Factors influencing patient uptake of an exercise referral scheme: a qualitative study.

Exercise referral schemes aim to increase physical activity amongst inactive individuals with or at risk of long-term health conditions. Yet many patients referred to these schemes (by health professionals) fail to take up the exercise opportunities on offer. Understanding factors influencing uptake to exercise referral schemes may help improve future attendance. Using the Socio-Ecological Model as a framework, this qualitative study aimed to explore factors influencing uptake to an exercise referral scheme based in the North West of England. Semi-structured interviews were conducted with referred patients (n = 38) about their reasons for referral, interactions with referring health professionals, events following referral and ideas to improve future uptake. Data were analysed thematically and mapped onto the constructs of the Socio-Ecological Model. Factors reported to influence uptake included intrapersonal (past PA experiences, motivation, competing priorities), interpersonal (scheme explanations, support) and organizational influences (scheme promotion, communication between service, cost). Whilst several intrapersonal-level factors influenced patient decisions to uptake the exercise referral scheme, modifiable interpersonal and organizational factors were identified as potential targets for intervention. Recommendations are made for improving awareness of exercise referral schemes and for enhancing communication between referring practitioners, patients and referral scheme staff.

Topical photodynamic therapy following excisional wounding of human skin increases production of transforming growth factor-ß3 and matrix metalloproteinases 1 and 9, with associated improvement in dermal matrix organization.

BACKGROUND: Animal studies report photodynamic therapy (PDT) to improve healing of excisional wounds; the mechanism is uncertain and equivalent human studies are lacking. OBJECTIVES: To explore the impact of methyl aminolaevulinate (MAL)-PDT on clinical and microscopic parameters of human cutaneous excisional wound healing, examining potential modulation through production of transforming growth factor (TGF)-ß isoforms. METHODS: In 27 healthy older men (60-77 years), a 4-mm punch biopsy wound was created in skin of the upper inner arm and treated with MAL-PDT three times over 5 days. An identical control wound to the contralateral arm was untreated and both wounds left to heal by secondary intention. Wounds were re-excised during the inflammatory phase (7 days, n = 10), matrix remodelling (3 weeks, n = 8) and cosmetic outcome/dermal structure (9 months, n = 9). Production of TGF-ß1, TGF-ß3 and matrix metalloproteinases (MMPs) was assessed by immunohistochemistry alongside microscopic measurement of wound size/area and clinical assessment of wound appearance. RESULTS: MAL-PDT delayed re-epithelialization at 7 days, associated with increased inflammation. However, 3 weeks postwounding, treated wounds were smaller with higher production of MMP-1 (P = 0·01), MMP-9 (P = 0·04) and TGF-ß3 (P = 0·03). TGF-ß1 was lower than control at 7 days and higher at 3 weeks (both P = 0·03). At 9 months, MAL-PDT-treated wounds showed greater, more ordered deposition of collagen I, collagen III and elastin (all P < 0·05). CONCLUSIONS: MAL-PDT increases MMP-1, MMP-9 and TGF-ß3 production during matrix remodelling, ultimately producing scars with improved dermal matrix architecture.

Risk of cancer following primary total hip replacement or primary resurfacing arthroplasty of the hip: a retrospective cohort study in Scotland.

BACKGROUND: Release and dispersion of particles arising from corrosion and wear of total hip arthroplasty (THA) components has raised concerns about a possible increased risk of cancer. Concerns have been heightened by a recent revival in the use of metal-on-metal (MoM) hip prostheses. METHODS: From a linked database of hospital discharge, cancer registration, and mortality records, we selected a cohort of patients who underwent primary THA (1990-2009) or primary resurfacing arthroplasty (mainly 2000-2009) in Scotland, with follow-up to the end of 2010. Available operation codes did not enable us to distinguish MoM THAs. Indirectly standardised incidence ratios (SIRs) were calculated for selected cancers with standardisation for age, sex, deprivation, and calendar period. RESULTS: The study cohort included 71 990 patients yielding 547 001 person-years at risk (PYAR) and 13 946 cancers diagnosed during follow-up. For the total period of observation combined, the risks of all cancers (SIR: 1.05; 95% CI: confidence interval 1.04-1.07), prostate cancer (SIR: 1.07; 95% CI: 1.01-1.14), and multiple myeloma (SIR: 1.22; 95% CI: 1.06-1.41) were increased. These modest increases in risk emerged in the context of effectively multiple tests of statistical significance, and may reflect inadequate adjustment for confounding factors. For 1317 patients undergoing primary resurfacing arthroplasty between 2000 and 2009 (PYAR=5698), the SIR for all cancers (n=39) was 1.23 (95% CI: 0.87-1.68). CONCLUSION: In the context of previous research, these results do not suggest a major cause for concern. However, the duration of follow-up of patients receiving recently introduced, new-generation MoM prostheses is too short to rule out a genuinely increased risk of cancer entirely.

Prioritization of THose aWaiting hip and knee ArthroplastY(PATHWAY): protocol for development of a stakeholder led clinical prioritization tool.

AIMS: The extended wait that most patients are now experiencing for hip and knee arthroplasty has raised questions about whether reliance on waiting time as the primary driver for prioritization is ethical, and if other additional factors should be included in determining surgical priority. Our Prioritization of THose aWaiting hip and knee ArthroplastY (PATHWAY) project will explore which perioperative factors are important to consider when prioritizing those on the waiting list for hip and knee arthroplasty, and how these factors should be weighted. The final product will include a weighted benefit score that can be used to aid in surgical prioritization for those awaiting elective primary hip and knee arthroplasty. METHODS: There will be two linked work packages focusing on opinion from key stakeholders (patients and surgeons). First, an online modified Delphi process to determine a consensus set of factors that should be involved in patient prioritization. This will be performed using standard Delphi methodology consisting of multiple rounds where following initial individual rating there is feedback, discussion, and further recommendations undertaken towards eventual consensus. The second stage will then consist of a Discrete Choice Experiment (DCE) to allow for priority setting of the factors derived from the Delphi through elicitation of weighted benefit scores. The DCE consists of several choice tasks designed to elicit stakeholder preference regarding included attributes (factors). RESULTS: The study is co-funded by the University of Aberdeen Knowledge Exchange Commission (Ref CF10693-29) and a Chief Scientist Office (CSO) Scotland Clinical Research Fellowship which runs from 08/2021 to 08/2024 (Grant ref: CAF/21/06). Approval from the University of Aberdeen Institute of Applied Health Sciences School Ethics Review Board was granted 22/03/2022 - Reference number SERB/2021/12/2210. CONCLUSION: The PATHWAY project provides the first attempt to use patient and surgeon opinions to develop a unified approach to prioritization for those awaiting hip and knee arthroplasty. Development of such a tool will provide more equitable access to arthroplasty services, as well as providing a framework for developing similar approaches in other areas of healthcare delivery.Cite this article: Bone Jt Open 2022;3(10):753-758.

Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response.

The generation of animals lacking SMAD proteins, which transduce signals from transforming growth factor-beta (TGF-beta), has made it possible to explore the contribution of the SMAD proteins to TGF-beta activity in vivo. Here we report that, in contrast to predictions made on the basis of the ability of exogenous TGF-beta to improve wound healing, Smad3-null (Smad3ex8/ex8) mice paradoxically show accelerated cutaneous wound healing compared with wild-type mice, characterized by an increased rate of re-epithelialization and significantly reduced local infiltration of monocytes. Smad3ex8/ex8 keratinocytes show altered patterns of growth and migration, and Smad3ex8/ex8 monocytes exhibit a selectively blunted chemotactic response to TGF-beta. These data are, to our knowledge, the first to implicate Smad3 in specific pathways of tissue repair and in the modulation of keratinocyte and monocyte function in vivo.

Estrogen accelerates cutaneous wound healing associated with an increase in TGF-beta1 levels.

The cellular and molecular mechanisms underlying the effects of aging on human cutaneous wound healing are poorly understood, and the possible role of reproductive hormones in this process has never been investigated. We report that aging in healthy females was associated with a reduced rate of cutaneous wound healing, but an improved quality of scarring both microscopically and macroscopically, and with reduced levels of transforming growth factor-beta1 (TGF-beta1) immunostaining and steady-state mRNA in the wound. These age-related changes were reversed by the systemic administration of hormone replacement therapy (HRT). Moreover, ovariectomized young female rodents exhibited a marked delay in repair of acute incisional wounds, which was reversed by the topical application of estrogen. The cellular mechanism underlying these changes appears to involve an estrogen-induced increase in latent TGF-beta1 secretion by dermal fibroblasts. These results suggest that both the rate and quality of wound healing depend on reproductive hormone levels.

Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing.

Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor with anti-microbial properties found in mucosal fluids. It is expressed during cutaneous wound healing. Impaired healing states are characterized by excessive proteolysis and often bacterial infection, leading to the hypothesis that SLPI may have a role in this process. We have generated mice null for the gene encoding SLPI (Slpi), which show impaired cutaneous wound healing with increased inflammation and elastase activity. The altered inflammatory profile involves enhanced activation of local TGF-beta in Slpi-null mice. We propose that SLPI is a pivotal endogenous factor necessary for optimal wound healing.

5alpha-dihydrotestosterone (DHT) retards wound closure by inhibiting re-epithelialization.

The ongoing search for explanations as to why elderly males heal acute skin wounds more slowly than do their female counterparts (and are more strongly disposed to conditions of chronic ulceration) has identified endogenous oestrogens and androgens as being respectively enhancers and inhibitors of repair. We previously demonstrated that blocking the conversion of testosterone to 5alpha-dihydrotestosterone (DHT) limits its ability to impair healing, suggesting that DHT is a more potent inhibitor of repair than is testosterone. The present study aimed to delineate the central mechanisms by which androgens delay repair. Whilst the contractile properties of neither rat wounds in vivo nor fibroblast-impregnated collagenous discs in vitro appeared to be influenced by androgen manipulations, the global blockade of DHT biosynthesis markedly accelerated re-epithelialization of incisional and excisional wounds and reduced local expression of beta-catenin, a key inhibitor of repair. Moreover, DHT retarded the in vitro migration of epidermal keratinocytes following scratch wounding. By contrast, it failed to influence the migratory and proliferative properties of dermal fibroblasts, suggesting that its primary inhibitory effect is upon re-epithelialization. These novel findings may be of particular significance in the context of chronic ulceration, for which being male is a key risk factor.

Clinically relevant doses of lidocaine and bupivacaine do not impair cutaneous wound healing in mice.

BACKGROUND: Lidocaine and bupivacaine are commonly infiltrated into surgical cutaneous wounds to provide local anaesthesia after surgical procedures. However, very little is known about their effects on cutaneous wound healing. If an inhibitory effect is demonstrated, then the balance between the benefits of postoperative local anaesthesia and the negatives of impaired cutaneous wound healing may affect the decision to use local anaesthesia or not. Furthermore, if a difference in the rate of healing of lidocaine- and bupivacaine-treated cutaneous wounds is revealed, or if an inhibitory effect is found to be dose-dependent, then this may well influence the choice of agent and its concentration for clinical use. METHODS: Immediately before incisional wounding, we administered lidocaine and bupivacaine intradermally to adult female mice, some of which had been ovariectomized to act as a model of post-menopausal women (like post-menopausal women, ovariectomized mice heal wounds poorly, with increased proteolysis and inflammation). Day 3 wound tissue was analysed histologically and tested for expression of inflammatory and proteolytic factors. RESULTS: On day 3 post-wounding, wound areas and extent of re-epithelialization were comparable between the control and local anaesthetic-treated animals, in both intact and ovariectomized groups. Both tested drugs significantly increased wound activity of the degradative enzyme matrix metalloproteinase-2 relative to controls, while lidocaine also increased wound neutrophil numbers. CONCLUSIONS: Although lidocaine and bupivacaine influenced local inflammatory and proteolytic factors, they did not impair the rate of healing in either of two well-established models (mimicking normal human wound healing and impaired age-related healing).

Effects of the COVID-19 lockdown on orthopaedic trauma: a multicentre study across Scotland.

AIMS: The UK government declared a national lockdown on 23 March 2020 to reduce transmission of COVID-19. This study aims to identify the effect of lockdown on the rates, types, mechanisms, and mortality of musculoskeletal trauma across Scotland. METHODS: Data for all musculoskeletal trauma requiring operative treatment were collected prospectively from five key orthopaedic units across Scotland during lockdown (23 March 2020 to 28 May 2020). This was compared with data for the same timeframe in 2019 and 2018. Data collected included all cases requiring surgery, injury type, mechanism of injury, and inpatient mortality. RESULTS: A total of 1,315 patients received operative treatment from 23 March 2020 to 28 May 2020 compared with 1,791 in 2019 and 1,719 in 2018. The numbers of all injury types decreased, but the relative frequency of hip fractures increased (36.3% in 2020 vs 30.2% in 2019, p < 0.0001 and 30.7% in 2018, p < 0.0001). Significant increases were seen in the proportion of DIY-related injuries (3.1% in 2020 vs 1.7% in 2019, p = 0.012 and 1.6% in 2018, p < 0.005) and injuries caused by falls (65.6% in 2020 vs 62.6% in 2019, p = 0.082 and 61.9% in 2018, p = 0.047). Significant decreases were seen in the proportion of road traffic collisions (2.6% in 2020 vs 5.4% in 2019, p < 0.0001 and 4.2% in 2018, p = 0.016), occupational injuries (1.8% in 2020 vs 3.0% in 2019, p = 0.025 and 2.3% in 2018, p = 0.012) and infections (6.8% in 2020 vs 7.8% in 2019, p = 0.268 and 10.3% in 2018, p < 0.012). Cycling injuries increased (78 in 2020 vs 64 in 2019 vs 42 in 2018). A significant increase in the proportion of self-harm injuries was seen (1.7% in 2020 vs 1.1% in 2019, p = 0.185 and 0.5% in 2018, p < 0.0001). Mortality of trauma patients was significantly higher in 2020 (5.0%) than in 2019 (2.8%, p = 0.002) and 2018 (1.8%, p < 0.0001). CONCLUSION: The UK COVID-19 lockdown has resulted in a marked reduction in musculoskeletal trauma patients undergoing surgery in Scotland. There have been significant changes in types and mechanisms of injury and, concerningly, mortality of trauma patients has risen significantly.Cite this article: Bone Joint Open 2020;1-9:541-548.

Polymorphisms spanning the 0N exon and promoter of the estrogen receptor-beta (ERbeta) gene ESR2 are associated with venous ulceration.

Venous ulcers are characterized by excessive inflammation and raised levels of proinflammatory cytokines. Estrogen has been shown to accelerate the rate of wound healing in elderly subjects by dampening the inflammatory response. The estrogen receptor (ER) proteins, ER-alpha (ERalpha) and ER-beta (ERbeta) mediate the actions of estrogen during wound repair through the activation or repression of target gene transcription. Recent evidence implicates the chromosomal region harboring the ERbeta gene with venous ulceration in a British Caucasian population, highlighting the need to conduct further genetic interrogation. To address this, we conducted a case-control study to investigate whether single nucleotide polymorphisms in the ERbeta gene are associated with venous ulceration in elderly (age >50 years) subjects. We recruited a case group (n = 124, 56 males and 68 females) consisting of patients with an active venous ulcer and a control group consisting of individuals from the general population with no evidence of venous disease or history of venous ulceration (n = 380, 189 males and 191 females). Polymorphisms in close proximity to upstream regulatory regions of the ERbeta gene, including the 0N exon and promoter transcribed in inflammatory cells, were significantly (p < 0.05) associated with venous ulceration. A major susceptibility haplotype carried by 23% (26/112) of cases compared with only 10% (27/276) of controls (odds ratio = 2.8, 95% confidence interval = 1.6-5.0) was significantly (p < 0.01) associated with elevated serum levels of tumor necrosis factor-alpha. In conclusion, common variation in the regulatory regions of the ERbeta gene may pre-dispose to venous ulceration in a British Caucasian population.

Loss of Smad3 modulates wound healing.

TGF-beta plays a central and critical role in tissue repair. The recent identification of TGF-beta signal transduction pathways involving Smad proteins has now made it possible to explore their contribution to the activities of TGF-beta in vivo. Both Smad3 and its closely related homolog Smad2 act as latent nuclear transcriptional activators and mediate intracellular signaling by TGF-betas and activin, each of which regulates cellular functions pivotal to cutaneous wound healing. Mice null for Smad3 (Smad3(ex8/ex8)) survive into adulthood and show accelerated cutaneous wound healing characterized by an increased rate of re-epithelialization and a reduced local inflammatory infiltrate. These data implicate Smad3 in specific pathways of tissue repair and suggest that it could be a target for the development of therapeutic strategies to modulate wound healing.

Femoral head viability after Birmingham resurfacing hip arthroplasty: assessment with use of [18F] fluoride positron emission tomography.

BACKGROUND: Total hip resurfacing has become increasingly popular over the last decade. There remains concern about the effect of the surgical approach on femoral head viability and the role of resurfacing in the management of established osteonecrosis. In view of these concerns, we examined femoral head viability following resurfacing through a modified anterolateral approach. METHODS: The viability of the femoral heads of ten patients who had undergone successful unilateral Birmingham hip resurfacing was assessed with use of positron emission tomography in conjunction with the injection of fluorine at a mean of twenty months after surgery. For each patient, in both the hip that had undergone resurfacing and the contralateral nonresurfaced hip, activity was measured in four regions of interest: the lateral aspect of the femoral head, the medial aspect of the femoral head, the lateral aspect of the femoral neck, and the proximal aspect of the femur. The uptake of fluorine in each area was converted to standard uptake volumes. RESULTS: No areas of osteonecrosis were seen in the femoral head of any patient. There were no significant differences in the standard uptake volumes as measured in the four regions of the nonresurfaced hips, whereas the median values were higher in all four regions of the resurfaced hips. The difference between the values in the resurfaced hips compared with those in the nonresurfaced hips was only significant (p < 0.05) in the lateral aspect of the femoral head. CONCLUSIONS: This study establishes positron emission tomography in conjunction with injection of fluorine as a possible modality for the assessment of femoral head viability after hip resurfacing. Viability following successful Birmingham hip resurfacing performed through a modified anterolateral approach has also been demonstrated. The increase in bone activity that was seen in the resurfaced hips in our study group may be related to bone remodeling or reperfusion of small areas of osteonecrosis. This technique offers the potential to study femoral head perfusion and viability following all types of resurfacing. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions to Authors on jbjs.org for a complete description of levels of evidence.

Wire tension in the Ilizarov system: accuracy of the wire-tensioning device.

The Ilizarov fixator consists of tensioned wires that attach bone segments to a modular frame. The aim of this study was to establish the accuracy and precision of the wire-tensioning device supplied with the Ilizarov external fixation system. The device was used to tension a wire in direct opposition to a calibrated load cell. Five subjects tested three devices, at each of their four tension settings, in two separate sessions. Subjects could not see the true tension during the test. There were significant differences between the results for different subjects (p < 0.01) and instruments (p < 0.01) but not for different tension settings or between the two sessions. Overall mean measured tensions were 4.9 per cent (standard deviation, 4.4 per cent) below intended values. Tensions obtained at the maximum edge (completely occluded) on the scale markings were significantly (p < 0.001) closer to the nominal values (mean discrepancy, 3.6 per cent) than those at the minimum edge (mean discrepancy, 17.6 per cent). Several factors influence wire tension. Tensioning devices are not identical and the results obtained with them depend on the user. If the scale markings are completely occluded, the discrepancy between intended and actual tensions of around 5 per cent is likely to be adequate for clinical practice since surgeons do not select the most suitable tension following quantitative data assessment, but rather it is a judgement based on surgical experience and consideration for the patient weight and expected level of activity.

Intraoperative changes in platelet function in relation to moderate haemorrhage.

BACKGROUND: Haemorrhage is associated with haemostatic dysfunction. Previous studies have focused on coagulation factors, but platelet function plays an equally important role. The time course of alterations in platelet function in relation to injurious stimuli is not known. AIM: To evaluate short-term, intra-operative changes in platelet function, by whole blood impedance aggregometry in patients undergoing hip arthroplasty. The primary outcome was platelet aggregation in response to adenosine diphosphate (ADP) stimulation. We also evaluated other agonists, and the feasibility of conducting platelet aggregometry measurement in the operating theatre. METHODS: Patients undergoing primary cemented hip arthroplasty had six peri-operative arterial blood samples analysed at pre-set stages of the operation, using the Multiplate Impedance Aggregometer. Four agonists were used: ADP, TRAP, Collagen and Arachidonic Acid. RESULTS: There was a statistically significant change (p<0.05, ANOVA) in platelet response to ADP over the course of the operations. The trend demonstrated an initial decrease in responsiveness, followed by increased platelet responsiveness in the later stages. Other agonists (TRAP, COL, ASPItest) demonstrated a similar pattern of changes. Of 360 tests conducted, 12 (3.3%) had to be re-run due to poor intra-assay variability. Satisfactory values were obtained on the second attempt in all 12 samples. CONCLUSION: Platelet function, as measured by impedance aggregometry, changes in response to a surgical stimulus involving blood loss. The clinical significance of these changes, and the potential of manipulating them for therapeutic purposes, remains to be elucidated.

Aging is associated with reduced deposition of specific extracellular matrix components, an upregulation of angiogenesis, and an altered inflammatory response in a murine incisional wound healing model.

The concept that aging impairs wound healing is largely unsubstantiated, the literature being contradictory because of poor experimental design and a failure to adequately characterize animal models. This study tested the hypothesis that aging retards the rate of wound repair using standardized cutaneous incisional wounds in a well-characterized aging mouse colony. Against the background of age-related changes in normal dermal composition, marked differences in healing were observed. Immunostaining for fibronectin was decreased in the wounds of the old mice, with a delay in the inflammatory response, re-epithelialization, and the appearance of extracellular matrix components. Heparan sulfate and blood vessel staining were both unexpectedly increased in the wounds of the old animals at late time points. Despite an overall decrease in collagen I and III deposition in the wounds of old mice, the dermal organization was surprisingly similar to that of normal dermal basket-weave collagen architecture. By contrast, young animals developed abnormal, dense scars. Intriguingly, some of these age-related changes in scar quality and inflammatory cell profile are similar to those seen in fetal wound healing. The rate of healing in young animals appears to be increased at the expense of the scar quality, perhaps resulting from an altered inflammatory response.

Bidirectional regulation of macrophage function by TGF-beta.

The dual role of transforming growth factor-beta (TGF-beta) in modulating macrophage function is an important concept gaining increasing recognition. In addition to its role as a 'macrophage-deactivating' agent, TGF-beta functions as a monocyte activator, inducing cytoke production and mediating host defence. These functions are context-dependent, modulated by the differentiation state of the cell, the local cytokine environment, and the local levels of TGF-beta in itself. In general, during the initial stages of inflammation, TGF-beta locally acts as a proinflammatory agent by recruiting and activating resting monocytes. As these cells differentiate specific immunosuppressive actions of TGF-beta predominate, leading to resolution of the inflammatory response. Increasing our understanding of the bidirectional regulation of macrophage function will facilitate prediction of the ultimate outcome of modulating TGF-beta levels in vivo.

Is Smad3 a major player in signal transduction pathways leading to fibrogenesis?

Transforming growth factor (TGF)-beta plays a central role in fibrosis, contributing both to the influx and activation of inflammatory cells, as well as to activation of fibroblasts to elaborate extracellular matrix. In the past few years, new insight has been gained into signal transduction pathways downstream of the TGF-beta receptor serine-threonine kinases with the identification of a family of evolutionarily conserved Smad proteins. Two receptor-activated Smad proteins, Smad2 and Smad3, are phosphorylated by the activated TGF-beta type I receptor kinase, after which they partner with the common mediator, Smad4, and are translocated to the nucleus to where they participate in transcriptional complexes to control expression of target genes. We have shown in wound healing studies of mice null for Smad3, that loss of this key signaling intermediate interferes with the chemotaxis of inflammatory cells to TGF-beta as well as with their ability to autoinduce TGF-beta. Moreover, studies with mouse embryo fibroblasts null for Smad3 show that TGF-beta-dependent induction of c-Jun and c-Fos, important in induction of collagen as well as in autoinduction of TGF-beta, is mediated by Smad3. Based on these observations, we hypothesize that loss of Smad3 will confer resistance to fibrosis and result in reduced inflammatory cell infiltrates, reduced autoinduction of TGF-beta, important to sustain the process, and reduced elaboration of collagen. Preliminary observations in a model of radiation-induced fibrosis confirm this hypothesis and suggest that inhibitors of Smad3 might have clinical application both to improve wound healing and to reduce fibrosis.

Behavioural effects of electrolytic and 6-hydroxydopamine lesions of the accumbens and caudate-putamen nuclei.

Selective bilateral destruction of dopaminergic neuronal terminals in the accumbens nuclei with 6-hydroxydopamine reduced spontaneous and amphetamine-induced locomotor and exploratory behaviour and sniffing activity; amphetamine-induced stereotyped behaviour appeared to be mildly potentiated. Similarly induced bilateral destruction of dopaminergic nerve endings in the caudate-putamen reduced spontaneous activity; amphetamine-induced stereotyped behaviour was abolished. Some animals with severe degrees of neostriatal dopamine depletion were completely unresponsive to amphetamine, apart from intense sniffing activity. Bilateral electrolytic lesions of the accumbens nuclei did not alter spontaneous or amphetamine-induced activity.

Behavioural responses to stereotactically controlled injections of monoamine neurotransmitters into the accumbens and caudate-putamen nuclei.

Bilateral stereotactically-controlled injections of dopamine (5--50 micrograms of the hydrochloride salt) into the nucleus accumbens of nialamide-pretreated rats induced a marked stimulation of exploratory and locomotor activity, accompanied by intense sniffing and rearing. Conversely, bilateral injection of domapine (12.5--50 micrograms of the hydrochloride salt) into the caudate-putamen induced intense stereotyped activity which was dose-related. Both responses were blocked by IP haloperidol. Bilateral injection of noradrenaline (50 micrograms of the hydrochloride salt) into the accumbens nuclei did not produce any particular behavioural changes. The same injection into the caudate-putamen led to a moderate stimulation of stereotyped activity. Bilateral injection of 5-HT (50 micrograms of the bimaleinate salt) into the accumbens nuclei induced a moderate locomotor activity with some hole-dipping activity and sniffing; these behaviours were incoordinated and indecisive. The same injections into the caudate-putamen led to a moderate stimulation of locomotor activity and hole-dipping which was predominantly 'stereotyped' in character; on visual observation no other striking abnormalities were noted.