An Introduction to Drugs and the Neuroscience of Behavior

This up-to-date text provides an introductory overview of the nervous system actions and behavioral effects of the major classes of psychoactive drugs, using pedagogy unique among pharmacology texts to make the topic approachable

The quetiapine active metabolite N-Desalkylquetiapine and the neurotensin NTS1 receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats

Major depressive disorder (MDD) is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that are apparent following one week of quetiapine treatment, and it is possible that the active metabolite N-Desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 are suggestive of antidepressant efficacy, but the effects of a NTS1 receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of the N-Desalkylquetiapine, the neurotensin NTS1 receptor agonist PD14916, quetiapine, the tricylic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate (DRL) 72 s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. The typical antipsychotic drug raclopride decreased both reinforcers and responses. These data suggest that N-Desalklyquetiapine likely contributes to quetiapine’s antidepressant efficacy and identifies NTS1 receptor activation as a potential novel pharmacologic strategy for antidepressant drugs

Neurotensin NTS1 and NTS2 receptor agonists produce anxiolytic-like effects in the 22-kHz ultrasonic vocalization model in rats

Neurotensin is a neuropeptide neurotransmitter that interacts with multiple neurotransmitter systems, including those regulating amygdalar function, via NTS1 and NTS2 receptors. Both receptors are expressed in the amygdala and agonists for NTS1 or NTS2 receptors have exhibited anxiolytic effects in animal models. Systemic adminstration of NTS1 receptor agonist PD149163 was recently shown to reduce footshock conditioned 22-kHz ultrasonic vocalizations in rats, suggesting that PD149163 produced an anxiolytic effect. The effects that neurotensin may have or a selective NTS2receptor agonist may have on 22-kHz vocalizations has yet to be examined. The current study evaluated the effects of intracerebroventricularly administered neurotensin (0.1–10.0 μg), PD149163 (0.1–10.0 ng), or the NTS2 receptor agonist JMV-431 (0.1–1.0 μg) on footshock conditioned 22-kHz vocalizations in male Wistar rats. Neurotensin, PD149163, and JMV-431 all significantly reduced the number 22-kHz calls. No changes in call duration were found, suggesting that non-specific drug effects do not account for the reductions in 22-kHz calls. These data support anxiolytic effects produced by activation of NTS1 or NTS2 receptors, and suggest that neurotensin plays a natural role in the expression of conditioned USVs. These data suggest that both receptor subtypes are putative pharmacologic targets

Discriminative stimulus properties of 1.25 mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors

The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug dis- crimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25 mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT2A inverse agonist M100907 and the two preferential D4/5-HT2/α1 receptor antagonists Lu 37-114 ((S)-1-(3-(2-(4- (1H-indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4-(1H-indol-5-yl) piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one). Partial substitution occurred with the D4 re- ceptor antagonist Lu 38-012 and the α1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT2C, 5-HT6 muscarinic, histamine H1, and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT2A inverse agonism and D4 receptor antagonism mediate the dis- criminative stimulus properties of 1.25 mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus

The renormalization group for interacting fermions: from Fermi liquids to quantum dots

The renormalization group approach as developed by the author for Fermi liquids is applied to clean Fermi liquids and ballistic quantum dots. In the former case Landau theory is shown to be a fixed point and in the latter the Universal Hamiltonian is shown to be a fixed point for weak coupling. The strong coupling phase is analyzed using large N and Random Matrix methods.Comment: Lectures given at the Fifteenth Chris Engelbrecht Summer School South Africa, January 2004. 6 eps figs and springer style file (svmult

Neurotensin analogs for neurocognitive deficits in schizophrenia

This grant provides me with a one term course reduction to work on a paper on the virtue of Patience and the vice of Wrath. Aristotle has it right; ?Getting angry [?] is easy and everyone can do it; but doing it to the right person, in the right amount, at the right time, for the right end, and in the right way is not easy, nor can everyone do it.? Building from Aristotle, we can relatively easily characterize a wrathful person: someone prone to extreme anger in inappropriate circumstances. A patient person, then, feels just the right amount of anger in just the appropriate circumstances. But saying exactly what the right amount of anger would be in which circumstances is quite difficult, as Aristotle suggests. In this project, I appeal to recent work in psychology and the philosophy of emotion to explore our reasons for feeling?and avoiding?anger. In doing so I relate virtue theory to the recent philosophical focus on reasons for attitudes. By pulling apart different reasons that bear on whether to be angry, how intensely to be angry, in what way, and in which situations, I explore the considerations to which the patient person is sensitive and the particular faults present in the wrathful person

Drugs and the Neuroscience of Behavior: An Introduction to Psychopharmacology

The up-to-date Second Edition presents an introduction to the rapidly advancing field of psychopharmacology by examining how drug actions in the brain affect psychological processes. The book provides historical background to give readers an appreciation for the development of drug treatments and neuroscience over time, covering major topics in psychopharmacology, including new drugs and recent trends in drug use. Pedagogical features informed by the latest scholarship in teaching and learning are integrated throughout the text to ensure that readers are able to process and understand the material with ease

Acute, but not repeated, administration of the neurotensin NTS1 receptor agonist PD149163 decreases conditioned footshock-induced ultrasonic vocalizations in rats.

Neurotensin is an endogenous neuropeptide that has significant interactions with monoamine neurotransmitter systems. To date, neurotensin NTS1 receptor agonists, such as PD149163, have been primarily evaluated for the treatment for schizophrenia, drug addiction, and pain. Recently, PD149163 was found to attenuate fear-potentiated startle in rats, an experimental procedure used for screening anxiolytic drugs. The present study sought to extend these findings through testing PD149163 in a conditioned footshock-induced ultrasonic vocalization (USV) model. Conditioning was conducted in Male Wistar rats using chambers equipped with shock grid floors and an ultrasonic vocalization detector. PD149163 and the 5-HT1A receptor partial agonist buspirone produced a statistically significant reduction of 22 kHz USV counts. The typical antipsychotic haloperidol also reduced 22 kHz USV counts, but did so at cataleptic doses. Ten days of repeated administration of PD149163 abolished the inhibitory effects of PD149163 on 22 kHz USVs. These findings further support an anxiolytic profile for PD149163. However, tolerance to these effects may limit the utility of these drugs for the treatment of anxiety