Effects of substance P (SP) and selective tachykinin agonists on neurotransmission at guinea-pig intracardiac ganglia were studied in vitro. Voltage responses of neurons to superfused tachykinins and nerve stimulation were measured using intracellular microelectrodes. Predominant effects of SP (1 μM) were to cause slow depolarization and enable synaptic transmission at low intensities of nerve stimulation. Augmented response to nerve stimulation occurred with 29 of 40 intracardiac neurons (approx. 73%). SP inhibited synaptic transmission at 23% of intracardiac neurons but also caused slow depolarization. Activation of NK3 receptors with 100 nM [MePhe 7]neurokinin B caused slow depolarization, enhanced the response of many intracardiac neurons to low intensity nerve stimulation or local application of acetylcholine, and triggered action potentials independent of other stimuli in 6 of 42 neurons. The NK1 agonist [Sar 9,Met(O2)11]SP had similar actions but was less effective and did not trigger action potentials independently. Neither selective agonist inhibited cholinergic neurotransmission. We conclude that SP can function as a positive or negative neuromodulator at intracardiac ganglion cells, which could be either efferent neurons or interneurons. Potentiation occurs primarily through NK3 receptors and may enable neuronal responses with less preganglionic nerve activity. Inhibition of neurotransmission by SP is most likely explained by the known blocking action of this peptide at ganglionic nicotine receptors.

Adolescence is a transitional period between childhood and adulthood, in which the individual undergoes significant cognitive, behavioral, physical, emotional, and social developmental changes. During this period, adolescents engage in experimentation and risky behaviors such as licit and illicit drug use. Adolescents' high vulnerability to abuse drugs and natural reinforcers leads to greater risk for developing substance use disorders (SUDs) during adulthood. Accumulating evidence indicates that the use and abuse of licit and illicit drugs during adolescence and emerging adulthood can disrupt the cholinergic system and its processes. This review will focus on the effects of peri-adolescent nicotine and/or alcohol use, or exposure, on the cholinergic system during adulthood from preclinical and clinical studies. This review further explores potential cholinergic agents and pharmacological manipulations to counteract peri-adolescent nicotine and/or alcohol abuse.

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The existence of a massive cholinergic projection from cells in the medical septal nucleus (MS) and nucleus of the diagonal band (DB) to the hippocampal formation has been recognized for some time. However, the actual percentages of cholinergic and non-cholinergic neurons in the MS and DB which project to the hippocampus have not been reported. A procedure which combines horseradish peroxidase (HRP) and acetylcholinesterase (AChE) histochemistry in the same tissue was used to determine these percentages in the rabbit. Less than 50% of the neurons in the MS and DB which were labeled with reaction product following an HRP injection into the dorsal hippocampus also stained for AChE. Moreover, 70% of all neurons containing HRP reaction product were located in the DB, but neurons in the DB could not be differentiated from those in the MS on the basis of size or morphology. These data are taken to indicate that much of the MS-DB hippocampal projection is not cholinergic. Substance P is suggested as another possible transmitter within this anatomical system.

The ability of derivatives of 2-aminotetralins (2AT), cis- or trans-isomers of octahydrobenzo[f]quinolines (BfQ) and clonidine to modulate acetylcholine release was studied using field-stimulated guinea pig ilea (GPI). Antihistaminic and antiacetylcholine activities were also determined using isolated superfused segments of GPI. Hydroxylated 2AT, BfQ and clonidine inhibited field stimulation-induced contractions through α-adrenoceptor mechanisms which were antagonized by phentolamine. In contrast, the inhibition produced by nonhydroxylated 2AT was not attenuated by α-adrenoceptor antagonism. 2AT, trans-7,8-dihydro-BfQ and cis-8,9-dihydroxy-BfQ inhibited contractions induced by nicotine bitartrate using superfused GPI. Clonidine was inactive as an antinicotinic agent and there was no correlation between a compound's ability to inhibit contractions induced by field stimulation and its antinicotinic activity. Various 2AT derivatives demonstrated weak antimuscarinic and/or antihistaminic activities on superfused ileal segments. These data demonstrate that these agents posses a spectrum of pharmacological activity.

<p> The pharmacology of autonomic innervation to the peripheral skin conductance (SC) effector was studied. The drugs used included atropine, bretylium, acetylcholine (ACh), epinephrine (EPI), and amphetamine. Drugs were administered by iontophoresis (IPS) and by local subcutaneous injection. Although several IPS procedures were used, all proved to be inefficient and unreliable. Subsequent experiments using atropine and ACh supported the theory that innervation to the peripheral SC effector was mainly cholinergic. However, results obtained using EPI suggest that an adrenergic component might also be involved. It was concluded though that this component probably had little physiological significance. Experiments using amphetamine and bretylium were inconclusive. A comparison of behavioral and drug induced changes in SC suggested that the psychological relevance of SC might be improved through a range-correction based on pharmacologically determined SC range scores.</p> / Thesis / Master of Arts (MA)

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