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Introduction: The concept of sensory processing sensitivity (SPS) was first introduced by Aron and Aron (1996) as an innate trait characterized by heightened processing of sensory, emotional, and physical stimuli. Since the concept's introduction in 1996, high SPS has been shown to be associated with poor physical and mental health. It is possible that this is especially true in university students, who are frequently faced with numerous stressors, such as intense workloads and test anxiety., Methods: This article is a systematic literature review conducted through EBSCOHost using the following databases: Academic Search Complete, APA PsycArticles, APA PsycInfo, Education Research Complete, ERIC, MEDLINE Complete, and SocINDEX. Search terms included terms regarding high sensory processing sensitivity, university or professional students, and mental health., Results: A total of 6 studies were included. University students with high SPS experienced heightened reactions to sensory, emotional, and physical stimuli. The studies demonstrate correlations of high SPS with outcomes such as depressive tendencies and difficulty adjusting to college., Discussion: These findings highlight that SPS is associated with poor mental health outcomes. The results underscore the importance of developing support methods for students with high SPS. Future studies should further explore SPS in university students to develop targeted support methods and programs., (© 2024 AAPP. The Mental Health Clinician is a publication of the American Association of Psychiatric Pharmacists.)

Objective: The aim of this study is to determine the effects of enhanced external counterpulsation (EECP) in patients with long COVID and objectively assessed cognitive impairment., Design: A retrospective evaluation of long COVID patients referred for EECP, with cognitive sequela, and having completed an objective digital assessment before and after therapy. Patients had either cognitive impairment or no cognitive impairment at baseline. We assessed changes in composite score using multifactor analysis of variance. Multiple linear and logistic regression analyses were conducted to evaluate several independent variables., Results: Eighty long COVID patients (38 cognitive impairment vs. 42 no cognitive impairment) were included for analyses. All baseline characteristics were well matched. There was significant improvement in composite score post EECP in those with objective cognitive impairment at baseline. There were no notable documented safety concerns., Conclusions: This is the first study showing that EECP led to significant improvement in cognitive functioning of long COVID patients with objectively defined cognitive impairment. Although a lack of a negative control group is a limitation of this study, EECP seems to be highly safe and effective with the potential for widespread application., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The COVID-19 pandemic has markedly affected academic and administrative facets of pharmacy education. However, to date, no study has systematically summarized pandemic-related changes at pharmacy schools across the United States. This study aimed to evaluate US pharmacy school faculty and administrators' perspectives on the pandemic's impact on pharmacy academia., Methods: A web-based survey was sent to US pharmacy school faculty and administrators in August 2020. The survey included questions assessing the pandemic's impact on the faculty's teaching, the school's financial status, administrative aspects, and mental well-being of faculty and administrators. Descriptive statistics and 1-sample Z tests were used for conducting statistical analyses., Results: The survey was sent to 6177 individuals, of whom 1068 participated (17.3% response rate). In total, 931 respondents (759 faculty and 172 administrators) completed the entire survey. Both faculty and administrators experienced increased workload while their mental health and job satisfaction declined. Faculty's teaching satisfaction, research productivity, and service activity worsened. Administrators identified decreases in revenue sources and increases in expenses associated with the pandemic. Administrators also indicated the negative impact of the pandemic on an array of administrative and academic aspects within their pharmacy schools. The qualitative analysis identified several overlapping themes highlighting the negative effects of the pandemic on the faculty's teaching., Conclusion: Present findings indicate the negative effects of the COVID-19 pandemic on a variety of academic and administrative aspects at US pharmacy schools. These findings could provide useful information to stakeholders in pharmacy academia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)

Objective: Mental health education can reduce the stigma held by medical and nursing students; however, findings in this regard are limited in pharmacy academia. This study investigated the impact of a neuropsychiatric therapeutics course followed by a case-based course on the mental health stigma held by pharmacy students., Methods: A survey was conducted of second-year pharmacy students (n = 202) on the first and last day of a neuropsychiatric therapeutics course and 4 months later, at the end of a case-based course. The questionnaires included the Opening Minds Stigma Scale for HealthCare Providers (OMS-HC) scale, Recovery scale, Empowerment scale, and Attribution Questionnaire (AQ-9). Omnibus Friedman tests evaluated the main effect of time, followed by Wilcoxon signed-rank post hoc tests to compare baseline and postcourse scores., Results: Friedman test outcomes showed significant main effects of Time for OMS-HC, Recovery, Empowerment, and AQ-9 scales. Post hoc analysis indicated that compared to the baseline scores, the scores on Recovery and Empowerment scales significantly increased, OMS-HC scores decreased, but AQ-9 scores did not change after the therapeutics course. Compared to the baseline, OMS-HC and AQ-9 scores decreased, Recovery scale score increased, but the Empowerment scale score did not change after the case-based course. The scores did not decrease further after the case-based course compared to those after the therapeutics course., Conclusion: The decreases in OMS-HC and AQ-9 scores and increases in Recovery and Empowerment scores indicate reductions in mental health stigma. Stigma among students was overall reduced after the therapeutics course and this reduction was maintained after the case-based course., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)

Objective: The present study identified common motives for nonmedical use of prescription stimulants (NMUS) among community college (CC) students and examined behavioral and demographic correlates of certain motives. Participants: The survey was completed by 3,113 CC students (72.4% female; 81.7% White). Methods: Survey results from 10 CCs were evaluated. Results: NMUS was reported by 9% ( n  = 269) participants. The most common motive for NMUS was to "focus on studies or to improve academic performance" (67.5%) followed by to "have more energy" (52.4%). Females were more likely to report NMUS for weight loss, and males were more likely to report NMUS to experiment. The motive "to feel good or get high" was linked to polysubstance use. Conclusions: CC students report similar motives for NMUS to those commonly endorsed by 4-year university students. These findings may help identify CC students susceptible to risky substance use.

Introduction: Postgraduate pharmacy residency and fellowship positions have remained competitive. We evaluated factors predicting students' pursuit and attainment of postgraduate pharmacy training positions., Methods: A web-based survey was administered to students from a three-year accelerated pharmacy program. The survey asked questions regarding the participants' demographics, cumulative academic pharmacy grade point average (GPA), school leadership positions in organizations or committees, and research activities. Students' resilience was measured by the Academic Pharmacy Resilience Scale questionnaire. Multiple logistic regression was used to determine variables that predicted the pursuit and attainment of residency positions., Results: The survey response rate was 46.7%. Students with greater cumulative GPA (odds ratio [OR] 6.3; 95% CI, 2.25-17.68), research experience (OR 3.3; 95% CI, 1.29-8.45), resilience scores (OR 1.07; 95% CI, 1.03-1.12), and leadership in an organization (OR 3.27; 95% CI, 1.46-7.33) or school committee (OR 2.29; 95% CI, 1.04-5.07) were more likely to apply to a residency program. Students with greater cumulative GPA (OR 9.93; 95% CI, 1.33-74.23), self-rated performance score in the residency interview (OR 5.32; 95% CI, 2.47-11.44), and leadership experience on a school committee (OR 15.37; 95% CI, 3.94-59.93) were more likely to match with a residency program. The average scores on interview performance and networking were significantly higher in students who obtained a fellowship position compared to those who did not obtain that., Conclusions: This study identified several predictors for the pursuit and attainment of residency or fellowship positions, which could inform pharmacy educators, students, and program directors., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Postoperative pain management solely with opioids elevates the risk of opioid-related adverse events during hospitalization and after discharge from the hospital. Clinical trials have demonstrated gabapentinoids as viable adjunctive treatments for spinal surgeries. However, only a few practice-based studies have examined the efficacy of gabapentin as an opioid-sparing agent for patients undergoing lumbar laminectomy in rural hospital settings., Objective: To determine the effects of gabapentin on opioid consumption and pain perception in patients who underwent lumbar laminectomy at a rural community hospital., Methods: Data were collected by retrospective chart reviews of 99 patients who underwent lumbar laminectomy at Yavapai Regional Medical Center from January 1, 2017, to July 1, 2019. The patients were stratified into 2 groups: those who were taking gabapentin as outpatients before surgery and were continued on the same dose postoperatively (n = 50, gabapentin group) and those who were not taking gabapentin preoperatively or postoperatively (n = 49, usual-treatment group). The primary end points were opioid consumption in morphine milligram equivalents (MME) and pain for 24 hours postsurgery., Results: Outcomes from the mixed-model analysis of variance showed significant main effects of group and time for opioid consumption in MME (F 1,97  = 4.3, P < 0.05 and F 3,291  = 133.9, P < 0.001, respectively) and numerical pain scale scores (F 1,99  = 4.0, P < 0.05 and F 3,241  = 21.4, P < 0.001, respectively) and group-time interaction for opioid consumption in MME (F 3,291  = 2.6, P = 0.05). Post hoc analyses showed that opioid consumption in MME was significantly lower in the gabapentin group than in the usual-treatment group for the first 6 hours postoperatively. The pain scores were significantly lower in the gabapentin group than in the usual-treatment group across all time periods., Conclusion: Patients on gabapentin showed reductions in pain perception and postoperative opioid consumption. The results extend the findings from randomized trials to a real-world clinical setting. These data support using gabapentin in conjunction with opioids for pain management of patients undergoing lumbar laminectomy., (Copyright © 2021 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study is to determine whether certain personality traits are as prominent in pharmacy practice residents who obtain positions through the post-Match process, previously referred to as the Scramble, as compared to residents who match directly with programs., Methods: Pharmacy residency program directors (RPDs) across the United States were asked to complete an electronic survey that gauged RPD perceptions of 13 personality traits commonly seen in pharmacy residents. RPDs were requested to separately evaluate residents who Scrambled and Matched to their respective programs. Exploratory factor analysis (EFA) was used to determine factor structure for the personality traits and to assess whether factors associate differentially between Matched and Scrambled residents., Results: A total of 1876 RPDs of post-graduate year one (PGY1), post-graduate year two (PGY2), and combined PGY1 and PGY2 pharmacy residency programs were contacted for study participation with a response rate of 21 percent. Demographic variables related to program type and number of residents per class were similar between Scrambled and Matched groups. The EFA identified two factors across 13 traits: we termed them as traditional traits and grit-like traits, and they significantly differed between the Scramble and Match groups. RPD perception of traditional traits (nine traits) were significantly higher in the Match group (p < 0.05), whereas perceived grit-like traits (four traits) were significantly higher in the Scramble group (p < 0.0001)., Conclusion: Residency candidates who Match versus candidates who Scramble are perceived to have unique and significantly different personality traits., (Published by Elsevier Inc.)

Background: Methamphetamine (MA) use disorders are major public health problems nationally and worldwide and treatment remains an unmet need., Objectives: (1) To review preclinical and clinical studies identifying the dopamine D3 receptor as a therapeutic target for substance use disorders (SUDs), including MA dependence, (2) to consider buspirone (Buspar®) as a potential medication based on its dopamine D3 receptor antagonist properties, and (3) to evaluate the safety and initial efficacy of buspirone in a pilot study of MA-dependent individuals., Methods: Literature on the dopamine D3 receptor as a therapeutic target and on the potential of buspirone as a novel therapy for MA dependence was reviewed. The cardiovascular and subjective effects of intravenous MA challenge were assessed in five non-treatment seeking individuals. Participants met DSM-IV criteria for MA dependence and were treated subacutely (9 days) with buspirone (60 mg daily)., Results: The literature identified the dopamine D3 receptor as a therapeutic target for MA dependence, a safe and approved medication, and a valuable opportunity to re-purpose buspirone for treating MA dependence and perhaps other SUDs. Pilot data (n = 5) indicated that buspirone is safe in MA-using individuals and comparison against historical placebo data from this laboratory suggested that at least some aspects of the subjective properties of MA may be diminished during buspirone treatment., Conclusion: Future studies should include a small-scale, placebo-controlled Phase IIa trial of buspirone in MA dependence.

Methamphetamine use disorders remain a significant public health concern. Methamphetamine produces its behavioral effects by facilitating release of monoamines like dopamine (DA) and serotonin (5-HT). Results from animal studies show that acute pretreatment with DA and 5-HT antagonists attenuates the effects of methamphetamine, but this area remains largely unexplored in humans. This study sought to assess whether aripiprazole, a partial agonist at D2/5-HT1A receptors and an antagonist at 5-HT2A receptors, would attenuate the reinforcing and subject-rated effects of oral methamphetamine. Seven subjects with histories of recreational stimulant use completed a placebo-controlled, crossover, double-blind protocol in which they first sampled doses of oral methamphetamine (0, 4, 8 or 16 mg) following acute pretreatment with aripiprazole (0 and 15 mg). During each Sampling Session, subjects also completed a battery of subject-rated, cardiovascular, and other performance measures. In subsequent Self-Administration Sessions, subjects were provided the opportunity to earn the previously sampled methamphetamine dose on a progressive-ratio procedure. Methamphetamine functioned as a reinforcer, and produced prototypical stimulant-like subject-rated and cardiovascular effects (e.g., increased ratings of Stimulated; elevated blood pressure). Aripiprazole reduced methamphetamine self-administration and attenuated some of the positive subject-rated effects of methamphetamine (e.g., ratings of Like Drug). These results indicate that acute aripiprazole pretreatment attenuates the abuse-related effects of methamphetamine., (© 2013.)

Objective: Individuals who are methamphetamine dependent exhibit higher rates of cognitive dysfunction than healthy people who do not use methamphetamine, and this dysfunction may have a negative effect on the success of behavioral treatments for the disorder. Therefore, a medication that improves cognition, such as modafinil (Provigil), may serve as a useful adjunct to behavioral treatments for methamphetamine dependence. Although cognitive-enhancing effects of modafinil have been reported in several populations, little is known about the effects of modafinil in methamphetamine-dependent individuals. We thus sought to evaluate the effects of modafinil on the cognitive performance of methamphetamine-dependent and healthy individuals., Method: Seventeen healthy subjects and 24 methamphetamine- dependent subjects participated in this randomized, double-blind, placebo-controlled, crossover study. Effects of modafinil (200 mg, single oral dose) were assessed on participants' performance on tests of inhibitory control, working memory, and processing speed/attention., Results: Across subjects, modafinil improved performance on a test of sustained attention, with no significant improvement on any other cognitive tests. However, within the methamphetamine-dependent group only, participants with a high baseline frequency of methamphetamine use demonstrated a greater effect of modafinil on tests of inhibitory control and processing speed than those participants with low baseline use of methamphetamine., Conclusions: Although modafinil produced limited effects across all participants, methamphetamine-dependent participants with a high baseline use of methamphetamine demonstrated significant cognitive improvement on modafinil relative to those with low baseline methamphetamine use. These results add to the findings from a clinical trial that suggested that modafinil may be particularly useful in methamphetamine-dependent subjects who use the drug frequently.

Methamphetamine is thought to produce its behavioral effects by facilitating release of dopamine, serotonin (5-HT) and norepinephrine. Results from animal studies support this notion, whereas results from human laboratory studies have not consistently demonstrated the importance of monoamine systems in the behavioral effects of methamphetamine. Human drug-discrimination procedures are well suited to assess neuropharmacological mechanisms of the training drug by studying pharmacological manipulation. In this human laboratory study, 6 participants with a history of recreational stimulant use learned to discriminate 10 mg oral methamphetamine. After acquiring the discrimination (ie, ≥ 80% correct responding on 4 consecutive sessions), the effects of a range of doses of methamphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with 0 and 20 mg aripiprazole (a partial agonist at D2 and 5-HT1A receptors), were assessed. Methamphetamine alone functioned as a discriminative stimulus, produced prototypical stimulant-like subject-rated drug effects (eg, increased ratings of Good Effects, Talkative-Friendly, and Willing to Pay For) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion methamphetamine-appropriate responding or produce subject-rated effects but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of methamphetamine, as well as some of the subject-rated drug effects. These results indicate that monoamine systems likely play a role in the behavioral effects of methamphetamine in humans. Moreover, given the concordance between past results with d-amphetamine and the present findings, d-amphetamine can likely serve as a model for the pharmacological effects of methamphetamine.

Progressive-ratio schedules are useful for studying the reinforcing effects of drugs. Earlier human laboratory studies showed that d-amphetamine significantly increased break points relative to placebo. However, the magnitude of the increase was modest, which may be attributable to rather high levels of placebo responding. We used novel response requirements in a modified progressive-ratio procedure and hypothesized that the altered range of response requirements would decrease responding for placebo and increase responding for d-amphetamine. Eight participants completed the study. The participants first sampled oral doses of d-amphetamine (0, 8, 16, and 24 mg). In subsequent sessions, the participants were offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure with response requirements ranging from 400 to 1800 mouse clicks. A battery of participant-rated drug-effect questionnaires, a performance measure, and cardiovascular measures were included to more fully characterize the effects of d-amphetamine. Placebo maintained low levels of responding. The intermediate dose of d-amphetamine increased responding significantly above placebo levels. d-Amphetamine produced prototypical subject-rated effects that were an orderly function of dose. These data suggest that the modified response requirements resulted in lower levels of placebo taking and a larger separation between the number of placebo and d-amphetamine capsules earned.

Objective: Several studies suggest a link between stimulant abuse and attention-deficit hyperactivity disorder (ADHD) symptoms (e.g., inattention and hyperactivity). To further assess the nature of this relationship, the present study examined the association between subclinical symptoms of inattention and hyperactivity and the behavioral effects of d-amphetamine., Methods: Participants were classified into a High- (n = 8) or Low-Score (n = 9) group based on their responses on a rating scale that assessed inattention and hyperactivity symptoms., Results: The participants did not differ across the High-Score and Low-Score groups in their ability to discriminate d-amphetamine. The participants in the High-Score group were significantly more sensitive to the positive participant-rated effects of d-amphetamine (e.g., Good Effects, Like Drug), but less sensitive to drug-induced increases in blood pressure and heart rate., Conclusion: The selective increase in positive subjective effects of d-amphetamine suggests that individuals with subclinical inattention and hyperactivity symptoms may have increased vulnerability to stimulant abuse.

The results of preclinical laboratory experiments and clinical trials indicate that agonist replacements such as d-amphetamine may be a viable option for managing cocaine dependence. This study determined the effects of d-amphetamine maintenance on cocaine choice behavior in human participants. We predicted that d-amphetamine maintenance would reduce cocaine choice. Nine cocaine-dependent participants completed the study. Two d-amphetamine maintenance conditions were completed in a counterbalanced order (0 and 40 mg/d). After 3 to 5 days of placebo or d-amphetamine maintenance, the participants completed 5 experimental sessions. During these sessions, the participants first sampled the placebo (ie, 4 mg of intranasal cocaine) identified as drug A. The participants then sampled a second intranasal drug dose (4, 10, 20, or 30 mg of cocaine) identified as drug B. The participants then made 6 discrete choices between drugs A and B. Drug choices were separated by 45 minutes. The primary outcome measure was the number of cocaine choices. All doses of cocaine were chosen significantly more than placebo during both maintenance conditions (ie, placebo and d-amphetamine). Choice of the 20-mg dose of cocaine was significantly lower during d-amphetamine maintenance relative to when this cocaine dose was tested during placebo-d-amphetamine maintenance. Cocaine produced prototypical subject-rated drug effects (eg, good effects, like drug, willing to take again). These effects were not altered to a significant degree by d-amphetamine maintenance. Cocaine was well tolerated during D-amphetamine maintenance, and no unexpected or serious adverse events occurred. These results are concordant with those of previous preclinical experiments, human laboratory studies, and clinical trials that suggest that agonist replacement therapy may be a viable strategy for managing cocaine dependence.

Despite the worldwide extent of methamphetamine dependence, no medication has been shown to effectively treat afflicted individuals. One relatively unexplored approach is modulation of cholinergic system function. Animal research suggests that enhancement of central cholinergic activity, possibly at nicotinic acetylcholine receptors (nAChRs), can reduce methamphetamine-related behaviors. Further, preliminary findings indicate that rivastigmine, a cholinesterase inhibitor, may reduce craving for methamphetamine after administration of the drug in human subjects. We therefore performed a double-blind, placebo-controlled, crossover pilot study of the safety and tolerability of varenicline in eight methamphetamine-dependent research subjects. Varenicline is used clinically to aid smoking cessation, and acts as a partial agonist at α4b2 nAChRs with full agonist properties at α7 nAChRs. Oral varenicline dose was titrated over one week to reach 1 mg twice daily, and then was co-administered with 30 mg methamphetamine, delivered in 10 intravenous (iv) infusions of 3 mg each. Varenicline was found to be safe in combination with iv methamphetamine, producing no cardiac rhythm disturbances or alterations in vital sign parameters. No adverse neuropsychiatric sequelae were detected either during varenicline titration or following administration of methamphetamine. The results suggest that varenicline warrants further investigation as a potential treatment for methamphetamine dependence.

Methamphetamine abuse is a significant public health concern. Although widely studied in laboratory animals, little is known about the abuse-related behavioral effects of methamphetamine relative to other abused stimulants in controlled laboratory settings in humans. The aim of this study was to examine the discriminative stimulus, subject-rated, performance, and cardiovascular effects of methamphetamine in humans. In the present study, subjects first learned to discriminate 10 mg of oral methamphetamine from placebo. After acquiring the discrimination (> or = 80% drug-appropriate responding on four consecutive sessions), a range of oral doses of methamphetamine (2.5-15 mg), d-amphetamine (2.5-15 mg), methylphenidate (5-30 mg), and triazolam (0.0625-0.375 mg) was tested. Methamphetamine functioned as a discriminative stimulus and produced prototypical stimulant-like subject-rated effects. d-Amphetamine and methylphenidate produced dose-related increases in methamphetamine-appropriate responding, whereas triazolam did not. d-Amphetamine and methylphenidate produced stimulant-like behavioral effects, whereas triazolam produced sedative-like effects. Methamphetamine, but no other drug, increased heart rate, systolic pressure, and diastolic pressure significantly above placebo levels. Performance in the Digit-Symbol Substitution Test was not affected by any of the drugs tested. Overall, these results demonstrate that the acute behavioral effects of methamphetamine, d-amphetamine, and methylphenidate overlap extensively in humans, which is concordant with findings from preclinical studies. Future studies should assess whether the similarity in the behavioral effects of methamphetamine and related stimulants can be extended to other behavioral assays, such as measures of reinforcement, in humans.

The high co-morbidity of eating disorders and substance abuse suggests that nutritional status can impact vulnerability to drug abuse. These studies used rats to examine the effects of food restriction on dopamine clearance in striatum and on the behavioral effects of amphetamine (locomotion, conditioned place preference), the dopamine receptor agonist quinpirole (yawning), and the dopamine receptor antagonist raclopride (catalepsy). Amphetamine increased locomotion and produced conditioned place preference. Food restriction reduced dopamine clearance, which was restored by repeated treatment with amphetamine or by free feeding. Food restriction also decreased sensitivity to quinpirole-induced yawning and raclopride-induced catalepsy; normal sensitivity to both drugs was restored by free feeding. The same amphetamine treatment that normalized dopamine clearance, failed to restore normal sensitivity to quinpirole or raclopride, suggesting that in food-restricted rats the activity of dopamine transporters and dopamine receptors is differentially affected by pathways that are stimulated by amphetamine. These studies show that modest changes in nutritional status markedly alter dopamine neurotransmission and the behavioral effects of direct-acting dopamine receptor drugs (agonist and antagonist). These results underscore the potential importance of nutritional status (e.g., glucose and insulin) in modulating dopamine neurotransmission and in so doing they begin to establish a neurochemical link between the high co-morbidity of eating disorders and drug abuse.

Experimentally-induced diabetes can modify the behavioral and neurochemical effects of drugs acting on dopamine systems, possibly through insulin-related regulation of dopamine transporter activity. In this study, several behavioral procedures were used to examine possible changes in sensitivity to amphetamine and other drugs in rats rendered diabetic by a single injection of streptozotocin. Conditioned place preference developed to food (Froot Loops) in both control and diabetic rats, demonstrating that conditioned place preference with tactile stimuli can occur in streptozotocin-treated rats. Baseline locomotion was lower in streptozotocin-treated as compared to control rats, although amphetamine significantly increased locomotion in all rats. Conditioned place preference developed to amphetamine regardless of whether rats had received streptozotocin or saline. A second study compared the potency of drugs to decrease lever pressing maintained by food, before and after streptozotocin treatment. Gamma-hydroxybutyrate and amphetamine were less potent after streptozotocin while the potency of raclopride, quinpirole, ketamine, haloperidol and cocaine was not significantly changed by streptozotocin. While markedly affecting locomotion, body weight and blood glucose, streptozotocin only modestly affected sensitivity to the behavioral effects of amphetamine and other drugs; these results fail to confirm previous reports of decreased behavioral actions of stimulants in diabetic rats.

Dopamine (DA) D2 receptors regulate DA transporter (DAT) activity, and mediate some behavioral effects of amphetamine. DA clearance and amphetamine-stimulated locomotion are reduced in hypoinsulinemic [streptozotocin (STZ)-treated] rats, and these deficits are normalized by repeated treatment with amphetamine. Here, a role for D2 receptors in mediating amphetamine-induced normalization of these parameters was investigated. One week after a saline or STZ injection (50 mg/kg), rats were treated with amphetamine (1.78 mg/kg), raclopride (0.056 mg/kg), saline, or combinations thereof, every-other-day for 8 days with locomotor activity measured following each treatment. Conditioned place preference (CPP) for amphetamine and in vivo chronoamperometry to measure DA clearance were carried out on days 17 and 18, respectively, after STZ or saline. Baseline locomotion and DA clearance were significantly reduced in STZ-treated rats compared with control rats. In STZ-treated rats, amphetamine treatment normalized DA clearance, and restored the locomotor-stimulating effects of amphetamine. Raclopride prevented normalization of these parameters. Amphetamine produced CPP in both STZ-treated and control rats; raclopride significantly attenuated amphetamine-induced CPP in control and not in STZ-treated rats. These results support a role for D2 receptors in regulating DA transporter activity, and further demonstrate that D2 receptors contribute to changes in sensitivity to amphetamine in hypoinsulinemic rats.

Streptozotocin (STZ)-induced diabetes can modulate dopamine (DA) neurotransmission and thereby modify the behavioral effects of drugs acting on DA systems. Insulin replacement, and in some conditions repeated treatment with amphetamine, can partially restore sensitivity of STZ-treated rats to dopaminergic drugs. The present study sought to characterize the role of insulin and amphetamine in modulating the behavioral effects of drugs that selectively act on D2/D3 receptors. In control rats, quinpirole and quinelorane produced yawning, whereas raclopride and gamma-hydroxybutyric acid (GHB) produced catalepsy. Raclopride antagonized quinpirole- and quinelorane-induced yawning with similar potency. STZ treatment increased blood glucose concentration, decreased body weight, and markedly reduced sensitivity to quinpirole-induced yawning, quinelorane-induced yawning as well as to raclopride-induced catalepsy, while enhancing sensitivity to GHB-induced catalepsy. Repeated treatment with amphetamine partially restored sensitivity of STZ-treated rats to amphetamine-stimulated locomotion and also produced conditioned place preference, without affecting blood glucose and body weight changes. However, amphetamine treatment did not restore sensitivity to the behavioral effects of quinpirole, raclopride, or GHB, suggesting differential regulation of dopamine transporter activity and sensitivity of D2 receptors in hypoinsulinemic rats. Insulin replacement in STZ-treated rats normalized blood glucose and body weight changes and fully restored sensitivity to quinpirole-induced yawning, as well as to raclopride-induced catalepsy, while reducing sensitivity to GHB-induced catalepsy. Overall, these data indicate that changes in insulin status markedly affect sensitivity to the behavioral effects of dopaminergic drugs. The results underscore the importance of insulin in modulating DA neurotransmission; these effects might be especially relevant to understanding the co-morbidity of eating disorders and substance abuse.

Insulin affects brain reward pathways and there is converging evidence that this occurs through insulin regulation of the dopamine (DA) transporter (DAT). In rats made hypoinsulinemic by fasting, synaptosomal DA uptake is reduced. Interestingly, [3H]DA uptake is increased in hypoinsulinemic rats with a history of amphetamine self-administration. The possibility that amphetamine and insulin act in concert to regulate DAT activity prompted this study. Here we show that [3H]DA uptake, measured in vitro and clearance of exogenously applied DA in vivo, is significantly reduced in rats made hypoinsulinemic by a single injection of streptozotocin. Strikingly, amphetamine (1.78 mg/kg, given every other day for 8 days) restored DA clearance in streptozotocin-treated rats but was without effect on DA clearance in saline-treated rats. Basal locomotor activity of streptozotocin-treated rats was lower compared to control rats; however, in streptozotocin-treated rats, hyperlocomotion induced by amphetamine increased over successive amphetamine injections. In saline-treated rats the locomotor stimulant effect of amphetamine remained stable across the four amphetamine injections. These results provide exciting new evidence that actions of amphetamine on DA neurotransmission are insulin-dependent and further suggest that exposure to amphetamine may cause long-lasting changes in DAT function.

To examine whether dopamine-mediated behavioral effects are altered in diabetes, this study compared the cataleptic effects of the dopamine receptor antagonist haloperidol (0.032-0.56 mg/kg) and gamma-hydroxybutyric acid (GHB; 56-1000 mg/kg) in control and streptozotocin (STZ)-treated rats. Haloperidol and GHB produced catalepsy in control and diabetic rats; haloperidol was less potent in diabetic rats (D(50)=0.44 mg/kg) than in controls (D(50)=0.19 mg/kg), while GHB was more potent in diabetic rats (D(50)=392 mg/kg) than in controls (D(50)=550 mg/kg). In diabetic rats, the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (0.32 mg/kg) further attenuated haloperidol-induced catalepsy (D(50)=1.2 mg/kg) and further enhanced GHB-induced catalepsy (D(50)=248 mg/kg). That haloperidol is less potent to produce catalepsy in diabetic rats is consistent with reports of altered dopamine receptor binding in diabetes.

gamma-Hydroxybutyrate (GHB) is a drug of abuse with multiple mechanisms of action. Consistent with its ability to modulate dopaminergic systems, GHB reportedly shares behavioral effects with neuroleptics and interacts with them in a synergistic manner. Here, we examined the ability of GHB and haloperidol to induce catalepsy and to affect operant responding. When given alone, both compounds induced catalepsy and decreased response rate. When given together, however, they produced these effects in an additive manner. This is further evidence that GHB has neuroleptic-like effects, but suggests that GHB interacts additively, not synergistically, with neuroleptics. The mechanisms involved in GHB- and haloperidol-induced catalepsy are different because the N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801), attenuated the cataleptic effects of haloperidol, but enhanced those of GHB. The latter finding suggests that other NMDA receptor antagonists (e.g., the drugs of abuse--phencyclidine and ketamine) may also interact synergistically with GHB.