Pharmacology of Antiparkinsonian Agents

The following is a summary of a two hour class on the basic pharmacology of antiparkinsonian agents. It is presented to fourth-year pharmacy students in pharmacotherapeutics III, a course structured using team-taught modules. Faculty from the Department of Pharmacy Sciences provide instruction on the basic pharmacology of therapeutic agents and faculty from the Department of Pharmacy Practice follow up with a discussion of the therapeutic applications of these agents. This course is lecture-based with opportunities for in-class discussion. One week prior to the lecture sequence on the basic pharmacology of antiparkinsonian drugs, students are provided a handout that includes the reading assignment (1), learning objectives and a topic outline. The topic outline contains the chemical structures of the agents to be discussed as well as the figures, patient scenarios and study questions appearing in this manuscript. During each 50- minute period, material is presented as a lecture tied to patient scenarios. The scenarios are presented in class immediately after covering the pharmacological concepts to which they apply. Students are asked to discuss in small groups potential solutions to the scenarios and to offer their answers to the rest of the class on a volunteer basis. The study questions are geared for preparing for exams and are not discussed in class unless students request. At the end of these two lectures, a homework problem is assigned that introduces the 6-hydroxydopamine rat model of Parkinson’s disease. The following week, a live demonstration related to the homework is presented in class with a short discussion afterwards

Hypothalamic excitatory amino acid receptors mediate stress-induced tachycardia in rats

The role of hypothalamic excitatory amino acid (EAA) receptors in mediating the cardiovascular response to stress was examined using conscious chronically instrumented rats. Microinjection of the EAA agonists N-methyl-D-aspartic acid (NMDA; 1-10 pmol), alpha-amino-3-hydroxy-5-methyl-4-isooxazolepropionic acid (AMPA; 0.3-3.0 pmol), or kainic acid (0.1-1.0 pmol) into the dorsomedial hypothalamus (DMH) elicited dose-related increases in heart rate and modest elevations in arterial pressure. Local microinjection of the NMDA antagonist 2-amino-5-phosphonopentanoic acid (AP5; 100 pmol) selectively blocked NMDA-induced cardiovascular changes, whereas the non-NMDA EAA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 50 pmol) selectively blocked the responses to AMPA and kainic acid. In the stress trials, microinjection of the nonselective EAA antagonist kynurenic acid (1-10 nmol) into the DMH blocked air stress-induced tachycardia in a dose-related manner. Similar injection of kynurenic acid at sites lateral or posterior to the DMH or injection of xanthurenic acid (a structural analogue of kynurenic acid with no antagonistic properties at EAA receptors) into the DMH failed to influence air stress-induced cardiovascular changes. Injection of either AP5 or CNQX into the DMH at doses shown to be selective for their respective EAA receptor subtypes also attenuated air stress-induced tachycardia. Thus activity at EAA receptors in the DMH appears to be necessary for the generation of stress-induced changes in heart rate

GABA\u3csub\u3eA\u3c/sub\u3e and excitatory amino acid receptors in dorsomedial hypothalamus and heart rate in rats

We have previously shown that microinjection of drugs that interfere with the function of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into the hypothalamus produces cardiorespiratory and behavioral changes resembling those seen in emotional stress. The purpose of this study was to determine whether excitatory amino acids (EAAs) can produce a cardiovascular response similar to that caused by the GABAA receptor antagonist bicuculline methiodide (BMI) when microinjected at the same hypothalamic site in urethan-anesthetized rats and to clarify the precise locus of action of these agents. N-methyl-D-aspartic acid (NMDA, 0.68-6.8 pmol/50 nl) and kainic acid (KA, 0.47-4.7 pmol/50 nl) produced dose-related increases in heart rate and blood pressure when injected at sites in the dorsomedial hypothalamus reactive to BMI (20 pmol/50 nl). Higher doses of NMDA (68 pmol), however, failed to elicit consistent increases in heart rate and blood pressure when injected at these same sites. The effects of NMDA were selectively blocked by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid, whereas the effects of KA were selectively blocked by the non-NMDA EAA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. These results demonstrate that 1) blockade of inhibitory amino acid receptors or stimulation of EAA receptors in the dorsomedial nucleus of the hypothalamus produces tachycardic and pressor responses in urethan-anesthetized rats and 2) use of high doses of EAAs may be an unreliable method of evoking local neuronal excitation in certain regions of the central nervous system

Interaction of hypothalamic GABA\u3csub\u3eA\u3c/sub\u3e and excitatory amino acid receptors controlling heart rate in rats

We have previously shown that microinjection of drugs that impair gamma-aminobutyric acid (GABA)-mediated synaptic inhibition into the dorsomedial hypothalamus (DMH) of rats generates cardiovascular and behavioral changes that mimic the response to stress. The purpose of this study was to examine the role of excitatory amino acid (EAA) receptors in the DMH in generating the cardiovascular changes caused by withdrawal of local GABAergic inhibition in urethan-anesthetized rats. Local treatment of the DMH with the nonselective EAA antagonist kynurenic acid blocked or reversed the increases in heart rate and blood pressure caused by microinjection of the GABAA antagonists bicuculline methiodide (BMI) or picrotoxin into the same region. Conversely, similar injection of xanthurenic acid, a structural analogue of kynurenic acid without significant effects on EAA receptors, did not significantly alter the cardiovascular changes produced by either GABAA antagonist. The tachycardic effects of BMI were also attenuated by injection of either the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid or the non-NMDA EAA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. When the two EAA receptor antagonists were combined, their effects to suppress the BMI-induced tachycardia were additive. These findings suggest that the cardiovascular effects caused by blockade of GABAergic inhibition in the DMH of the rat are dependent on activation of local NMDA and non-NMDA EAA receptors

Interaction of GABA and Excitatory Amino Acids in the Basolateral Amygdala: Role in Cardiovascular Regulation

Activation of the amygdala in rats produces cardiovascular changes that include increases in heart rate and arterial pressure as well as behavioral changes characteristic of emotional arousal. The objective of the present study was to examine the interaction of GABA and excitatory amino acid (EAA) receptors in the basolateral amygdala (BLA) in regulating cardiovascular function. Microinjection of the GABAA receptor antagonist bicuculline methiodide (BMI) or the E A A receptor agonists NMDA or AMPA into the same region of the BLA of conscious rats produced dose-related increases in heart rate and arterial pressure. Injection of the nonselective EAA receptor antagonist kynurenic acid into the BLA prevented or reversed the cardiovascular changes caused by local injection of BMI or the noncompetitive GABA antagonist picrotoxin. Conversely, local pretreatment with the glutamate reuptake inhibitorl-trans-pyrrolidine-2,4-dicarboxylic acid enhanced the effects of intra-amygdalar injection of BMI. The cardiovascular effects of BMI were also attenuated by injection of either the NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) or the AMPA receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX). When these two EAA receptor antagonists were combined, their ability to suppress BMI-induced tachycardic and pressor responses was additive. These findings indicate that the cardiovascular effects caused by blockade of GABAergic inhibition in the BLA of the rat are dependent on activation of local NMDA and AMPA receptors

For common community phylogenetic analyses, go ahead and use synthesis phylogenies

Should we build our own phylogenetic trees based on gene sequence data, or can we simply use available synthesis phylogenies? This is a fundamental question that any study involving a phylogenetic framework must face at the beginning of the project. Building a phylogeny from gene sequence data (purpose‐built phylogeny) requires more effort, expertise, and cost than subsetting an already available phylogeny (synthesis‐based phylogeny). However, we still lack a comparison of how these two approaches to building phylogenetic trees influence common community phylogenetic analyses such as comparing community phylogenetic diversity and estimating trait phylogenetic signal. Here, we generated three purpose‐built phylogenies and their corresponding synthesis‐based trees (two from Phylomatic and one from the Open Tree of Life, OTL). We simulated 1,000 communities and 12,000 continuous traits along each purpose‐built phylogeny. We then compared the effects of different trees on estimates of phylogenetic diversity (alpha and beta) and phylogenetic signal (Pagel’s λ and Blomberg’s K). Synthesis‐based phylogenies generally yielded higher estimates of phylogenetic diversity when compared to purpose‐built phylogenies. However, resulting measures of phylogenetic diversity from both types of phylogenies were highly correlated (Spearman’s ρ > 0.8 in most cases). Mean pairwise distance (both alpha and beta) is the index that is most robust to the differences in tree construction that we tested. Measures of phylogenetic diversity based on the OTL showed the highest correlation with measures based on the purpose‐built phylogenies. Trait phylogenetic signal estimated with synthesis‐based phylogenies, especially from the OTL, was also highly correlated with estimates of Blomberg’s K or close to Pagel’s λ from purpose‐built phylogenies when traits were simulated under Brownian motion. For commonly employed community phylogenetic analyses, our results justify taking advantage of recently developed and continuously improving synthesis trees, especially the Open Tree of Life.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151322/1/ecy2788_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151322/2/ecy2788.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151322/3/ecy2788-sup-0001-AppendixS1.pd

Rates of niche and phenotype evolution lag behind diversification in a temperate radiation

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Environmental change can create opportunities for increased rates of lineage diversification, but continued species accumulation has been hypothesized to lead to slowdowns via competitive exclusion and niche partitioning. Such density-dependent models imply tight linkages between diversification and trait evolution, but there are plausible alternative models. Little is known about the association between diversification and key ecological and phenotypic traits at broad phylogenetic and spatial scales. Do trait evolutionary rates coincide with rates of diversification, are there lags among these rates, or is diversification niche-neutral? To address these questions, we combine a deeply sampled phylogeny for a major flowering plant clade—Saxifragales—with phenotype and niche data to examine temporal patterns of evolutionary rates. The considerable phenotypic and habitat diversity of Saxifragales is greatest in temperate biomes. Global expansion of these habitats since the mid-Miocene provided ecological opportunities that, with density-dependent adaptive radiation, should result in simultaneous rate increases for diversification, niche, and phenotype, followed by decreases with habitat saturation. Instead, we find that these rates have significantly different timings, with increases in diversification occurring at the mid-Miocene Climatic Optimum (∼15 Mya), followed by increases in niche and phenotypic evolutionary rates by ∼5 Mya; all rates increase exponentially to the present. We attribute this surprising lack of temporal coincidence to initial niche-neutral diversification followed by ecological and phenotypic divergence coincident with more extreme cold and dry habitats that proliferated into the Pleistocene. A lack of density-dependence contrasts with investigations of other cosmopolitan lineages, suggesting alternative patterns may be common in the diversification of temperate lineages

Evidence of neutral transcriptome evolution in plants

The transcriptome of an organism is its set of gene transcripts (mRNAs) at a defined spatial and temporal locus. Because gene expression is affected markedly by environmental and developmental perturbations, it is widely assumed that transcriptome divergence among taxa represents adaptive phenotypic selection. This assumption has been challenged by neutral theories which propose that stochastic processes drive transcriptome evolution. To test for evidence of neutral transcriptome evolution in plants, we quantified 18 494 gene transcripts in nonsenescent leaves of 14 taxa of Brassicaceae using robust cross-species transcriptomics which includes a two-step physical and in silicobased normalization procedure based on DNA similarity among taxa. Transcriptome divergence correlates positively with evolutionary distance between taxa and with variation in gene expression among samples. Results are similar for pseudogenes and chloroplast genes evolving at different rates. Remarkably, variation in transcript abundance among root-cell samples correlates positively with transcriptome divergence among root tissues and among taxa. Because neutral processes affect transcriptome evolution in plants, many differences in gene expression among or within taxa may be nonfunctional, reflecting ancestral plasticity and founder effects. Appropriate null models are required when comparing transcriptomes in space and time

The acoustic space of pain: cries as indicators of distress recovering dynamics in preverbal infants

Crying is a vital built-in survival mechanism for the Human baby. Yet both the information carried by cries and the factors driving the perception and reaction of adult listeners remain under-investigated. Here, we contrasted the relevance of psychoacoustic vs. acoustic evaluation for the assessment of distress levels in babies' cries recorded during baths and during an immunization event. Parents asked to rate the level of distress experienced by babies from listening to their cries attributed lower pain ratings to mild discomfort (bath) than to distress (vaccination) cries but failed to discriminate between different putative levels of pain experienced during different vaccination sequences. In contrast, vocal "roughness", a composite acoustic factor characterising the level of aperiodicity of the cries, not only differed between mild discomfort and distress cries but also between the levels of pain experienced during the different vaccination sequences. These observations suggest that acoustic analyses are more powerful than psychoacoustic evaluations for discriminating distress levels in babies’ cries, and opens the way for the design of a tool based on the acoustics of cries for assessing and monitoring pain levels in preverbal infants

Visualizing sound emission of elephant vocalizations: evidence for two rumble production types

Recent comparative data reveal that formant frequencies are cues to body size in animals, due to a close relationship between formant frequency spacing, vocal tract length and overall body size. Accordingly, intriguing morphological adaptations to elongate the vocal tract in order to lower formants occur in several species, with the size exaggeration hypothesis being proposed to justify most of these observations. While the elephant trunk is strongly implicated to account for the low formants of elephant rumbles, it is unknown whether elephants emit these vocalizations exclusively through the trunk, or whether the mouth is also involved in rumble production. In this study we used a sound visualization method (an acoustic camera) to record rumbles of five captive African elephants during spatial separation and subsequent bonding situations. Our results showed that the female elephants in our analysis produced two distinct types of rumble vocalizations based on vocal path differences: a nasally- and an orally-emitted rumble. Interestingly, nasal rumbles predominated during contact calling, whereas oral rumbles were mainly produced in bonding situations. In addition, nasal and oral rumbles varied considerably in their acoustic structure. In particular, the values of the first two formants reflected the estimated lengths of the vocal paths, corresponding to a vocal tract length of around 2 meters for nasal, and around 0.7 meters for oral rumbles. These results suggest that African elephants may be switching vocal paths to actively vary vocal tract length (with considerable variation in formants) according to context, and call for further research investigating the function of formant modulation in elephant vocalizations. Furthermore, by confirming the use of the elephant trunk in long distance rumble production, our findings provide an explanation for the extremely low formants in these calls, and may also indicate that formant lowering functions to increase call propagation distances in this species'