Brain dysfunctions and neurotoxicity induced by psychostimulants in experimental models and humans: an overview of recent findings.

Preclinical and clinical studies indicate that psychostimulants, in addition to having abuse potential, may elicit brain dysfunctions and/or neurotoxic effects. Central toxicity induced by psychostimulants may pose serious health risks since the recreational use of these substances is on the rise among young people and adults. The present review provides an overview of recent research, conducted between 2018 and 2023, focusing on brain dysfunctions and neurotoxic effects elicited in experimental models and humans by amphetamine, cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine, methylphenidate, caffeine, and nicotine. Detailed elucidation of factors and mechanisms that underlie psychostimulant-induced brain dysfunction and neurotoxicity is crucial for understanding the acute and enduring noxious brain effects that may occur in individuals who use psychostimulants for recreational and/or therapeutic purposes.

Prenatal and postnatal drug exposure: focus on persistent central effects.

Clinical studies indicate significant use of prescription, nonprescription and social/recreational drugs by women during pregnancy; however, limited knowledge exists about the detrimental effects that this practice may have on the developing central nervous system of the fetus. Importantly, few experimental and clinical data are available on how gestational exposure could exacerbate the effects of the same or a different drug consumed by the offspring later in life. The present review summarizes recent findings on the central toxicity elicited by several classes of drugs, administered prenatally and postnatally in experimental animals and humans, focusing on prescription and nonprescription analgesics, anti-inflammatory agents, alcohol and nicotine.

Deep versus Shallow Processing: A Learning and Memory Experiment for Asynchronous and Synchronous Online Platforms.

Processing of words can be meaning-based (deep processing) or appearance/sound-based (shallow processing). A simple experiment that can be conducted online, asynchronously or synchronously, demonstrates that the number of words recalled from a list of 24 words read aloud depends on the instructions given to students beforehand. Students in the deep processing group were asked to write 'yes' or 'no' - is the word likeable/pleasant, while students in the shallow processing group were asked to write 'yes' or 'no' - does the word contain an E or G. After a one-minute delay in which students performed a backward calculation task, they had two minutes to recall as many words as possible from the list. Regardless of how the online experiment was conducted, asynchronously or synchronously, the deep processing group recalled an average of 11-14 words compared to the shallow processing group, which recalled an average of 8-10 words. The deep processing group consistently recalled 3-6 more words on average than the shallow processing group. After debriefing the students about the experiment, the instructor can focus class discussion on topics that include experimental design, methodology, reproducibility, data analysis, as well as using these data as an evidence-based starting point for best learning practices.

The Neuroscience Classroom Remodeled with Team-Based Learning.

As neuroscience faculty we strive to have students be invested in their learning and be engaged in the process. However, these attributes are difficult to promote using a lecture-based format. Flipping the classroom so that students prepare before coming to class obliges them to take responsibility for their learning. This, combined with having them work in Teams with their classmates - across the entire semester - provides incentive and support. This article describes how I applied a method called Team-Based Learning (TBL) to my Neurobiology course. TBL requires that students read the assigned text before class and demonstrate their knowledge through quizzes called Readiness Assurance Tests (RATs) that are completed first individually (iRAT) then by each Team (tRAT). This process uncovers the most challenging material and identifies student misconceptions that the instructor addresses through mini-lectures. In subsequent classes, students work in Teams solving content-specific application questions (ungraded) and complete four written Team assignments (graded) that require critical thinking and collective decisions. Teams represent a safe space for students to share knowledge, ask questions, learn from and teach one another. Placing students in Teams promotes regular attendance and ensures preparation before class. Students report that working in Teams helps them to remember content and how to use the group's knowledge to solve problems. They also note the benefits of hearing multiple perspectives, diverse arguments, and different ways to reason. Scores on hourly exams and course grades show that TBL is an effective means for students to learn Neurobiology.

Non-Fiction Memoirs in the Neuroscience Classroom: A Window into the Minds of Those Affected by Addiction.

When I first developed an Addiction course for the Honors College at UMass-Boston in 2006, it focused exclusively on the acute and long-term effects of psychoactive substances on the brain. However, I soon realized that a strictly biological perspective failed to capture how this complex disorder affected the whole person. Students had no insight into addicts' thoughts, feelings, behaviors or how their addiction affected others. To remedy this, students read two non-fiction memoirs: Tweak (Nic Sheff, young adult addict) and Beautiful Boy (David Sheff, Nic's father) along with learning underlying neurobiology and pharmacology. Reading memoirs students saw firsthand the impact of addiction on individuals. Inspired by the diary structure of Tweak, one assignment asked students to collect data about themselves in order to determine their daily patterns/rituals and to contemplate the impact of removing these activities - like the addict after rehabilitation. Other assignments asked students to do close reading by selecting passages from Tweak and explaining how they related to different facets of addiction (biological, environmental, effect on individual), and to perform a comparative analysis between Beautiful Boy and Tweak to find points of intersection and divergence. Most recently, students used the text of Tweak to create interactive performances for a visiting high school class. Memoirs provided students with detailed, honest accounts of lives affected by addiction. The assignments and class discussions facilitated students understanding of the impact of addiction on individuals and their families, which was a powerful adjunct to learning about its underlying neurobiology and pharmacology.

The use of haiku to convey complex concepts in neuroscience.

Conveying scientific content with accuracy and fluency takes practice and requires deep understanding of the concepts being conveyed. This depth of knowledge comes from internalizing information and constructing it into a form that is unique and coherent to the individual. Often in science classrooms there is little or no opportunity for students to practice this type of thinking, activities that we believe are fundamental to effective science communication. This article describes the use of haiku - a 17 syllable poem - as a means for students to convey neurobiological concepts in a succinct manner by forcing them to focus on the most salient features of the observed processes. In our assignments haiku writing was successfully paired with explanations of the students' thought processes (Addiction course) or the scientific evidence to support claims (Neurodegenerative Disease course). We provide examples of student haiku and explanations as evidence of the power of this approach. The coupling of poetry and prose together create rich, accurate descriptions of scientific phenomena by encouraging higher-order thinking. Poetry writing can thus be used across the curriculum to forge comprehension of complex ideas in any discipline and to bridge the arts and the sciences.

Abnormal involuntary movement (AIM) expression following D2 dopamine agonist challenge is determined by the nature of prior dopamine receptor stimulation (priming) in 6-hydroxydopamine lesioned rats.

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions show sensitization (priming) of rotational behavior upon repeated treatment with dopamine agonists. To relate these observations to dyskinesias exhibited by Parkinson's Disease patients, we assessed abnormal involuntary movements (AIMs) in 6-OHDA rats, which were primed with three injections of either the following: water, D1/D2 agonist apomorphine (Apo) (0.5mg/kg), D1 agonist SKF38393 (SKF) (10mg/kg) or D2 agonist quinpirole (Quin) (1 or 2.5mg/kg). The rats were challenged one week later with Quin (0.25mg/kg). Axial, limb, orolingual, locomotor, and grooming AIMs were scored (0-4) every 5min. Priming with water did not produce AIMs. Priming with Quin (1mg/kg) produced axial and locomotor AIMs, while priming with Apo, SKF or Quin (2.5mg/kg) produced axial, locomotor, limb, and grooming AIMs. The disparity in AIM profiles between Quin (1mg/kg) and (2.5mg/kg) was not the result of D1 receptor stimulation since there was little striatal Fos expression following the third priming injection with Quin (1 or 2.5mg/kg) compared to following SKF, which led to robust striatal Fos expression. Challenge with Quin (0.25mg/kg) essentially reproduced the categories of AIMs exhibited during priming, with no AIMs in water-primed 6-OHDA rats, mild, non-significant, axial and locomotor AIMs in Quin (1 and 2.5mg/kg)-primed 6-OHDA rats, and axial, limb, locomotor, and grooming AIMs in Apo- and SKF-primed 6-OHDA rats. These data suggest that the types of AIMs expressed following challenge with Quin depend on the dopamine receptor subtype and dose of dopamine agonist used during priming.

Prior treatment (priming) with caffeine sensitizes D2-dopamine-mediated contralateral rotational behavior in 6-hydroxydopamine-lesioned rats.

BACKGROUND/AIMS: In unilaterally dopamine-depleted rats, repeated treatment with dopamine agonists sensitizes contralateral rotational behavior. Since A2a adenosine receptors are co-localized with D2 dopamine receptors in the brain, it was hypothesized that repeated treatment with the adenosine antagonist caffeine could sensitize D2 dopamine-mediated rotational behavior. METHODS: Rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA), and pretreated (primed) with 3 injections of caffeine or water. One week later, rats were challenged with the D2 agonist quinpirole (0.25 mg/kg). RESULTS: 6-OHDA rats primed with caffeine (50 mg/kg) displayed contralateral rotational behavior following challenge with quinpirole - an effect not observed with caffeine (10 or 75 mg/kg) or water. CONCLUSIONS: These results suggest that prior administration of caffeine can sensitize D2 dopamine-mediated rotational behavior in dopamine-depleted rats.

D1 priming enhances both D1- and D2-mediated rotational behavior and striatal Fos expression in 6-hydroxydopamine lesioned rats.

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions exhibit behavioral sensitization upon repeated treatment with dopamine agonists, a phenomenon called 'priming'. We examined the effectiveness of priming with D1 or D2 agonists on rotational behavior and striatal Fos expression following challenge with D1 or D2 agonists. Twenty-one days post-lesion, rats received three priming injections, spaced 3-6days apart, with water, D1 agonist SKF38393 (10mg/kg) or D2 agonist quinpirole (1mg/kg). One week later, 6-OHDA rats were challenged with water, SKF38393 (1 or 10mg/kg) or quinpirole (0.25mg/kg). 6-OHDA rats challenged with SKF38393 (1mg/kg) showed no contralateral rotational behavior, but robust striatal Fos expression in D1-primed animals. Challenge with SKF38393 (10mg/kg) led to pronounced contralateral rotational behavior and striatal Fos expression in all priming groups - with the largest behavioral response in D1- and D2-primed rats. Quinpirole challenge (0.25mg/kg) led to robust contralateral rotational behavior and striatal Fos expression in D1-primed animals, but only mild rotational behavior and baseline levels of striatal Fos expression in D2-primed animals. These data suggest that D1- or D2-priming enhances rotational behavior following challenge with D1 or D2 agonist, but only D1-priming enhances D1- and D2-mediated striatal Fos expression in 6-OHDA rats.

Exploring the Complexities of Experimental Design: Using an On-line Reaction Time Program as a Teaching Tool for Diverse Student Populations.

Students are rarely given an opportunity to think deeply about experimental design or asked to develop experimental protocols on their own. Without participating in these endeavors, they are often unaware of the many decisions necessary to construct a precise methodology. This article describes an on-line reaction time program, and how I have used this program as a teaching tool for students to explore experimental design. This approach can be tailored to meet the level of any undergraduate student - from non-science majors to upper-level biology/psychology/neuroscience majors, affording all students the opportunity to think like a scientist. Described is how I use the reaction time program for a whole class demonstration and discussion, as well as, how it can be used for a written assignment in which each student designs and conducts his/her own experiment outside of the classroom. Comments from several students, who did the written assignment, are included to provide a sense of their thoughts and considerations. When students are given a simple method, such as the measurement of reaction time, it allows them to focus exclusively on developing precise methodology, which taps into types of thinking that they are not often asked to exhibit in other science classes.

Muscarinic receptor blockade attenuates reserpine-mediated Fos induction in the rat striatopallidal pathway.

Acute administration of the dopamine-depleting agent reserpine (10 mg/kg) induces Fos expression in striatopallidal neurons of intact rats-an effect that is blocked by pretreatment with the D2 agonist quinpirole (0.5 mg/kg). Systemic administration of the muscarinic antagonist scopolamine (50 mg/kg) partially attenuates reserpine-mediated striatal Fos expression. These data suggest that muscarinic receptors, either within the striatum or in extrastriatal sites, regulate D2 receptor-mediated Fos expression in rat striatopallidal neurons.

Role of NMDA and AMPA glutamate receptors in the induction and the expression of dopamine-mediated sensitization in 6-hydroxydopamine-lesioned rats.

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions exhibit behavioral sensitization following repeated treatment with dopamine agonists, a phenomenon called "priming." Priming has two distinct phases: induction and expression. Priming induction using three injections with D1/D2 agonist apomorphine (0.5 mg/kg) or D1 agonist SKF38393 (10 mg/kg) allows priming expression, robust contralateral rotational behavior and striatal Fos expression, following a challenge with the D2 agonist quinpirole (0.25 mg/kg). We examined the roles of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors on dopamine agonist priming. Administration of the NMDA antagonist (+)5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK801) (0.5 mg/kg) blocked apomorphine-priming of quinpirole-mediated responses, while MK801 dose-dependently attenuated SKF38393-priming of quinpirole-mediated striatal Fos expression and had no effect on SKF38393-priming of quinpirole-mediated rotational behavior. In contrast, administration of the AMPA antagonist 2,3-dihydroxy-6-nitro-7sulfamoyl-benzo[f]quinoxaline (NBQX) (5 or 10 mg/kg) potentiated apomorphine- and SKF38393-priming of quinpirole-mediated striatal Fos expression, but had no effect on their priming of quinpirole-mediated rotational behavior. In SKF38393-primed 6-OHDA rats, administration of MK801 (0.5 mg/kg) blocked the expression of quinpirole-mediated responses, while administration of NBQX (10 mg/kg) or the noncompetitive AMPA antagonist 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine dihydrochloride (GYKI52466) (5 or 15 mg/kg) had no effect. These results suggest that NMDA and AMPA glutamate receptors have differing roles in dopamine agonist priming-with NMDA receptors required for D1/D2 priming induction and D2-mediated priming expression, and AMPA receptors inhibiting priming induction of D2-mediated immediate early gene expression in the striatum, but not affecting priming induction of D2-mediated rotational behavior or the expression of D2-mediated responses.