conditioning procedure, we measured the rewarding effects of morphine following intra-BLA microinfusions of specific DA D1 or D2 receptor agonists in either opiate-naive or opiate-dependent/withdrawn rats. Activation of intra-BLA D1 receptors strongly potentiated the behaviorally rewarding effects of opiates, only in the opiate-naive state. However, once opiate dependence and withdrawal occurred, the intra-BLA DA-mediated potentiation of opiate reward salience switched to a D2 receptor-dependent substrate. We next performed single-unit, in-vivo extracellular neuronal recordings in the NAc shell (NA shell), to determine if intra-BLA D1/D2 receptor activation may modulate the NA shell neuronal response patterns to morphine. Consistent with our behavioral results, intra-BLA D1 or D2 receptor activation potentiated NAc 'shell' (NA shell) neuronal responses to sub-reward threshold opiate administration, following the same functional boundary between the opiate-naive and opiate-dependent/withdrawn states. Finally, blockade of N-methyl-d-aspartate transmission within the NA shell blocked intra-BLA DA D1 or D2 receptor-mediated opiate reward potentiation. Our findings demonstrate a novel and functional DA D1/D2 receptor-mediated opiate reward memory switch within the BLA→NA shell circuit that controls opiate reward magnitude as a function of opiate exposure state.