COVID-19 infection among patients with cancer in Australia from 2020 to 2022: a national multicentre cohort study.

Background: The global COVID-19 pandemic disproportionately affected certain populations and its management differed between countries. This national study describes characteristics and outcomes of COVID-19 in patients with cancer in Australia. Methods: We performed a multicentre cohort study of patients with cancer and COVID-19 from March 2020 to April 2022. Data were analysed to determine varying characteristics between cancer types and changes in outcomes over time. Multivariable analysis was performed to determine risk factors associated with oxygen requirement. Findings: 620 patients with cancer from 15 hospitals had confirmed COVID-19. There were 314/620 (50.6%) male patients, median age 63.5 years (IQR 50-72) and majority had solid organ tumours (392/620, 63.2%). The rate of COVID-19 vaccination (≥1 dose) was 73.4% (455/620). Time from symptom onset to diagnosis was median 1 day (IQR 0-3), patients with haematological malignancy had a longer duration of test positivity. Over the study period, there was a significant decline in COVID-19 severity. Risk factors associated with oxygen requirement included male sex (OR 2.34, 95% CI 1.30-4.20, p = 0.004), age (OR 1.03, 95% CI 1.01-1.06, p = 0.005); not receiving early outpatient therapy (OR 2.78, 95% CI 1.41-5.50, p = 0.003). Diagnosis during the omicron wave was associated with lower odds of oxygen requirement (OR 0.24, 95% CI 0.13-0.43, p < 0.0001). Interpretation: Outcomes from COVID-19 in patients with cancer in Australia over the pandemic have improved, potentially related to changing viral strain and outpatient therapies. Funding: This study was supported by research funding from MSD.

Administration of immune checkpoint inhibitors at rural towns using the Teleoncology model of care-A North Queensland perspective.

OBJECTIVE: This study aimed at evaluating the safety of administering immune checkpoint inhibitors (ICIs) and monitoring for immune-related adverse events (irAEs) using the Teleoncology model of care. DESIGN: A retrospective cohort study comparing two patient groups. SETTING: The North Queensland Teleoncology Network (NQTN) operated by the Townsville (THHS) and Cairns Hospital Health Services (CHHS) with the Townsville Cancer Centre (TCC) acting as the control group setting. PARTICIPANTS: Patients who received ICI treatment via the NQTN between January 2015 and April 2019. Patients who received ICI at the TCC over the same time period were used for comparison. MAIN OUTCOME MEASURES: Rates of high-grade irAEs and irAE-related deaths. RESULTS: Fifty-two patients received a total of 822 cycles of ICIs via the Teleoncology model through NQTN. Over the same time period, 142 patients received a total of 1521 cycles at the TCC. There were no significant differences in all demographic characteristics between either group, including tumour profile and Indigenous status. There were no statistically significant differences between the rates of high-grade irAE across multiple body organ systems (p = 0.151) and rate of hospital admissions (13.5% (NQTN) vs 5.6% (TCC), p = 0.702). There were no irAE-related deaths in either group. CONCLUSIONS: The results suggest that with adequate governance and clinical resources, ICIs can be administered safely using Teleoncology models to rural and remote towns.

Durability of response to immune checkpoint inhibitors in metastatic Merkel cell carcinoma after treatment cessation.

BACKGROUND: Metastatic Merkel cell carcinoma (mMCC) is highly responsive to immune checkpoint inhibitors (ICIs); however, durability of response after treatment cessation and response to retreatment in the setting of progression is unknown. METHODS: Patients (pts) having mMCC from 10 centres who discontinued ICI treatment for a reason other than progression were studied. RESULTS: Forty patients were included. Median time on treatment was 13.5 months (range 1-35). Thirty-one patients (77.5%) stopped treatment electively while 9 patients (22.5%) stopped due to treatment-related toxicity. After median of 12.3 months from discontinuation, 14 pts (35%) have progressed (PD). Disease progression rate following ICI discontinuation was 26% (8 of 31) in patients who discontinued in complete response (CR), 57% (4 of 7) in patients in partial response and 100% (2 of 2) in those with stable disease. Median progression-free survival (PFS) after treatment cessation was 21 months (95% confidence interval [CI], 18- not reached [NR]), with a third of patients progressing during their first year off treatment. PFS was longer for patients who discontinued ICI electively (median PFS 29 months; 95% CI, 21-NR) compared to those who stopped due to toxicity (median PFS 11 months; 95% CI, 10-NR). ICI was restarted in 8 of 14 pts (57%) with PD, with response rate of 75% (4 CR, 2 partial response, 1 stable disease, 1 PD). CONCLUSION: ICI responses in mMCC do not appear durable off treatment, including in patients who achieve a CR, though response to retreatment is promising. Extended duration of treatment needs to be investigated to optimise long-term outcomes.

Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade-resistant Melanoma for Anti-PD-L1 Rechallenge.

Purpose: Drug repurposing offers the opportunity for chemotherapy to be used to reestablish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (avelumab) in patients with advanced ICB-resistant melanoma. Experimental Design: A total of 20 participants with ICB-resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB rechallenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB rechallenge. Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA sequencing, and reduced representation bisulfite sequencing of biopsies at baseline, after priming and after six cycles of avelmuab was performed. Results: The overall response rate (ORR) determined after azacitidine and carboplatin priming was 10% (2/20) with two partial responses (PR). The ORR determined after priming followed by six cycles of avelumab (week 22) was 10%, with 2 of 20 participants achieving immune partial response (iPR). The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by six cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks [95% confidence interval (CI): 14.87-21.13 weeks] and the median OS was 47.86 weeks (95% CI: 9.67-86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T cells, in particular CD8+, showed the greatest increase in infiltration. Conclusions: Priming with azacitidine and carboplatin can induce disease stabilization and resensitization to ICB for metastatic melanoma. Significance: There are limited treatments for melanoma once resistance to ICB occurs. Chemotherapy induces immune-related responses and may be repurposed to reinstate the response to ICB. This study provides the first evidence that chemotherapy can provide clinical benefit and increase OS for ICB-resistant melanoma.

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.

PURPOSE: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown. METHODS: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined. RESULTS: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%, P = 0.655). Time to AR was 11 months (95% confidence interval [CI], 8-15 months). After a median follow-up of 16 months (95% CI, 10-25 months), responders to reinduction had a median progression-free survival of 14 months (95% CI, 13, NR months), and in the whole cohort, the median overall survival from reinduction was 17 months (95% CI, 12-NR months). Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred. CONCLUSIONS: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.

BACKGROUND: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1). METHODS: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1. FINDINGS: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis. INTERPRETATION: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma. FUNDING: None.

Enhancing Chemotherapy Capabilities in Rural Hospitals: Implementation of a Telechemotherapy Model (QReCS) in North Queensland, Australia.

INTRODUCTION: The Queensland Remote Chemotherapy Supervision (QReCS) model enables rural nurses to administer chemotherapy in smaller rural towns under supervision by health professionals from larger centers using telehealth. Its implementation began in North Queensland, Australia (population, 650,000), in 2014 between two regional cancer centers (Townsville and Cairns as primary sites) and six rural sites (125 to 1,000 kilometers from primary sites). Our study examined the implementation processes, feasibility, and safety of this model. METHODS: Details of implementation and patients' clinical details for the period of 2014 to 2016 for descriptive analysis were extracted from telechemotherapy project notes and oncology information systems of North Queensland, respectively. RESULTS: After a successful pilot study in Townsville Cancer Centre, statewide rural and cancer networks of Queensland Health, in collaboration with clinicians and managers across the state of Queensland, developed the QReCS model and a guide for operationalizing it. QReCS was implemented at six sites from 2014 to 2016. Main enablers across North Queensland included collaboration among clinicians and managers, availability of common electronic medical records, funding from Queensland Health, and installation of telehealth infrastructure by statewide telehealth services. Main barriers included turnover of senior management and nursing staff at two rural towns. Sixty-two patients received 327 cycles of low- to medium-risk chemotherapy agents. Rates of treatment delays, adverse events, and hospital admissions were similar to those in face-to-face care. CONCLUSION: Implementation of the QReCS model across a large geographic region is feasible with acceptable safety profiles. Leadership by and collaboration among clinicians and managers, adequacy of resources and common governance are key enablers.

Metastasis-specific patterns of response and progression with anti-PD-1 treatment in metastatic melanoma.

This study evaluated patterns of response as discerned by comprehensive metastasis-specific analysis in metastatic melanoma patients receiving anti-PD-1 antibodies. Bi-dimensional measurements of every metastasis in patients enrolled in the KEYNOTE-001 trial at a single institution were obtained at baseline and throughout treatment. Twenty-seven evaluable patients had 399 baseline metastases measurable on CT imaging. Complete response (CR) which occurred in 52.6% of metastases was smaller (mean 223 mm2 versus 760 mm2 , p < .01) and occurred more frequently in the lungs (65% versus 39.4%, p < .01). Response was heterogenous (new/progressing metastases alongside CR metastases) at first assessment in 4/14 patients with objective response (OR) as opposed to 7/13 patients with non-OR. CR of individual metastases is common and influenced by site and size. Most patients with OR demonstrate homogenous regression in all metastases at the first assessment. In contrast, patients with early heterogeneity had a poor outcome.

The molecular profile of metastatic melanoma in Australia.

Targeted therapy directed at driver oncogenic mutations offers an effective treatment option for select patients with metastatic melanoma. The aim of this study was to assess the prevalence of clinically significant somatic mutations, specifically BRAF, NRAS and KIT, in a large cohort of Australian patients with metastatic melanoma. We performed a cross-sectional cohort study of consecutive patients with American Joint Committee on Cancer (AJCC) stage IIIc unresectable or stage IV melanoma managed at Melanoma Institute Australia, and affiliated sites, that underwent molecular testing between 22 June 2009 and 19 July 2013. Additionally, we examined the change in BRAF testing methodology and patient population over time, and how this influenced the prevalence of mutations. A total of 767 molecular tests were conducted for 733 patients. BRAF V600 mutation testing was performed for 713 patients (97.2%), with an overall mutation prevalence of 37.7% (269/713); 74.3% (200/269) were the V600E genotype and 22.3% (60/269) V600K. The BRAF mutation prevalence and proportion of BRAF V600E and V600K genotypes varied across the study period, as did testing methodology and the median age of the cohorts. Of 222 patients who underwent NRAS testing, 58 (26.1%) had a mutation identified. The overall prevalence of KIT mutations was 3.7% (11/296). In Australia the prevalence of BRAF mutations is lower than initially reported, although this remains the most common mutation identified in metastatic melanoma and an important therapeutic target. NRAS mutations are more prevalent than initially described; however, other mutations reported in melanoma, including KIT, are rare in an unselected population of patients.

Clinicopathologic features associated with efficacy and long-term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors.

BACKGROUND: The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown. METHODS: For 142 consecutive immunotherapy- and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n = 111) or a combination of dabrafenib and trametinib (n = 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival. RESULTS: The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31; P < .001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients. CONCLUSIONS: Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur.

Newly Identified Characteristics and Suggestions for Diagnosis and Treatment of Diffuse Leptomeningeal Glioneuronal/Neuroepithelial Tumors: A Case Report and Review of the Literature.

Diffuse leptomeningeal glioneuronal tumor is unique for communicating hydrocephalus, diffuse leptomeningeal enhancement, cystic changes, absence of tumor cells in cerebral spinal fluid, and a cell population of both glial and neuronal copositivity. It has likely been misdiagnosed as mixed glioneuronal tumors, oligodendrogliomas, and neuroepithelial tumors. Children with signs of this tumor are often worked up for infection, rheumatologic disease, or disseminated primary malignancy, resulting in unnecessary testing and treatment. We describe a 14-year-old female with recurrent headaches, hydrocephalus, and diffuse leptomeningeal enhancement discovered to be neoplastic 1 year after initial presentation, owing to extensive and unrevealing infectious and immunologic workups. Biopsies revealed atypical cells with markers of both glial and neuronal cells, positivity for OLIG-2, and focal p53 positivity. Great response was seen with temozolomide and craniospinal irradiation. Additionally, we postulate additional diagnostic indicators that may aid in earlier diagnosis and treatment decisions.

The nature and management of metastatic melanoma after progression on BRAF inhibitors: effects of extended BRAF inhibition.

BACKGROUND: The v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor (BRAFi) drugs dabrafenib and vemurafenib have high response rates in BRAF-mutant, metastatic melanoma; however, 50% of patients progress by 7 months. In this study, the authors examined the nature and management of disease progression (PD) on BRAFi treatment, including characteristics and outcomes of patients who received continued BRAFi treatment beyond disease progression (TBP). METHODS: Clinicopathologic data at baseline and at the time of PD were collected for all patients with BRAF-mutant metastatic melanoma who received BRAFi monotherapy within clinical trials between July 2009 and September 2012. Management and survival after PD were examined, including continued BRAFi TBP (> 28 days beyond Response Evaluation Criteria in Solid Tumor [RECIST]-defined PD). RESULTS: Ninety-five of 114 BRAFi-treated patients had PD. Fifty-three of those 95 patients (56%) progressed in extracranial sites alone, 18% (17 of 95 patients) progressed in intracranial and extracranial sites simultaneously, and 16% (15 of 95 patients) progressed in intracranial sites alone. Twenty-nine of the 95 patients (31%) who had PD progressed in a single site or organ, 48% (46 of 95 patients) progressed in existing metastases only, and 18% (17 of 95 patients) had new metastases alone. At the time of PD, 35 of 95 patients (37%) received no subsequent systemic treatment, 20% (19 of 95 patients) changed systemic treatments, and 39% (37 of 95 patients) continued BRAFi TBP for a median of 97 days. BRAFi TBP and known prognostic factors (Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, RECIST sum of the greatest dimensions of target lesions) were associated with overall survival (OS) from the time of PD; however, in multivariable analysis, BRAFi TBP improved OS (hazard ratio, 0.50; 95% confidence interval, 0.27-0.93; P = .029). CONCLUSIONS: Most BRAFi-treated patients progressed in existing extracranial sites, and 31% progressed in isolated sites. Compared with cessation, continued BRAFi TBP is associated with prolonged OS even after adjusting for potential prognostic factors at PD.

Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma.

BRAF and MEK inhibitors are not established treatments for non-V600 mutation-positive metastatic melanoma. We carried out a retrospective analysis of efficacy and safety in four patients with BRAF K601E and one patient with L597Q mutation-positive metastatic melanoma treated with the MEK inhibitor trametinib. Three patients achieved a RECIST partial response, including the patient with an L597Q mutation. Paired biopsies available in one of the five patients showed reduced phospho-ERK signalling and this corresponded to a metabolic response on F-fluorodeoxyglucose-PET scanning. Trametinib toxicity was manageable. Trametinib has antitumour activity in patients with BRAF K601E and L597Q mutation-positive metastatic melanoma.

The role of systemic therapies in the management of melanoma brain metastases.

PURPOSE OF REVIEW: Brain metastases in metastatic melanoma are highly prevalent and are associated with significant morbidity and a poor prognosis. Local therapy (surgery or radiotherapy) has been the mainstay of treatment, due in part to the lack of efficacy of systemic therapy. This review will focus on new systemic therapies for metastatic melanoma and their evolving role in the management of brain metastases. RECENT FINDINGS: BRAF inhibitors have demonstrated efficacy in active (i.e. untreated or progressing) brain metastases in BRAF mutated metastatic melanoma. The cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody, ipilimumab, has also shown activity, particularly in asymptomatic metastases. Studies of programmed death 1/programmed death ligand 1 checkpoint inhibitors and combination BRAF and MEK inhibitor therapy in brain metastases are planned. Emerging evidence on the molecular biology of melanoma brain metastases, particularly the role of the phosphatidylinositol 3-kinase-AKT pathway, may identify additional therapeutic targets. SUMMARY: The development of systemic therapy effective in controlling both intra-cranial and extra-cranial melanoma metastases has resulted in a change in the paradigm of management. More research is required in patients with active brain metastases to improve patient outcomes, including studies early in the development of novel therapies, and studies to determine the safe and effective combination or sequencing of local and systemic therapies.

Diagnosis and treatment of KIT-mutant metastatic melanoma.

A 52-year-old man has unresectable locally recurrent melanoma of the left foot (Fig 1) and pulmonary metastases. Nine months before this presentation, he underwent a wide local excision and sentinel node biopsy for an acral melanoma on his left heel. Pathology disclosed Breslow thickness of 4.8 mm, Clark level IV, and tumor ulceration with a mitotic rate of 37 mitoses/mm(2). Both sentinel nodes in the left groin were positive for melanoma cells, which expressed S100, HMB45, and melan A. At subsequent left inguinal dissection, seven more nodes showed no additional nodal metastases. Within 3 months of his original surgery, the patient developed a local recurrence in the foot, and over the subsequent 6 months, he underwent serial local excisions and topical diphencyprone treatment. A recent staging scan showed at least 20 foci of in-transit disease in the left lower leg and foot, as well as a solitary lung metastasis (12 mm). His Eastern Cooperative Oncology Group performance status is 1, with no significant comorbidities. High-resolution melt followed by sequencing of an in-transit metastasis showed there is no BRAF exon 15 mutation. However, Sanger sequencing of KIT exons 9, 11, 13, and 17, performed as screening for a clinical trial enrolling patients with metastatic acral and mucosal melanomas, showed an exon 13 K642E mutation.

Disulfiram attenuates drug-primed reinstatement of cocaine seeking via inhibition of dopamine ß-hydroxylase.

The antialcoholism medication disulfiram (Antabuse) inhibits aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde upon ethanol ingestion and produces the aversive 'Antabuse reaction' that deters alcohol consumption. Disulfiram has also been shown to deter cocaine use, even in the absence of an interaction with alcohol, indicating the existence of an ALDH-independent therapeutic mechanism. We hypothesized that disulfiram's inhibition of dopamine ß-hydroxylase (DBH), the catecholamine biosynthetic enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons, underlies the drug's ability to treat cocaine dependence. We tested the effects of disulfiram on cocaine and food self-administration behavior and drug-primed reinstatement of cocaine seeking in rats. We then compared the effects of disulfiram with those of the selective DBH inhibitor, nepicastat. Disulfiram, at a dose (100 mg/kg, i.p.) that reduced brain NE by ∼40%, did not alter the response for food or cocaine on a fixed ratio 1 schedule, whereas it completely blocked cocaine-primed (10 mg/kg, i.p.) reinstatement of drug seeking following extinction. A lower dose of disulfiram (10 mg/kg) that did not reduce NE had no effect on cocaine-primed reinstatement. Nepicastat recapitulated the behavioral effects of disulfiram (100 mg/kg) at a dose (50 mg/kg, i.p.) that produced a similar reduction in brain NE. Food-primed reinstatement of food seeking was not impaired by DBH inhibition. Our results suggest that disulfiram's efficacy in the treatment of cocaine addiction is associated with the inhibition of DBH and interference with the ability of environmental stimuli to trigger relapse.

Effects of environmental enrichment on sensitivity to cocaine in female rats: importance of control rates of behavior.

Environmental enrichment produces functional changes in mesolimbic dopamine transmission and alters sensitivity to psychomotor stimulants. These manipulations also alter the control rate of many behaviors that are sensitive to stimulant administration, which can make comparison of drug effects between isolated and enriched subjects difficult. The purpose of this study was to examine the effects of environmental enrichment on control rates of behavior and on sensitivity to cocaine in tests of locomotor activity, drug self-administration, conditioned place preference, and toxicity. In the locomotor activity test, isolated rats exhibited greater activity after the administration of cocaine, but also had higher control rates of activity. When locomotor activity was expressed as a percentage of saline control values, enriched rats exhibited a greater increase relative to their own control than isolated rats. In the drug self-administration procedure, isolated rats had higher breakpoints on a progressive-ratio schedule of reinforcement when responding was maintained by cocaine; however, isolated rats also had higher breakpoints in saline substitution tests and higher rates of inactive lever responding. When the self-administration data were expressed as a percentage of these control values, enriched rats exhibited a greater increase in responding relative to their own control rates than isolated rats. No differences were observed between isolated and enriched rats under control conditions in the place preference and toxicity studies. In both of these procedures, enriched rats were more sensitive than isolated rats to all the doses of cocaine tested. These data emphasize the importance of considering control rates of behavior in studies examining environmental enrichment and drug sensitivity, and suggest that environmental enrichment increases sensitivity to cocaine across a range of dependent measures when differences in control rates of behavior are taken into account.

The effects of repeated opioid administration on locomotor activity: I. Opposing actions of mu and kappa receptors.

Repeated administration of many addictive drugs leads to a progressive increase in their locomotor effects. This increase in locomotor activity often develops concomitantly with increases in their positive-reinforcing effects, which are believed to contribute to the etiology of substance use disorders. The purpose of this study was to examine changes in sensitivity to the locomotor effects of opioids after their repeated administration and to determine the role of mu and kappa receptors in mediating these effects. Separate groups of rats were treated with opioid receptor agonists and antagonists every other day for 10 days, and changes in locomotor activity were measured. Repeated administration of the mu agonists, morphine and buprenorphine, produced a progressive increase in locomotor activity during the treatment period, and this effect was blocked by coadministration of the opioid antagonist naltrexone. The kappa agonist spiradoline decreased locomotor activity when administered alone and blocked the progressive increase in locomotor activity produced by morphine. The ability of spiradoline to block morphine-induced increases in locomotor activity was itself blocked by pretreatment with the kappa antagonist nor-binaltorphimine. Repeated administration of high doses, but not low or moderate doses, of the mixed mu/kappa agonists butorphanol, nalbuphine, and nalorphine produced a progressive increase in locomotor activity during the treatment period. Doses of butorphanol, nalbuphine, and nalorphine that failed to produce a progressive increase in locomotor activity when administered alone did so when subjects were pretreated with nor-binaltorphimine. These findings suggest that mu and kappa receptors have functionally opposing effects on opioid-mediated locomotor activity and sensitization-related processes.

The effects of repeated opioid administration on locomotor activity: II. Unidirectional cross-sensitization to cocaine.

Sensitization refers to an increase in sensitivity to the effects of a drug and is believed to play a role in the etiology of substance use disorders. Cross-sensitization has been observed between drugs from different pharmacological classes and may play a role in the escalation of drug use in polydrug-abusing populations. The purpose of this study was to examine cross-sensitization between opioids and cocaine and to determine the extent to which cross-sensitization is mediated by an opioid's selectivity for mu, kappa, and delta receptors. Separate groups of rats were treated with opioid receptor agonists and antagonists every other day for 10 days, and the locomotor effects of cocaine were tested 8 days later. The mu agonists, morphine and buprenorphine, and the delta agonist, BW373U86 [(+/-)-4-[(R(*))-[(2S(*),5R(*))-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide hydrochloride], produced cross-sensitization to cocaine, such that repeated administration of these drugs over a 10-day period significantly enhanced cocaine's locomotor effects when tested later. Coadministration of the opioid antagonist naltrexone prevented morphine and buprenorphine from producing cross-sensitization. Coadministration of naltrexone, but not the delta antagonist naltrindole, also prevented BW373U86 from producing cross-sensitization. The kappa agonist spiradoline failed to produce cross-sensitization, but coadministration of spiradoline prevented morphine and buprenorphine from producing cross-sensitization. The ability of spiradoline to block cross-sensitization was itself blocked by the kappa antagonist nor-binaltorphimine. The mixed mu/kappa opioids butorphanol, nalbuphine, and nalorphine did not produce cross-sensitization under any condition examined. These data indicate that agonist activity at mu receptors positively modulates cross-sensitization between opioids and cocaine, whereas agonist activity at kappa receptors negatively modulates this effect.

Chronic exercise increases sensitivity to the conditioned rewarding effects of cocaine.

The purpose of this study was to determine whether chronic exercise alters sensitivity to the conditioned rewarding effects of cocaine. Female rats were obtained at weaning and randomly assigned to either sedentary or exercise conditions. After 6 weeks under these conditions, the effects of cocaine were examined in the conditioned place preference procedure. Cocaine produced a dose-dependent conditioned place preference in both groups of rats. Exercising rats were more sensitive than sedentary rats to cocaine in this procedure, and this effect was most pronounced at the highest dose of cocaine. These data suggest that chronic exercise increases sensitivity to the conditioned rewarding effects of cocaine.