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M W Oglesby

Publications and source records attributed to M W Oglesby.

8 recordsLinked to original sources
PubMed2001

Use of negatively reinforcing electrical brain stimulation to detect conventional and nonconventional anxiolytics as well as an anxiogenic drug.

The present study determined whether anxiolytics such as diazepam (DZP), the benzodiazepine (BZD) receptor-selective agonist abecarnil (ABC), or the 5-HT1(A) agent buspirone (BUS) would increase the response latency of rats to switch-off electrical brain stimulation (EBS) of the periaqueductal gray (PAG). We also investigated the effects of pentylenetetrazole (PTZ), a purported anxiogenic. Given acutely, DZP (2.5 and 5 mg/kg, ip) and ABC (0.5 and 1 mg/kg, ip) increased response latency. The BZD receptor antagonist flumazenil (10.0 mg/kg, ip) blocked these effects. Increasing the frequency of EBS reversed the effects of DZP and ABC, suggesting that motor disruption did not account for the increase in latency seen with these drugs. Given acutely, BUS (10.0 mg/kg, ip) also increased response latency, which was likely due to motor disruption because it was not reversed by increasing the frequency of EBS. When BUS (2.5 mg/kg, ip) was given every 8 h for 3 days, an increase in latency was also obtained, which was reversible by increasing the frequency of EBS. Finally, PTZ (10 and 20 mg/kg, ip) shortened the latency to respond. These results (1) suggest that DZP, ABC, and chronic BUS attenuate, whereas PTZ potentiates, the negative reinforcing stimulus (NRS) induced by PAG stimulation, and (2) support the hypothesis that the switch-off procedure accurately detects anxiolytic and anxiogenic drugs.

Animals↗
PubMed2001

Nitric oxide and substance dependence.

The free-radical gas nitric oxide (NO) plays an important role in a diverse range of physiological processes. It is synthesized from the precursor L-arginine by the enzyme NO synthase (NOS), which transforms L-arginine into NO and citrulline. This synthetic pathway exists in the central nervous system (CNS), and NO appears to be a messenger molecule in the CNS, fulfilling most of the criteria of a neurotransmitter. Recent studies indicate that NO may play an important role in dependence on drugs of abuse. The purpose of this review is to address the role of NO in dependence on substances such as opioids, ethanol, psychostimulants and nicotine. Inhibitors of NOS modulate withdrawal from opioids and ethanol, diminishing many signs of withdrawal. In addition, NOS inhibitors suppress signs of withdrawal from nicotine. These data suggest that NO may be involved in the expression of withdrawal signs, and they leave open the possibility that NO may mediate the development of many of these signs. Although preliminary, data to date suggest that glutamate neurotransmission may be related to these beneficial effects of NOS inhibitors on signs of withdrawal. Emerging data further suggest that NO may have a general role in the dependence potential of various classes of drugs of abuse. Thus, modulation of NO systems may be a potential therapeutic target for treatment of substance abuse.

Humans↗
PubMed1999

Increased sensitivity to cocaine, and over-responding during cocaine self-administration in tPA knockout mice.

Tissue plasminogen activator, tPA, is induced in the brain by electrical activity leading to synaptic remodeling. It is also induced in the prefrontal cortex (PFC) by acute cocaine. We investigated cocaine-induced locomotor activity, the development of sensitisation to cocaine and cocaine self-administration in mice lacking the gene encoding tPA. Mice lacking tPA (tPA knockout mice, tPA-/-) showed normal spontaneous activity, exhibited cocaine-induced locomotor activity at lower doses than wild-type (WT) control mice and showed a greater degree of cocaine-induced locomotor activity following repeated administration. tPA-/- and WT mice did not differ significantly in the time to acquire self-administration of cocaine (20 microg/i.v. infusion) under an FR2 schedule. Following acquisition of this behavior, these groups also did not differ significantly in the rate of cocaine self-administration across the next three sessions. However, WT mice decreased responses on the active lever during signaled periods when reinforcer was not available; in contrast, tPA-/- mice did not. The emission of non-reinforced responses was most marked at the beginning of each 90 min daily session. This pattern of responding was not seen in tPA-/- mice pressing for food under an FR2 schedule of reinforcement. These results suggest that tPA may play a specific role either in retention of information between sessions or in behavioural inhibition in cocaine self-administration.

Animals↗
PubMed1998

Discriminative stimulus effects of diazepam, ketamine and their mixture: ethanol substitution patterns.

When ethanol is used as a training stimulus in drug discrimination experiments, benzodiazepines (such as diazepam) as well as non-competitive N-methyl-D-aspartate (NMDA) antagonists (such as ketamine) substitute for ethanol; in contrast, when a benzodiazepine or an NMDA antagonist is used as a training drug, ethanol does not substitute reliably. In the present experiments, we trained rats to discriminate a mixture of diazepam and ketamine, to test the hypothesis that ethanol would substitute for this drug combination. Using a two-lever choice procedure with food as a reinforcer, 22 rats were trained to discriminate a mixture of diazepam (5.6 mg/kg) and ketamine (10 mg/kg) from vehicle. When administered as a mixture, diazepam and ketamine substituted for the training mixture in a dose-dependent manner. When administered separately, diazepam or ketamine substituted for the mixture with full substitution occurring at 5.6 and 17.8 mg/kg, respectively. Ethanol almost completely substituted for the mixture at 1 g/kg. There was no cross-substitution between diazepam and ketamine in rats trained to discriminate diazepam (5.6 mg/kg, n = 10) or ketamine (10 mg/kg, n = 12) from vehicle. In addition, ethanol did not substitute for the training drug in either of these discriminations. These results suggest that the simultaneous action of GABAA agonist and NMDA antagonist mechanisms produce a greater ethanol-specific discriminative stimulus than activation of either component individually.

Animals↗
PubMed1975

Catecholamines and drug-behavior interactions.

The effects of several drugs on schedule-controlled operant behavior depend on the baseline rate of responding and on the nature of the environmental conditions that maintain the behavior. For example, the effects of amphetamine and alpha-methylpara-tyrosine (alphaMT) on operant performances depend to a large extent on the rate at which organisms respond under nondrug control conditions. A neurochemical mechanism for these rate-dependent effects has not been established. However, several lines of evidence suggest that catecholamines are functionally important in the maintenance of many types of behavior, including operant behavior. The fact that many drugs which exhibit drug-behavior interactions also produce characteristic effects on the metabolism of central nervous system catecholamines suggests that the performance of operant behavior per se modifies brain catecholamine metabolism and thereby the subsequent drug effect. Experiments measuring the depletion of catecholamines following synthesis inhibition with alphaMT, or changes in the specific activity of norepinephrine after tritium labeling, have shown that operant behavior alters the metabolism of catecholamines. Preliminary evidence is also presented from experiments designed to determine variables associated with the performance-induced changes in catecholamine metabolism. These variables include: rate of responses; rate or density of reinforcement; and response-reinforcer contingencies. The results of these experiments suggest a neurochemical mechanism for the rate-dependent effects of amphetamine and alphaMT. A model is presented that may account for the general phenomenon of drug-behavior interactions in neurochemical terms.

Animals↗