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No / This paper begins by recalling that advances in neuroscience were used for hostile purposes, for example, in the development of lethal nerve gasses, in the last century, and it is argued that in the kinds of asymmetric warfare likely to characterize coming decades, such advances could again be utilized to develop novel weapons. The paper then suggests that the idea that the problem is that bioterrorists will immediately be able to design and use advanced biological and chemical weapons is misguided and that the real question is how the wholesale militarization of the life sciences can be prevented. It is in that context that the paper examines the dangers of misuse that could arise from some current developments in neuroscience. It is argued, for example, that benignly intended civil work on transcranial magnetic stimulation (TMS) and brain-computer interfaces (BCIs) has to be understood in the context of modern military interests in data collection and analysis from drones and the probable development of autonomously acting systems. The difficulties that such novel weapon-related developments will cause for our present understanding of morality and international law are reviewed, and finally, it is suggested that neuroscientists trying to adjust their concepts of responsible conduct in these circumstances will need the help of neuroethicists.

A mathematical model for goal oriented learning in a network of neuron-like elements was developed. Using a mouse/goal box analogy, a simulation of a network with four elements was programmed in Turbo Pascal, Version 4.0 (Borland International) to test the model. Each location in the network corresponded to a particular network input. The output of the network consisted of one of four behaviors: forward, backward, left or right. The network successfully learned sequences of up to six movements in increasingly complex mazes. / Master of Science

Reversible hyperosmotic blood-brain barrier disruption (BBBD) has been used in pharmaceutical research as well as human medicine to enhance drug delivery across the blood-brain barrier. However a technique for repeatable BBBD in the canine has not been described. This study describes a repeatable technique for BBBD in the dog and evaluates the clinical and morphological effects of BBBD. Using fluoroscopic guidance, an arterial catheter was directed into the internal carotid artery via the femoral artery in ten dogs. BBBD was achieved in 5 dogs using 25% mannitol while 5 control dogs received only saline. Following recovery, dogs were monitored for clinical signs before a second, non-survival procedure was performed 2-3 weeks later. BBBD was estimated using CT densitometry as well as Evan's blue staining on post-mortem exam. Histopathological evaluation of the brain was performed on all dogs. Seven dogs completed the study. Two treatment dogs were lost after the first infusion with deteriorating neurologic function attributed to CNS edema and increased intracranial pressure. One control dog was lost due to vessel wall damage during catheterization. The remaining dogs exhibited only transient neurologic, ocular, and vasculature injury. Successful BBBD was demonstrated in all treatment dogs as evidenced by CT and Evan's blue staining. Histopathological evaluation revealed multifocal areas of infarction in all dogs indicating refinement of the technique is needed. This study shows that repeatable disruption the BBB in the dog is possible and opens the way for further investigations of BBBD using the dog as a model. / Master of Science

To test whether SKF 38393 could ontogenetically sensitize dopamine (DA) D$\sb1$ receptors and whether this sensitization would be associated with biochemical changes, intact and neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats (200 $\mu$g i.c.v.) were treated daily from birth with SKF 38393 (3.0 mg/kg i.p. x 28 days) or its vehicle. In DA D$\sb1$ neonatally sensitized 6-OHDA rats, enhanced locomotor responses were observed with the first SKF 38393 challenge dose (3.0 mg/kg i.p.) at 6 weeks. This response increased further with weekly SKF 38393 treatments. Enhanced stereotyped behaviors were seen in both lesioned and sensitized rats at 8 weeks. There was no change in the percentage of high affinity D$\sb1$ sites in these groups of rats. Striatal mRNA levels for D$\sb1$ receptors were reduced in the lesioned rats, but restored to control level after treatments with SKF 38393 in adulthood. Basal, DA-, NaF- and forskolin-stimulated adenylate cyclase activities were similar among treatment groups. Striatal DA content was reduced ($>$99%), whereas serotonin (5-HT) content was elevated ($>$50%) in the 6-OHDA groups. To study possible interaction between DA and 5-HT systems, the effects of a series of 5-HT agents on the induction of oral activity were determined. The 5-HT$\sb{\rm 1C}$ receptor agonist, m-chlorophenylpiperazine (m-CPP), produced a marked increase in oral activity in 6-OHDA-lesioned rats. The respective 5-HT$\sb{\rm 1A}$ and 5-HT$\sb{\rm 1B}$ agonists, 8-OH-DPAT and CGS-12066B did not increase oral activity. The m-CPP-induced oral response in the lesioned rats was attenuated by mianserin, a 5-HT$\sb{\rm 1C}$ antagonist, but not by ketanserin or MDL-72222, 5-HT$\sb2$ and 5-HT$\sb3$ antagonists, respectively. Although the supersensitized oral response of lesioned rats to m-CPP was not attenuated by SCH 23390, the enhanced response of SKF 38393 was attenuated by mianserin. Additionally, mRNA levels for 5-HT$\sb{\rm 1C}$ receptor were not altered in both intact and lesioned rats. These findings demonstrate that ontogenetic treatments of neonatal 6-OHDA-lesioned rats with a D$\sb1$ agonist produce partial sensitization of DA D$\sb1$ receptors in adulthood without altered biochemical markers, and that this neonatal lesion is associated with both supersensitized DA D$\sb1$ and 5-HT$\sb{\rm 1C}$ receptors. Moreover, induction of oral activity by DA agonists is mediated via a serotonergic system.

The signaling mechanisms for muscarinic receptor-mediated vasoconstriction in coronary resistance arteries were studied in KCl-arrested isolated rat hearts perfused at a constant flow rate. The cholinergic agonists acetylcholine and bethanechol were given by bolus injection or constant infusion. The coronary vascular resistance was monitored by measuring the changes in perfusion pressure. The selective muscarinic agonist bethanechol caused a similar vasoconstrictor response as ACh, but with less potency and efficacy. Bolus injection of bethanechol evoked a phasic vasoconstriction in a dose-dependent manner, while infusion of bethanechol evoked a tonic vasoconstriction without producing tachyphylaxis. Coronary vascular responses to bethanechol were further examined in the absence and presence of a specific inhibitor or blocker for the potential signaling components. The bethanechol-induced phasic vasoconstriction was eliminated by perfusion with a Ca2+ -free medium. The maximal vasoconstriction to bethanechol was suppressed by 31% in the presence of the Ca2+ -dependent Cl- -channel blocker A-9-C. The L-type voltage-operated Ca2+ channel blocker nifedipine decreased the maximal constrictor response to bethanechol by 59%, while the putative receptor-operated Ca 2+ channel blocker SK&F 96365 converted this vasoconstriction into vasodilation which was not affected by the nitric oxide synthase inhibitor L-NAME. Coronary vascular responses to bethanechol were almost abolished by a combination of nifedipine and SK&F 96365. The protein kinase C inhibitor chelerythruine reduced bethanechol-evoked peak vasoconstriction by 79%. The bethanechol-induced tonic vasoconstriction was rapidly converted into vasodilation by the concomitant infusion of SK&F 96365 or nifedipine, but the simultaneous infusion of chelerythrine gradually attenuated this response. These data suggest that the novel receptor-operated Ca2+ channel, voltage-operated Ca2+ channel, and protein kinase C are the most crucial signaling components for muscarinic receptor-mediated coronary vasoconstriction in the isolated rat heart. Extracellular Ca 2+ influx via receptor-operated Ca2+ channels and voltage-operated Ca2+ channels is essential to both phasic and tonic vasoconstrictor responses to bethanechol. Protein kinase C plays a pivotal role in the regulation of bethanechol-evoked vasoconstriction by sensitizing the contractile apparatus and modulating the activity of Ca 2+ channels.