Stable Response Rates Research Articles

The effects of intra-accumbal administration of the nicotinic acetylcholine receptor agonist cytisine on the operant oral self-administration of ethanol were prevented by the GABAB receptor agonist baclofen in rats

RationaleAlthough the mesocorticolimbic dopamine (DA) system is the main neurochemical substrate that regulates the addictive and reinforcing effects of ethanol (EtOH), other neurotransmitter systems, such as the acetylcholine (Ach) system, modulate DAergic function in the nucleus accumbens (nAcc). Previously, we reported that intra-nAcc administration of the nicotinic Ach receptor agonist cytisine increased oral EtOH self-administration. GABAB receptors in the nAcc are expressed in DAergic terminals, inhibit the regulation of DA release into the nAcc, and could modulate the effects of cytisine on oral EtOH self-administration. The present study assessed the effects of intra-nAcc administration of the GABAB receptor agonist baclofen (BCF) on the impacts of cytisine on oral EtOH self-administration. Methods: Male Wistar rats were deprived of water for 23.30 h and then trained to press a lever to receive EtOH on an FR3 schedule until a stable response rate of 80 % was achieved. After this training, the rats received an intra-nAcc injection of the nAch receptor agonist cytisine, BCF, and cytisine or 2-hydroxysaclofen, BCF, and cytisine before they were given access to EtOH on an FR3 schedule. Results: Intra-nAcc injections of cytisine increased oral EtOH self-administration; this effect was reduced by BCF, and 2-hydroxysaclofen blocked the effects of BCF. Conclusions: These findings suggest that the reinforcing effects of EtOH are modulated not only by the DA system but also by other neurotransmitter systems involved in regulating DA release from DAergic terminals.

Response time fluctuations in the sustained attention to response task predict performance accuracy and meta-awareness of attentional states.

Previous research suggests that response time (RT) patterns in the Sustained Attention to Response Task(SART) differentially predict different features of mind wandering but it is unknown how they relate to meta-awareness of attentional states. We applied principal component analysis to blocks of non-target (go) trials prior to target(no-go) trials and attentional state and meta-awareness probes in the SART and identified three distinct patterns that replicated those observed in previous research. A stable response rate was associated with superior target performance, whereas RT acceleration prior to targets was associated with poorer target performance. Self-reported attentional state was not significantly predicted by any of the pattern components. By contrast, meta-awareness was independently associated with two distinct RT fluctuation patterns with evidence that each pattern was specifically related to either meta-awareness of off-task or on-task states. These results suggest that mind wandering and meta-awareness of attentional states have distinct and overlapping imprints on RT patterns in the SART. We conclude by highlighting implications of these results for introspective methods and the measurement of mind wandering.

Effect of macrocytosis on erlotinib response in metastatic non-small cell lung cancer

Background/Aim: Numerous studies have assessed the relationship between macrocytosis and responses to chemotherapeutic agents and TKIs such as sunitinib and imatinib. However, there is limited data in the literature regarding the prognostic or predictive value of macrocytosis in using erlotinib. If a relationship is detected, early response/resistance assessment can be performed before imaging time in the follow-up of treatments, and a more cost-effective, non-invasive method can be employed for response monitoring. This study aimed to elucidate the effect of macrocytosis on response rates in patients treated with erlotinib for non-small cell lung cancer. Methods: Seventy-five individuals diagnosed with non-small cell lung cancer (NSCLC) and admitted to our institution were enrolled in this retrospective cohort study. Baseline demographics, time of diagnosis, previous treatment, and the initiation or cessation of erlotinib were recorded. Data of patients with and without macrocytosis were analyzed. Stable disease, partial and complete response rates, and progressive disease response were evaluated separately as response rates. Progression-free survival between drug initiation and discontinuation due to progression was interpreted using Kaplan-Meier curves. Results: The distribution of the overall survival (OS) and progression-free survival (PFS) evaluations revealed that 84% (n=63) of the patients were deceased, and the progression rate was 94.7% (n=71). The median OS of the patients was 18 months, and the median PFS was 11 months. There was a statistically significant difference in overall survival in females, with a median OS of 25 months (95% CI 17–32 months) and a median OS of 13 months in males (95% CI 9–20 months) (P=0.008). PFS was 14.5 months (95% CI 11–21 months) in women and six months (95% CI 4–17 months) in men, and there was a statistically significant difference (P=0.02). A statistically significant difference was achieved between MCV values measured during diagnosis and the third month between age groups (P=0.044). Conclusion: The outcomes of this research suggest a statistically significant difference between the MCV values measured at the time of diagnosis and the third month regarding age groups. Both OS and PFS in women were statistically significantly higher than in men.

Fostamatinib: A Review in Chronic Immune Thrombocytopenia.

Fostamatinib (Tavalisse®; Tavlesse®) is the first spleen tyrosine kinase (Syk) inhibitor approved for the treatment of chronic immune thrombocytopenia (ITP) in adult patients who have had an insufficient response to previous treatment. By inhibiting Syk activation in macrophages, fostamatinib blocks autoantibody-mediated platelet phagocytosis. In the placebo-controlled phaseIII FIT1 and FIT2 trials, 24weeks of oral fostamatinib therapy increased platelet count in previously treated adults with ITP. A significantly higher proportion of patients achieved stable response with fostamatinib than with placebo in FIT1, but not in FIT2; however, pooled analyses of the two studies showed that fostamatinib produced significantly higher stable and overall response rates than placebo. Interim findings from the ongoing FIT3open-label extension study suggested that the efficacy of fostamatinib was maintained with long-term treatment (up to 62months; median duration 6months), including in patients receiving fostamatinib as second- or later-line treatment. Fostamatinib had a generally manageable tolerability profile in all three FIT studies, with no serious safety risks. Fostamatinib therefore provides an alternative treatment option for chronic ITP in adult patients with an insufficient response to previous treatment.

P174 Upadacitinib response rates in patients with psoriatic arthritis enrolled in the SELECT-PsA-1 and SELECT-PsA-2 trials assessed according to modified PsARC

P174 Upadacitinib response rates in patients with psoriatic arthritis enrolled in the SELECT-PsA-1 and SELECT-PsA-2 trials assessed according to modified PsARC

Partial reinforcement in rat autoshaping with a long CS: Effects of pramipexole and chlordiazepoxide on sign and goal tracking

Abstract In Pavlovian autoshaping, sign-tracking responses (lever pressing) to a conditioned stimulus (CS) are usually invigorated under partial reinforcement (PR) compared to continuous reinforcement (CR). This effect, called the PR acquisition effect (PRAE), can be interpreted in terms of increased incentive hope or frustration-induced drive derived from PR training. Incentive hope and frustration have been related to dopaminergic and GABAergic activity, respectively. We examined the within-trial dynamics of sign and goal tracking in rats exposed to 20-s-long lever presentations during autoshaping acquisition under PR vs. CR conditions under the effects of drugs tapping on dopamine and GABA activity. There was no evidence of the PRAE in these results, both groups showing high, stable sign-tracking response rates. However, the pharmacological treatments affected behavior as revealed in within-trial changes. The dopamine D2 receptor agonist pramipexole (0.4 mg/kg) suppressed lever pressing and magazine entries relative to saline controls in a within-subject design, but only in PR animals. The allosteric benzodiazepine chlordiazepoxide (5 mg/kg) failed to affect either sign or goal tracking in either CR or PR animals. These results emphasize the roles of dopamine and GABA receptors in autoshaping performance, but remain inconclusive with respect to incentive hope and frustration theories. Some aspects of within-trial changes in sign and goal tracking are consistent with a mixture of reward timing and response competition.

Various Aspects of Tiagabine Effectiveness as Add-on Therapy in Patients with Refractory Epilepsy.

The aim of the present study was to investigate various aspects of tiagabine (TGB) effectiveness in Bulgarian patients with drug-resistant epilepsy. This open, prospective study recruited the patients with epilepsy attending the Clinic of Neurology at the University Hospital of Plovdiv, Bulgaria. The patients completed diaries about the seizure frequency, severity, and adverse events. There were regular documented visits at 3 or 6 months during the first year of treatment with TGB and at 6 months or 1 year afterwards, with dynamic assessment of seizure frequency, severity, adverse events, and EEG recordings. TGB was applied as an add-on treatment in 43 patients (24 males, mean age 39 years). There was relatively mild and transient dynamic improvement of seizure severity, satisfactory seizure frequency reduction in 32.6% of participants, stable mean seizure frequency reduction (40-50%) from month 6 to month 24 and a stable response rate (52.3-50%) during the same period. New seizure types (myoclonic, myoclonic-atonic) occurred in 2 patients. The final clinical efficacy was higher in patients with initial monotherapy. There were adverse events (dizziness/vertigo, sedation, memory impairment, loss of appetite and weight, confusion, psychosis, insomnia, transient diplopia, lymphadenomegaly, rash, nausea, depression, anxiety, tremor of hands, unstable gait, legs edema, thrombocytopenia, cervical muscles tightening) in 26.19% of patients. In conclusion, TGB treatment is associated with low and transient improvement of seizure severity, good and stable improvement of seizure frequency, possible worsening of seizure control, possible appearance of new seizure types, and acceptable safety and tolerability.

Distance from the anal verge as an indirect measure to predict response to anti-EGFR therapy in left side metastatic colon cancer.

e15153 Background: Right and left sided colon cancers (RC, LC) differ with respect to biology and response to therapy. Several retrospective analyses have assessed the clinical effect of epidermal growth fator receptor (EGFR) targeted agents in patients with metastatic CRC (mCRC) according to the primary tumor location. Differentiating only right from left. But can in the LC responses differ according to the distance from the anal verge (DAV)? Methods: Exploratory retrospective analyses was planned to evaluate if LC responses differ according to the DAV. LC was defined as tumors originating anywhere from the distal rectum to the left colic flexure (splenic flexure). DAV was describe in cm measured by previous to surgery or treatment, colonoscopy, CT or MRI. Patients were divided for analysis purposes in two groups: Group A (tumors above 12cm from de anal verge), Group B (tumors below 12cm from the anal verge). Results: We retrospectively evaluated 29 patients with left metastatic colorectal cancer treated with anti-EGFR therapy as part of their treatment at the Paulistano Hospital -São Paulo from 2011 to 2018. Median population age 51.8 years (48.5-62.3). Median DAV 14.5 (4.6-25 cm). Median follow-up 12.8 months. No significant difference on stable and partial response rate was detected (Group A 43.7% vs Gropup B 56.3%), p=0.211. Long-rank test with a median pFS 8,5 meses and a PFS at 6 months of 66.7 vs 78,8 (Group A and Group B respectively ), p=0.901. Two-year OS was 58.4 % in Group A and 100% in Group B, p=0.17. Conclusions: Although no significant diferences were detected, responses rates were numerically higher in patients with tumors located below 12 cm from the anal verge. Further studies are needed to evaluate the association between response and DAV.

Measuring the survey climate: the Flemish case

Researchers in several countries have regularly reported decreasing response rates for surveys and the need for increased efforts in order to attain an acceptable response rate: two things that can be seen as signs of a worsening survey climate. At the same time, differences between countries and surveys with regard to the actual level and evolution of response rates have also been noted. Some of these differences are probably linked to differences in the survey content or design. This may hinder the study of the evolving survey climate over time, based on different surveys in different countries, because more readily comparable conditions are desirable. An optimal opportunity for describing the changing survey climate is offered by the Survey of Social-Cultural Changes in Flanders. We analyse yearly data from 1996 to 2013 to examine the evolution of several survey climate indicators. Some indicators reveal a declining survey climate, such as an increased refusal rate and a greater number of contact attempts per respondent. Other indicators reveal a stable survey climate, such as a stable response rate and respondents’ positive, stable attitude towards surveys. Results show that, within the same survey, one can compensate for negative evolution by increasing the efforts made to ensure completed interviews.

Anabolic–androgenic steroids and appetitive sexual behavior in male rats

Anabolic–androgenic steroids (AAS) increase libido and sexual behavior, but the underlying behavioral mechanisms are unclear. One way AAS may enhance expression of sexual behavior is by increasing the willingness to work for sex. In the present study, sexually-experienced male rats received daily injections of testosterone at supraphysiologic doses (7.5mg/kg in water with 13% cyclodextrin) or vehicle and were tested for appetitive sexual behavior measured by operant responding for access to an estrous female. Initially, rats were trained in their home cage to respond on a nose-poke under a 10-min fixed-interval schedule for food reward. Once rats achieved stable response rates, the food was replaced by a female, followed by mating for 10min. There was no effect of testosterone on operant responding for food (28.1±4.4 responses/10min for testosterone, 30.6±4.3 for vehicle) or sex (35.0±4.0 responses/10min for testosterone, 37.3±5.2 for vehicle). However, rats made significantly more responses for sex than for food (p<0.05), and responses for food and sex were positively correlated among individuals (R2=0.6). Additional groups of rats were trained to respond on a lever for the female under a 2nd-order schedule of reinforcement, where 5 responses opened a door to show the female for 5s. After 15 door openings, the male gained access to the female. There was no effect of testosterone on time to complete 75 responses: 38.4±7.8min for vehicle controls vs 43.3±6.6min for testosterone-treated rats (p>0.05). These findings suggest that chronic high-dose testosterone does not enhance appetitive drive for sexual behavior.

EFFECTS OF DIFFERING RESPONSE‐FORCE REQUIREMENTS ON FOOD‐MAINTAINED RESPONDING IN C57BL/6J MICE

The effect of force requirements on response effort was examined using inbred C57BL/6J mice trained to press a disk with their snout. Lateral peak forces greater than 2 g were defined as responses (i.e., all responses above the measurement threshold). Different, higher force requirements were used to define criterion responses (a subclass of all responses) that exceeded the requirement and produced a reinforcer. The reinforcer was sweetened, condensed milk, delivered upon response termination. All mice were exposed to two ascending series of criterion force requirements (2, 4, 8, 16, and 32 g). Increasing the force requirement initially decreased criterion response rates, but criterion response rates recovered with continued exposure, except at the 32-g requirement. Response rates for all measured responses initially increased with increasing force requirements, but then decreased with continued exposure. The second exposure series produced more stable response rate changes than the first series. The time-integral of force (area under the force-time curve for individual responses, which is proportional to energy expenditure for each response) increased with the increase in the force requirement. The C57BL/6J inbred strain generated average force output similar to CD-1 outbred stock mice trained on the same force requirements. C57BL/6J inbred strain mice differed from CD-1 mice in initial response rates (for all responses above threshold) and had lower response rates at the 16 and 32 g requirements resulting in lower total force output. These data show for both mice types that increased force requirements resulted in increased overall responding (all measured responses), which contradicts a punishment interpretation of criterion response decrements. C57BL\6 inbred mice showed individual differences comparable to the outbred CD-1 stock. C57BL/6 mice did not maintain responding as well at the higher force requirements, which may be due to their small body size and weight, compared to the larger and heavier CD-1 mice.

Persistent Increase of Alcohol-Seeking Evoked by Neuropeptide S: an Effect Mediated by the Hypothalamic Hypocretin System

The association of ethanol's reinforcing effects with specific environmental stimuli is thought to be a critical factor for relapse risk in alcoholism. This study examined in rats the effects of a newly deorphanized neuropeptide receptor and its cognate ligand, Neuropeptide S (NPS), on ethanol consumption and reinstatement of ethanol-seeking by environmental cues previously associated with ethanol availability. In the self-administration experiments, the stable response rates observed for ethanol reinforcement were not modified by intracerebroventricular (ICV) injection of NPS (1.0 and 2.0 nmol per rat). In the reinstatement experiments, ethanol-associated cues induced robust rates of ethanol seeking, which were highly resistant to extinction over repeated sessions of reinstatement testing. ICV NPS treatment (1.0, 2.0 and 4.0 nmol per rat) resulted in a significant increase of ethanol seeking elicited by ethanol-associated cues. In contrast, NPS did not affect the reinstatement of responding to water-paired stimuli. Site-specific NPS injection (0.1 and 0.5 nmol per rat) into the lateral hypothalamus also reinstated extinguished responding to ethanol. This effect was selectively blocked by pre-treatment with the hypocretin-1/orexin-A antagonist SB-334867 (10 mg/kg, i.p.). At the dose tested, SB-334867 did not modify alcohol reinstatement per se. These results provide the first demonstration that activation of NPS receptors in the LH intensifies relapse to ethanol-seeking elicited by environmental conditioning factors. This effect is selective, and is mediated by activation of LH hypocretin neurones. Based on the present findings, we also predict that antagonism at NPS receptors could represent a novel pharmacological approach to alcohol relapse treatment.

Effects of nicotine withdrawal on performance under a progressive-ratio schedule of sucrose pellet delivery in rats

Although numerous studies have examined the motivational effects of nicotine withdrawal using intracranial self-stimulation (ICSS) threshold assays, relatively few have employed other methods for assessing motivation that use naturally reinforcing stimuli (e.g., food). The objective of the present study was to determine the effects of nicotine withdrawal on motivation using a progressive-ratio (PR) schedule of sucrose pellet delivery. Rats were trained to respond for sucrose pellets under a PR schedule. When stable breaking points and response rates were achieved, PR sessions were suspended and rats were exposed to a continuous infusion of saline or nicotine (3.2 or 8.0 mg/kg/day of the base) via subcutaneous osmotic minipump for nine days. On day nine, pumps were removed. PR sessions resumed 22 h later and continued daily for five consecutive days. Only rats exposed to 8.0 mg/kg/day nicotine exhibited a significant decrease in breaking point and overall response rate compared to saline-exposed rats on day one of nicotine withdrawal. These rats also showed an increasing trend in breaking point and overall response rate over the course of withdrawal, such that these measures were significantly increased on day five of withdrawal compared to baseline. Response rates under each ratio in the PR progression in rats exposed to 8.0 mg/kg/day did not differ from baseline or from those in saline-treated rats, suggesting suppression of breaking points and overall response rates were not attributable to nonspecific motor impairment. In addition, changes in performance throughout the protocol were not associated with changes in body weight. Consistent with findings from ICSS studies, the present study demonstrates that nicotine withdrawal can produce a motivational deficit as indexed under a PR schedule. However, in contrast to ICSS, PR performance appears to be sensitive to increases in motivation late in the withdrawal period. Therefore, PR schedules of natural reinforcement may provide information on the motivational effects of nicotine withdrawal complimentary to that obtained from ICSS threshold studies.

Sensitivity and Strength: Effects Of Instructions on Resistance to Change

Several research laboratories have found that instructed behavior can be less sensitive to changes in contingencies than shaped behavior. The current experiment examined whether these differences in sensitivity could be related to resistance to change. Two groups of subjects, who were matched on the basis of an initial disruption assessment, were exposed to a variable-interval 30-s schedule of reinforcement with and without a disrupter. The disrupter was a video presentation of a popular television situation comedy. One group received minimal instructions (MI) that told them only that they could earn points exchangeable for money. Each member of the second group received a complete instruction (CI) that described the topography of the target response that was yoked to a MI subject’s stable baseline response rate. The response rates under the disruption condition for the CI subjects were more resistant to change than the MI subjects in 14 out of 15 disruption sessions. These findings are discussed in terms of resistance to change being increased by instructional conditions like those manipulated and that the procedures used to test disruption provide an additional method to !waluate differences between instructed and contingency-governed behavior.

Efficacy and safety of gefitinib in chemo-naive patients with non-small cell lung cancer (NSCLC) in an expanded access program (EAP)

7094 Background: Patients (pts) with advanced NSCLC who cannot tolerate or refuse chemotherapy (CT) have few or no treatment options. The EGFR-TKI gefitinib (Iressa) has antitumor activity and favorable tolerability in pts with recurrent advanced NSCLC. A global EAP made gefitinib available to >37,000 pts with NSCLC who had failed standard treatment or were ineligible for or refused cytotoxic CT. Methods: Retrospective chart review of 1671 pts enrolled at 11 sites in the US EAP identified 198 pts (89 men, 109 women, median age 72.7 y [range 37.8–89.9 y]) who had not received prior CT for advanced NSCLC. Pts received 250 mg/d gefitinib until treatment failure or undue toxicity. Outcomes analyzed included clinical response, survival, and adverse events (AEs). Results: Reasons for enrollment were disease progression (57.6%), CT intolerance (22.2%), significant comorbidity (21.7%), and CT refusal (21%). Predominant (66%) histology was adenocarcinoma, 16.2% with bronchioloalveolar subtype: 186 pts (93.9%) had stage III/IV disease, 3 (1.5%) were stage I/II, and 9 (4.5%) had no staging data recorded. Fifty-six (28.3%) patients had ECOG performance status (PS) ≥2. Although PS was not recorded for 69 (34.8%) pts, at enrollment 60% were nonambulatory, 15.2% required oxygen, and 4% were in a hospice. Median survival was 6 months (95% CI, 5–8 mo); estimated 1-year survival rate was 29.7% (95% CI, 22.1–37.3%). In 142 (72.2%) pts with ≥1 imaging study postenrollment, complete, partial, and stable response rates were 0.7%, 5.6%, and 40.6%, respectively. Most common AEs were diarrhea (31.3%), rash (31.3%), asthenia (15.7%), anorexia (11.6%), and nausea (11.1%). Mean treatment duration was 4.7 months (range 0.1–26 mo). Post-EAP treatment data were available for 157 (79.3%) pts: 36 (22.9%) of this group went on to further treatment, 25 received CT, and 11 received radiation therapy. Conclusions: Oral gefitinib was well tolerated and effective in this unselected population of chemo-naive pts with NSCLC who were unsuitable for or refused CT. Median and 1-year survival were significantly better than with best supportive care alone and similar to CT, with substantially less toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, Ligand Amgen, AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly, Genentech, Merck, Pfizer Amgen, AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly, Genentech, Genta, Ligand, Pfizer AstraZeneca Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly

Capacitive-type gas sensors combining silicon semiconductor and NaNO 2-based solid electrolyte for NO 2 detection

A capacitive-type NO 2 gas sensor, developed by replacing metal in metal–insulator–semiconductor structure with solid electrolyte as sensing material, was investigated to improve the response and recovery rates and the operating temperature by modifying NaNO 2-sensing material. Binary sensing materials of NaNO 2–Ca 3(PO 4) 2 and NaNO 2–WO 3 were tested for auxiliary phase of the device. The Ca 3(PO 4) 2-containing phase showed a response closer to ideal Nernstian behavior at 140 °C as compared to WO 3-containing phase. On the other hand, the WO 3-containing phase showed faster response and recovery rates at 160 °C, while the response deviated from Nernstian correlation. In order to obtain optimum sensor response, a ternary phase of NaNO 2–Ca 3(PO 4) 2–WO 3 was used as sensing phase. The device with ternary auxiliary phase was found to show more stable and faster response and recovery rates at 130 °C, as compared to previous devices attached with binary phases, corresponding Nernstian correlation in the concentration range of 20–500 ppb NO 2. Furthermore, the effects of modification process on the auxiliary phase were investigated through SEM observation of the surface structures and measurement of ionic conductivity.

Avoidance of Time-Out From Response-Independent Food Presentation: Effects of Chlordiazepoxide and Buspirone

VAN HAAREN, F. AND K. G. ANDERSON. Avoidance of time-out from response- independent food presentation: Effects of chlordiazepoxide and buspirone. PHARMACOL BIOCHEM BEHAV 61(2) 207–214, 1998.—Five male Wistar rats were exposed to a two- component multiple schedule. In one component, signaled by a tone, food pellets were presented on a random-time 120-s schedule. In the other component, food pellets were presented on a random-time 30-s schedule. Pellets were only presented during a 10-s time-in period that alternated with a 50-s time-out period, unless the subject pressed a lever to postpone time-out presentation by 20 s. Response-independent food pellets were never presented within 2 s of this avoidance response. For most subjects avoidance rates were consistently higher when response-independent food pellets were delivered infrequently than when they were delivered more often. The amount of time spent in time-in varied considerably between subjects but was not consistently related to the frequency of response-independent pellet presentation. Once stable response rates were established subjects were intraperitoneally injected with different doses of chlordiazepoxide (1, 3, 10, 17, or 30 mg/kg) or buspirone (0.1, 0.3, 1.0, 1.7, 3.0, or 4.2 mg/kg). Low doses of chlordiazepoxide either did not affect or slightly increased avoidance response rates, whereas higher doses (10 mg/kg and up) produced a dose-dependent decrease in avoidance responding. The time subjects spent in the presence of stimuli associated with the availability of response-independent food either did not change or increased slightly after the lower doses of chlordiazepoxide, while it decreased dose dependently following the higher doses. Low doses of buspirone increased avoidance rates in subjects first exposed to chlordiazepoxide, but did not alter rates in the remaining subjects. Intermediate doses of buspirone decreased avoidance rates more in the component with the lower frequency of pellet presentation, higher doses further decreased response rates. The amount of time spent in the presence of stimuli associated with pellet presentation was minimally affected by the lower doses of buspirone, but decreased dose dependently following the higher doses. The results of this experiment add further credence to the notion that the behavioral effects of drug administration may depend on nonpharmacological variables including, but not limited to, the nature of the consequent event.

Withdrawal from IV cocaine "binges" in rats: ultrasonic distress calls and startle

Human cocaine abusers report that they experience intense anxiety during withdrawal from chronic use or "binging". Because the symptoms of cocaine withdrawal are not easily observed, it has been difficult to develop an adequate animal model for cocaine withdrawal that detects anxiety-like behavior. The objective of the present study was to examine the effects of continuous access to i.v. self-administered cocaine on ultrasonic vocalizations (USVs) induced by startling tactile stimuli as a possible animal model for cocaine withdrawal. Five days after implantation of a jugular catheter, rats were placed into self-administration chambers with access to cocaine (0.25 mg/infusion). Once the animal had a stable response rate over 3 days, on a fixed schedule of reinforcement (FR5), they were given unlimited access to cocaine (0.25 mg/infusion) for 48 or 12 h. Subsequently, animals were exposed to 18 air puffs (20 or 10 psi) at 6, 24, 72 h, 7 and 14 days after the "binge". Rats that self-administered cocaine for 48 h and were subsequently startled with 20 psi stimuli increased the number of automatically recorded ultrasonic distress calls and showed an enhanced startle response at 6 h after the last cocaine infusion when compared to handled controls. Animals that self-administered cocaine for 48 h and were subsequently startled with 10 psi stimuli showed increased USVs and an enhanced startle reflex at both 6 and 24 h after the unlimited access. Animals that self-administered cocaine for 12 h also showed an increase in ultrasonic distress calls and enhanced startle responses to 10 psi tactile stimuli when compared to handled controls. USVs during cocaine withdrawal may be interpreted to reflect affective distress during the first 24 h after the last cocaine infusion of 12 or 48 of continuous access to drug.

Current Issues in Cancer: Multiple myeloma

Multiple myeloma occurs in over 2000 new patients in England and Wales each year. It presents most frequently as bone pain and patients tend to become dehydrated and may develop renal failure. No available treatment is curative, but about two thirds of patients achieve a stable response with low dose combination chemotherapy. Combination chemotherapy including doxorubicin and carmustine with the alkylating agents cyclophosphamide and melphalan achieve a higher stable response rate than conventional treatment with melphalan and prednisone without additional haematological toxicity. These responses are associated with loss of bone pain and patients remain symptom free for months without further treatment. Relapse occurs on average in a little under two years and, though second responses are frequently obtained, the disease eventually becomes refractory. This paper looks at who should be treated and the benefits that may be expected from the treatments available.

Post training lysine-vasopressin injections increase conditioned suppression in rats

Male rats were trained to lever press for food reward on a variable interval schedule of reinforcement. When stable response rates had been achieved they were trained to avoid footshock (UCS) in a two way shuttle box using a compound conditioning stimulus (CS) of tone and light. Having reached the learning criterion of ten consecutive avoidance responses they were returned to their home cage and injected with saline or lysine vasopressin (LVP 1 μg/rat/SC) after 30 min. Twenty four hours later, the suppressive effect of the avoidance CS on the appetitive baseline was tested. Rats which had been injected with LVP after avoidance training showed significantly more suppression of the operant response than saline controls. The results are discussed in terms of the behavioural substrate underlying the long term effects of vasopressin on behaviour.