Implications of the density of clonogenic infestation in radiotherapy.

Treatment schemes must be evaluated in a clinical context. It was observed by Coutard in the 1920s that exophytic tumors disappear by the third to fourth week of treatment and are more often controlled, stage for stage, than ulcerative and/or infiltrative tumors. It has also been demonstrated that the control rate is higher in patients whose tumor has clinically disappeared at the end of treatment than in those with clinically residual tumor. A possible explanation is that, after the clinical disappearance tumor cells that remain are euoxic during the latter part of treatment. Since some parameters, such as reoxygenation and proliferation, may work in opposite directions, a balance has to be found for each tumor mass. Furthermore, there are clinical facts that, although without explanation, must be considered.

Keynote address: the scientific basis of the present and future practice of clinical radiotherapy.

At mid-century radiotherapy was more an art than a science, but is presently based on radiobiological parameters and cell kinetics. This close interaction between basic scientific principles and clinical practice has been made possible because one can correlate quantitatively doses of irradiation with observed responses. First, a short historical review will be made because it gives a perspective for the understanding both of progress made and prevailing misconceptions. The important radiobiological parameters and cell kinetics will then be discussed in some detail to demonstrate that they should be thoroughly understood in their relationship to radiotherapy. The overall treatment planning must be based on the clinical applications of the main radiobiological parameters. The combined treatment with surgery, either pre- or postoperatively, and multiple daily fractionations will be used as examples. The teaching of radiobiology should be considerably expanded, not only for its own scientific merit but also to show how it applies to clinical situations. This should be reflected in the expansion of the board examination.

Analysis of the parameters relating to failures above the clavicles in patients treated by postoperative irradiation for squamous cell carcinomas of the oral cavity or oropharynx.

One hundred and two patients with squamous cell carcinoma of the oral cavity or oropharynx were treated from January 1955 through August 1976 with surgical excision followed by irradiation. Twelve patients had T2 lesions and 90 had T3 or T4 lesions. Failures above the clavicles were associated with disease present at the margins of resection, location of the recurrence close to the periphery, or outside of the irradiated portals. Failure in the neck essentially were a result of no elective irradiation. In patients with disease present at the margins of resection, there is a risk both of gross residual disease and hypoxic microscopic disease left behind; 4500 to 5000 rad is not adequate for a significant control rate. In situation where there is definite disease at the margin of resection, 6500 rad, or in specific situations, 7000 rad, should be given through reduced fields.

Guidelines for radiotherapeutic techniques for cervical metastases from an unknown primary.

Between 1968 and 1980, radiotherapy was part of the treatment of 120 patients with cervical nodes from an unknown primary tumor. Thirteen patients presented with supraclavicular nodes only and 14 presented with massive adenopathy; they are analyzed separately. The remaining 93 patients are analyzed in this report with emphasis on the applied radiotherapeutic techniques. Twenty of the 93 patients received radiation treatment to the neck only, 26 to the naso- and oropharynx and neck, and 47 to the naso-, oro-, and hypopharynx and neck. Fourteen patients subsequently developed a tumor at a primary site or a recurrence of metastases in the neck; in nine patients the disease recurrence was in areas that had not been irradiated. There was an increase in failures above the clavicles in patients who received irradiation to the neck alone. No correlation was found between initial tumor staging and subsequent failure, nor between types of surgical procedures and failure. In 86 of 93 (92.5%) patients there was eventual control of disease above the clavicles; 22 of the 93 patients died of disease, whereas 36 died of other causes. The determinate survival rate for the 93 patients treated with curative intent is 70% at 10 years. Guidelines for selection of techniques based on tumor and patient factors are discussed.

Long-range results for breast cancer patients treated by radical mastectomy and postoperative radiation without adjuvant chemotherapy: an update.

Between 1963 and 1977, 941 patients with carcinoma of the breast received, at the University of Texas M.D. Anderson Cancer Center, peripheral lymphatic irradiation alone or with chest wall irradiation after a radical or modified radical mastectomy. None of the patients received adjuvant chemotherapy. The incidence of patients with histologically involved axillary nodes was 70%. The lymphatics of the apex of the axilla, of the supraclavicular area, and of the internal mammary chain were irradiated in patients with histologically positive axillary nodes and/or in patients with central or inner quadrant primaries regardless of the axillary status. When in 1963 an electron beam became available, chest wall irradiation has been added to the peripheral lymphatics irradiation, primarily when there was a heavy infestation of the axillary nodes. The disease-free survival curves tend to flatten out at 10 years. At 10 and 20 years, the disease-free survival rates are respectively 55% and 50% for all patients, 44% and 40% for all patients with positive nodes, 56% and 48% for the patients with one to three positive nodes, and 33% and 30% for the patients with four or more positive nodes. The comparison of the mortality curves between the general population and the breast cancer patients seems to indicate a cured fraction, since the curves become parallel at 17 years. The highest incidence of failures is between 0 and 5 years, still a significant incidence between 5 and 10 years, but after 10 years the incidence of failures is relatively small.

Analysis of the severe complications of irradiation of carcinoma of the cervix: whole pelvis irradiation and intracavitary radium.

From January, 1967 to December, 1974, 325 patients with carcinoma of the uterine cervix were treated with a minimum of 4,000 rad whole pelvis irradiation plus intracavitary radium. These patients had large, sometimes massive, tumors. Generally, the larger the primary tumor the greater the amount of external irradiation delivered, with an appropriate reduction in the amount of intracavitary radium. Patients who had a positive lymphangiogram or a pre- or postirradiation hysterectomy or lymphadenectomy are not included in this analysis. All patients were followed for a minimum of 5 years. Local and regional failure rate in 193 patients receiving 4,000 rad whole pelvis irradiation plus radium was 1% and 4%, respectively, with a 3.1% incidence of severe complications. In 111 patients who received 5,000 rad whole pelvis irradiation plus radium, the local and regional failure rate was 3.5% and 4.5%, respectively, with a 10% incidence of severe complications. In patients who received 5,000 rad whole pelvis irradiation, complications were associated with unilateral parametrial boosts and with protruding vaginal sources. Of 21 patients who received 6,000 rad whole pelvis irradiation, three patients developed fistulae associated with high doses to the vagina delivered with protruding vaginal sources.

Anatomical coverage in elective irradiation of the neck for squamous cell carcinoma of the oral tongue.

From January 1954 through December 1978, 146 patients with squamous cell carcinoma of the oral tongue and clinically negative neck had their primary lesion controlled with irradiation. Metastases to the neck developed later in: 27 of 76 patients (36%) treated by interstitial implantation; nine of 27 patients (33%) who received 2,000 rad in five fractions to the upper neck prior to the implant; eight of 19 (42%) patients who received 5,000 rad through an upper ipsilateral neck field prior to the implant; four of 24 patients (16.6%) who received 5,000 rad through bilateral portals to the upper neck with or without irradiation of the lower neck. In the 43 ipsilateral neck failures, 23 were in the upper jugular chain, (posterior subdigastric nodes), 12 in the mid-jugular, three in the lower jugular, and four in the more anterior part of the subdigastric area. There was one failure in the posterior cervical chain, and five contralateral neck failures. A review of the treatment charts showed that the patients who had an ipsilateral upper neck field only, had smaller portals because the irradiation was tailored to produce shrinkage of the primary tumor prior to needling. To include adequate coverage of the posterior subdigastric nodes (upper jugular), the bodies of the vertebrae must be seen on the simulator films. Also the junction of the subdigastric and the mid-jugular lymphatics must be covered. Although there were only three failures in the lower jugular nodes, it is technically easier to treat the upper mid-jugular nodes through an anterior appositional portal to the lower neck. A dose of 5,000 rad must be given since 2,000 rad, even if delivered in five fractions, gives a failure rate as if there had been no irradiation to the neck.

T1-T2 squamous cell carcinoma of the glottic larynx treated with radiation therapy: relationship of dose-fractionation factors to local control and complications.

This is an analysis of 304 patients with invasive, previously untreated T1-T2 squamous cell carcinoma of the glottic larynx treated with radiation therapy at the University of Florida between October 1964 and December 1984. All patients had a minimum 2-year follow-up and 82% had at least 5 years of follow-up. Patients were excluded from the analysis of local control if they died within 2 years of treatment with the primary site continuously disease-free; all patients were included in the analysis of treatment complications. Patients were staged according to the 1983 AJCC system. Stage T2 was subdivided into 2 groups as follows: T2a (normal mobility) and T2b (decreased mobility). The rates of local control with radiation therapy were as follows: T1, 159/171 (93%); T2a, 50/65 (77%); and T2b, 31/43 (72%). Patients were further divided into subsets based on T stage and the surgical procedure that would have been required to resect the lesion. Local control was noted to improve with higher doses and dose per fraction in 4 of 7 subsets. In 2 of 3 subsets where a dose-fractionation relationship was not observed, there were no local recurrences in 1 subset and only 2 local recurrences in the other. The overall incidence of serious complications was 5/304 (1.6%) and was associated with T stage and with increasing total dose and dose per fraction.

Accelerated fractionation vs hyperfractionation: rationales for several treatments per day.

Treatment with several doses per day offers the prospect of a significant therapeutic gain using readily available low LET beams. These regimens can be classified as either accelerated fractionation or hyperfractionation according to their rationales. With accelerated fractionation a conventional number of dose fractions is delivered in a significantly shortened overall treatment time in order to reduce the opportunity for tumor cell regeneration during treatment. With hyperfractionation, on the other hand, a large number of significantly reduced dose fractions is used to give a greater total dose in a conventional overall treatment time. The rationale for this strategy is threefold: 1) increased opportunity for tumor cell redistribution and reoxygenation between dose fractions: 2) a possibly lower oxygen enhancement ratio with small incremental doses; and 3) different sparing of late reacting normal tissues with small dose fractions. A review of the published clinical experience with multiple fractions per day treatment reveals few studies of either pure accelerated fractionation or hyperfractionation since both are limited by acute normal tissue reactions. This has led to a variety of hybrid regimens, some of which have no clear rationale. The choice between accelerated fractionation and hyperfractionation is determined by the regenerative capability of tumor clonogens during treatment. A method of selection based on potential doubling times is presented.

Postoperative irradiation in malignant epithelial tumors of the parotid.

From 1954 through 1979, 77 patients with malignant tumors of the parotid gland were referred from the Department of Head and Neck Surgery for postoperative irradiation. The analysis has been made by grouping the patients according to the estimated amount of disease left after the surgical procedure and by the histological types. There were no local failures in the low-grade tumors, and there were 6 in the 63 patients with high-grade tumors. With gross residual disease or potential residual disease the patients received slightly higher doses than those without. Although there were only 6 failures in the various histological types, there was perhaps a trend to more failures in the adenocarcinomas. There was no difference in the failure rates in patients having had a total resection of the facial nerve or partial resection or no resection. The preferred treatment has been a combination of 20 MeV photons and 18 MeV electrons. Five neck failures were essentially a result of lack of elective irradiation of the neck. Severe complications appeared only in the patients irradiated either for gross residual disease or excision of a recurrence with a high risk of widespread microscopic residual disease.

Changes in early and late radiation responses with altered dose fractionation: implications for dose-survival relationships.

Clinical and experimental evidence for divergent changes in early and late radiation responses in normal tissues after changes in dose fractionation indicate a greater sensitivity of late responses to changes in dose per fraction. In experimental studies of the effect of dose per fraction on early and late isoeffects, a larger number-of-fractions exponent for the late responses is the rule. These findings imply that the shape of the dose-survival curve for the target cells whose depletion results in late effects is different from that for target cells for acute effects: as the dose increases the contribution to cell killing from accumulated sublethal injury, relative to killing from single hit events, increases more rapidly in the target cells for late effects. In other words, the survival curve for the target cells for late injury must be "curvier" than that for acute effects. Although such survival curve characteristics are independent of the survival curve model chosen to describe them, they would represent, in terms of the parameters of the linear quadratic model, S = e -alphaD-beta D2, a higher beta/alpha ratio for late effects. If the dose survival characteristics of tumor clonogens resemble those of the target cells in acutely responding normal tissues, and if late injury in normal tissues is dose-limiting, then a therapeutic gain would result from reducing the size of dose per fraction by hyperfractionation. Conversely, increasing the size of dose per fraction should reduce the therapeutic differential.

Tumor radioresistance in clinical radiotherapy.

Tumor radioresistance in clinical radiotherapy implies failure to achieve loco-regional disease control with radiation doses producing an acceptable degree of morbidity. Such radioresistance may be a result of many different causes (biological and technical) which are reviewed in terms of possible remedial actions. Dose response relationships for human cancers suggest that in many sites, tumors are heterogenous with respect to their cure-limiting characteristics. The case is developed that unless the predominant cure-limiting factor can be predicted, little benefit may be seen in trails of new treatment strategies using heterogeneous tumor populations. The fundamental problem of clinical radioresistance is therefore perceived as the inability to predictively identify its cause in the individual patient.

Twice-daily fractionation schemes for advanced head and neck cancer.

Eighty-five patients with advanced squamous cell carcinoma of the head and neck were treated with twice-a-day fractionation schedules between April 1972 and December 1980. Two types of treatment were distinguished: hyperfractionation, by which 65 patients (Group I) were treated at a weekly dose rate of 1100 to 1200 rad (10 fractions of 110 to 120 rad) in 5 to 6 1/2 weeks for either advanced primary disease (Group 1A) and/or advanced neck metastases (Group IB); and accelerated treatment, used to treat 20 patients (Group 2) who had fast-growing and usually massive neck nodes, at a weekly dose rate of 1300 to 1500 rad in 7 to 10 fractions, to a total dose of 6100 to 8000 rad in 4 to 6 weeks. The radiation portals for patients in Group 2 excluded the mucosa of mouth and throat for part of the treatment. The local control rate at 1 year in Groups 1A and 1B was 41 and 54%, respectively; the incidence of complications was 17%, 5% of them fatal. The local control rate in Group 2 was 80%. Seven patients in this group underwent a neck dissection 6 to 8 weeks following irradiation. Four specimens were negative for tumor. In two, only necrotic tumor cells were identified, and in one specimen morphologically intact tumor cells were seen. There were no fatal complications.

Results of mastectomy and postoperative irradiation in the management of locoregionally advanced carcinoma of the breast.

Between 1955 and 1984, 376 patients with locoregionally advanced breast carcinoma were treated at The University of Texas M. D. Anderson Cancer Center with mastectomy and irradiation and without adjuvant chemotherapy. Patients with inflammatory carcinoma or synchronous bilateral primary tumors were excluded. There were 202 patients with Stage IIIA disease and 174 patients with Stage IIIB disease (AJC Staging--1983). In 124 patients the surgical management was confined to the breast only--total mastectomy (BR) and in 252 dissection of the axilla was performed--extended total, modified radical, or classic radical mastectomy (BR + AX). All patients had postoperative irradiation. The follow-up period ranged between 8 and 34 years. At 10 years, the actuarial disease-specific, relapse-free survival (DSRFS) rate for the entire group was 40%, and the actuarial locoregional control rate was 82%. For patients with Stage IIIA disease the DSRFS was 48% and locoregional control rate was 88%. For those with Stage IIIB disease, the figures were 30% and 74%, respectively. Most of the failures occurred within 5 years of the mastectomy and essentially all occurred within 10 years. When analyzed by type of surgery, both the locoregional control and DSRFS rates were improved by the axillary dissection, the difference being largely caused by fewer axillary node recurrences after dissection of both the breast and axilla than after removal of the breast alone. In the 252 patients in whom the axilla was assessed, the number of positive nodes was a powerful predictor of both locoregional control and survival. The DSRFS rates at 10 years for patients with 0, 1-3, and greater than or equal to 4 positive nodes were 63%, 48%, and 30%, respectively. The actuarial locoregional control rates at 10 years exceeded 95% for patients with 0-3 positive nodes and 75% for those with greater than or equal to 4 nodes. These results show that locoregionally advanced breast cancer is not a uniformly fatal disease when treated without chemotherapy and provide a baseline upon which to assess the value of adjuvant systemic therapy for this stage of disease.

Definitive radiotherapy for squamous cell carcinoma of the tonsillar fossa.

Between July 1968 and December 1983, 150 patients with previously untreated squamous cell carcinomas of the tonsillar fossa received megavoltage external beam irradiation with curative intent at U.T.M.D. Anderson Cancer Center. These patients were treated following a series of patients who had received radiotherapy between 1954 and May 1968. One hundred and thirty-seven patients were treated with conventional fractionation, the mean doses to the primary being 64.3 Gy, 67.8 Gy, 70.2 Gy, and 72.6 Gy for T1, T2, T3, and T4 lesions respectively. Thirteen patients were treated by altered fractionation schedules, 7 by hyperfractionation, and 6 by a concomitant boost to the primary. Elective bilateral neck irradiation was routine in all patients. A planned neck dissection was performed in 26 patients. The 5-year actuarial overall and disease-specific survival rates were 47% and 70%, respectively. Absolute local control rates with a minimum of 2 years follow-up after irradiation were 94%, 79%, 58%, and 50% for patients with T1, T2, T3, and T4 disease respectively. A total of 37 patients had local treatment failure; in 5 of 18 surgical salvage was successful. Only 4 patients with primary disease control developed failure in the neck and none of those with N0 or N1 disease did so when the primary was controlled. Twelve patients developed transient self-limited bone exposure, 7 developed osteoradionecrosis of the mandible, all requiring surgical resection. Most severe late complications occurred in patients with T3 and T4 lesions whose dose to the primary exceeded 67.5 Gy.

Multimodal treatment for inflammatory breast cancer.

This is a retrospective study of 61 patients with clinically diagnosed breast cancer (IBC) treated with multimodality therapy between September 1977 and September 1985. All patients were scheduled to receive three courses of doxorubicin-based chemotherapy followed by mastectomy, further chemotherapy, and postoperative irradiation. Ten patients (16%) obtained a complete response, defined as either resolution of the clinical signs of inflammatory breast cancer (IBC) (4 patients) or no evidence of tumor in the mastectomy specimen (6 patients). Twenty-seven patients (45%) obtained a partial response, defined as a greater than 50% reduction in the clinical signs of inflammatory breast cancer. No response occurred in 24 patients (39%). Immediate mastectomy was done in 56 patients. Five patients whose disease was not resectable received preoperative irradiation. Nine patients at high risk for locoregional failure received postoperative irradiation immediately after mastectomy and before additional chemotherapy. Postoperative irradiation was given to the chest wall and peripheral lymphatics using standard or accelerated fractionation to a maximum dose of 60 Gy. Forty-six patients completed planned treatment including chemotherapy, surgery, and radiotherapy without failure. The minimum follow-up was 36 months. The 5-year actuarial disease-free survival was 70% for the complete response group, and 35% for the partial response group. All patients with no response failed by 34 months. The actuarial 5-year disease-free survival rate for the entire group was 27%. The 5-year actuarial locoregional control was 89% in the complete response group, 68% in the partial response group, 33% in the no response group, and 58% for all patients. Most failures were on the chest wall within the irradiated volume. Chest wall failures were more frequent in those who did not achieve brisk erythema or moist desquamation after postoperative irradiation. We conclude that multimodal treatment of patients with inflammatory breast cancer results in a low incidence of failure if complete response is obtained following initial chemotherapy. The locoregional control rate and actuarial 5-year disease-free survival for the entire group were not improved when mastectomy was done. Surgery should be done in those patients who respond adequately to chemotherapy, so that late sequelae of high-dose breast irradiation can be eliminated. Higher doses of postoperative irradiation may be required to improve local control in those patients with the poorest response to initial chemotherapy.

Results of irradiation in the squamous cell carcinomas of the anterior faucial pillar-retromolar trigone.

Between January 1966 and August 1981, 159 patients with previously untreated squamous cell carcinomas of the anterior faucial pillar or retromolar trigone received definitive radiation therapy at The University of Texas M. D. Anderson Hospital and Tumor Institute. All except 11 patients were treated by external radiation including combination of electron beams with high-energy photons or 60Co to doses ranging from 60 Gy to 75 Gy. In the N0 patients, as a rule, only the ipsilateral subdigastric nodes were treated electively to a dose of 50 Gy. The 5-year determinate survival rate for the overall group was 83%. The cumulative recurrence rate showed that 92% of the patients had recurrence by 2 years. Therefore, all patients except those who died with no evidence of local disease less than 2 years after treatment were evaluated for local control. The failure rate for the evaluable patients was 29% for T1 lesions, 30% for T2 lesions, 24% for T3 lesions, and 40% for T4 lesions. After salvage surgery, which consisted of intraoral resection in one-third of the patients and of a composite operation in the other two-thirds, the ultimate failure rate was 0% for T1 lesions, 6% for T2 lesions, 8% for T3 lesions, and 20% for T4 lesions. Whereas stage was a poor indicator for treatment outcome, there was a significantly higher failure rate for infiltrative and/or ulcerated lesions (35%) than for exophytic or superficial lesions (15%). Histologic grade was of no prognostic significance, nor was there any significant difference in the failure rate for lesions originating on the anterior faucial pillar versus that for lesions on the retromolar trigone. Following radiotherapy, 30% of the patients developed some degree of bone exposure but only 5.6% (9 patients) required a segmental mandibular resection. The probability of bone exposure was not dose related and more likely reflected tumor location on the mucoperiosteum. Of the whole group, 16 patients (10%) experienced a neck failure with 8 ultimate failures after salvage surgery. Among the 16 patients who had neck failures, 13 were originally staged N0; 6 of these patients had failures that occurred in the electively treated ipsilateral subdigastric area, but the field was too small to cover the nodes adequately. Aspects of the radiotherapy techniques with combined electron and photon beams that may influence the treatment outcome are discussed.

Topography of dopamine behaviours mediated by D1 and D2 receptors revealed by intrastriatal injection of SKF 38393, lisuride and apomorphine in rats with a unilateral 6-hydroxydopamine-induced lesion.

Stereotaxic injections of a dopamine D1 receptor agonist (SKF 38393) into different regions of the supersensitive striatum of rats with a unilateral 6-hydroxydopamine-induced lesion duplicated the systemic effects of the drug in a topographical manner. Although there was considerable overlap, it was possible to recognize discrete active zones or "hot-spots" giving rise to prominent sniffing, head movements and contralaterally directed circling, posture and grooming, both in the coronal plane and along the rostro-caudal axis. Two behaviours peculiar to D1 stimulation included contralateral forepaw myoclonus and forepaw nibbling, which paradoxically was directed mainly ipsilaterally. Each of the behavioural elements occurred independently of the others and after an inexplicably long latency. They were inhibited by the D1 antagonist SCH 23390, but not by the D2 blocking drug metoclopramide. Comparable circling responses were evoked by a D2 agonist (lisuride) injected into the neostriatum after a short delay, and instantaneously by apomorphine (D1/D2 agonist). Both drug behaviours originated diffusely from all parts of the denervated striatum with no obvious "hot-spots", except for circling which exhibited a bimodal distribution rostro-caudally. The actions of lisuride were blocked by systemic metoclopramide, but not by SCH 23390, while the actions of apomorphine were inhibited by both antagonists. Topographies of D2 receptor-mediated events were quite different from those encountered for D1 receptor stimulation by SKF 38393, though neither corresponded to the autoradiographic distribution of D1 and D2 binding sites in the intact striatum. These results reiterate the importance of D1 receptors in motor control and provide a basis for future investigations of the output pathways subserving D1-mediated behaviours.

The actions of the kappa 1 opioid agonist U-50,488 on presynaptic nerve terminals of the chick ciliary ganglion.

The actions of the kappa 1 opioid receptor agonist U-50,488 (trans-(+-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benz ene - acetamide methane sulfonate) on the membrane properties of presynaptic calyciform nerve terminals of the chick ciliary ganglion were examined using intracellular recordings obtained from intact ganglion preparations maintained in vitro. U-50,488 produced a concentration-dependent (30-1000 microM) hyperpolarization with an apparent increase in input resistance. This hyperpolarization resulted from inhibition of the Na(+)-K+ inward rectifier, since it was blocked by 3 mM Cs+ and was not observed when terminals were depolarized beyond resting potential where inward rectification was voltage inactivated. A depolarizing effect on membrane potential with a further rise in input resistance was commonly observed at the highest perfused U-50,488 concentration (1 mM). The depolarizing event appears to result from a decrease in membrane potassium conductance, as the reversal potential for the response was estimated to be between -70 and -90 mV and the potassium channel blocker Ba2+ (1 mM) abolished the response. The kappa 1 opioid receptor agonist also blocked spontaneously occurring miniature hyperpolarizations in the terminals, which are considered to be due to a Ca(2+)-dependent K+ conductance. Most of the responses to U-50,488 were abolished in the presence of the kappa 1 receptor antagonist norbinaltorphimine. In conclusion, the excitability of presynaptic nerve terminals in the chick ciliary ganglion can be modulated by the inhibition of at least three separate ion conductances following activation of kappa 1 opioid receptor sites in the nerve terminal region.

Differential effects of pallidal lesions on the behavioural responses to SKF 38393, LY 171555 and apomorphine in the rat.

The purpose of this study was to determine the role of the globus pallidus in the expression of dopamine D1- and D2-receptor mediated motor events. Rats were first injected stereotaxically with 6-hydroxydopamine in one medial forebrain bundle to denervate the ascending dopamine pathways in that hemisphere. Apomorphine and selective D1 and D2 agonists were then administered, at two dose levels, to establish characteristic response patterns. Subsequently the animals were given a secondary lesion by injecting kainic acid (0.2-1 microgram) into the ipsilateral globus pallidus and retested with the dopamine agonists over a period of two months. The kainate treatment itself caused spontaneous motor asymmetries, followed by aphagia, adipsia and hypersensitivity to touch. Contraversive circling, contralateral posture and grooming induced by systemic apomorphine were all abolished by the kainate treatment, whilst sniffing and head movements were facilitated. All activities induced by D1 stimulation were abolished or severely reduced under these conditions. By contrast, the contralateral posture and grooming elicited by D2 stimulation were spared, and only D2-dependent contraversive rotation, sniffing and head movements were reduced. All behavioural deficits were temporary and recovered partially or completely during the course of the experiment, but could not be overcome by increasing the dose of dopamine agonist. Post mortem histology revealed a consistent loss of pallidal neurons, together with more variable damage to extrapyramidal structures and the thalamus. The results show that all the D1-mediated, and certain of the D2-mediated motor responses depend on the integrity of the pallidum for their expression in the unilaterally 6-hydroxydopamine-treated rat.