Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but ...antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDAR glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open-field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/kainate receptor activation, as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 h) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels, as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of 'metaplasticity' by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.
GHB: a new and novel drug of abuse Nicholson, Katherine L.; Balster, Robert L.
Drug and alcohol dependence,
06/2001, Letnik:
63, Številka:
1
Journal Article
Recenzirano
There has been increasing attention in the United States to problems of abuse of
gamma-hydroxybutyrate (GHB), with some evidence for problems in other parts of the world as well. In vitro and animal ...research show that, while GHB shares some properties with abused central nervous system depressant drugs, it has unique aspects of its pharmacology as well, including actions at a specific neural receptor which probably mediates many of its effects. Abuse potential assessment of GHB using standard animal models has not yielded a picture of a highly abusable substance, but little human testing has yet been done. Very little systematic data exist on tolerance and dependence with GHB, but both have been seen in human users. Quantitative data on the prevalence of GHB abuse is incomplete, but various qualitative measures indicate that a mini-epidemic of abuse began in the late 1980s and continues to the present. GHB is often included with the group of ‘club drugs’, and can be used as an intoxicant. It also has been used as a growth promoter and sleep aid and has been implicated in cases of ‘date rape’, usually in combination with alcohol. Undoubtedly the easy availability of GHB and some of its precursors has contributed to its popularity. Recent changes in the control status of GHB in the US may reduce its availability with as yet unknown consequences for the scope of the public health problem. Drug abuse experts need to familiarize themselves with GHB as possibly representing a new type of drug abuse problem with some unique properties.
A selective wavelet shrinkage algorithm for digital image denoising is presented. The performance of this method is an improvement upon other methods proposed in the literature and is algorithmically ...simple for large computational savings. The improved performance and computational speed of the proposed wavelet shrinkage algorithm is presented and experimentally compared with established methods. The denoising method incorporated in the proposed algorithm involves a two-threshold validation process for real-time selection of wavelet coefficients. The two-threshold criteria selects wavelet coefficients based on their absolute value, spatial regularity, and regularity across multiresolution scales. The proposed algorithm takes image features into consideration in the selection process. Statistically, most images have regular features resulting in connected subband coefficients. Therefore, the resulting subbands of wavelet transformed images in large part do not contain isolated coefficients. In the proposed algorithm, coefficients are selected due to their magnitude, and only a subset of those selected coefficients which exhibit a spatially regular behavior remain for image reconstruction. Therefore, two thresholds are used in the coefficient selection process. The first threshold is used to distinguish coefficients of large magnitude and the second is used to distinguish coefficients of spatial regularity. The performance of the proposed wavelet denoising technique is an improvement upon several other established wavelet denoising techniques, as well as being computationally efficient to facilitate real-time image-processing applications.
Commentary to: Clinical provision of improvised nasal naloxone without experimental testing and without regulatory approval: imaginative shortcut or dangerous bypass of essential safety procedures?
Regulatory control of drugs with abuse liability is an important component of drug control policy and is believed to help prevent nonmedical use. To be maximally effective, this requires a scientific ...assessment of abuse liability of drugs considered for regulatory control. These assessments have relied extensively on laboratory-based animal and human testing, but also utilize information from clinical trials, actual abuse and other sources. Here, we discuss recommendations and guidelines that have been proposed for abuse liability assessment and describe important review papers and conference proceedings that have addressed this matter, focusing primarily on drugs with medical usefulness. Historically, there is substantial consensus about how to approach abuse liability evaluation of drugs with actions similar to those of abused opiates, stimulants, depressants, and to a somewhat lesser extent, cannabinoids and hallucinogens, and much of what has been recommended for abuse potential assessment in the past remains valid and useful. On the other hand, novel CNS-active medications which cannot be readily classified with these traditional drugs of abuse are increasingly under development. In addition, advances in the science of abuse liability assessment need to be incorporated into future guidelines and recommendations on this subject. Developers of new medications need guidance on how to utilize scientific research to maximize therapeutic benefit while minimizing risk for abuse. Thus, another goal of this review has been to identify areas where critical thinking and new guideline development are needed.
Electronic cigarettes (ECIGs) are a relatively new class of tobacco products and a subject of much debate for scientists and policymakers worldwide. Objective data that address the ECIG risk-benefit ...ratio for individual and public health are needed, and addressing this need requires a multidisciplinary approach that spans several areas of psychology as well as chemistry, toxicant inhalation, and physiology. This multidisciplinary approach would benefit from methods that are reliable, valid, and swift. For this reason, we formed a multidisciplinary team to develop methods that could answer questions about ECIGs and other potential modified risk tobacco products. Our team includes scientists with expertise in psychology (clinical, community, and experimental) and other disciplines, including aerosol research, analytical chemistry, biostatistics, engineering, internal medicine, and public health. The psychologists on our team keep other members focused on factors that influence individual behavior, and other team members keep the psychologists aware of other issues, such as product design. Critically, all team members are willing to extend their interests beyond the boundaries of their discipline to collaborate effectively with the shared goal of producing the rigorous science needed to inform empirically based tobacco policy. In addition, our trainees gain valuable knowledge from these collaborations and learn that other disciplines are accessible, exciting, and can enhance their own research. Multidisciplinary work presents challenges: learning other scientists' languages and staying focused on our core mission. Overall, our multidisciplinary team has led to several major findings that inform the scientific, regulatory, and public health communities about ECIGs and their effects.
A combined spatial- and temporal-domain wavelet shrinkage algorithm for video denoising is presented in this paper. The spatial-domain denoising technique is a selective wavelet shrinkage method ...which uses a two-threshold criteria to exploit the geometry of the wavelet subbands of each video frame, and each frame of the image sequence is spatially denoised independently of one another. The temporal-domain denoising technique is a selective wavelet shrinkage method which estimates the level of noise corruption as well as the amount of motion in the image sequence. The amount of noise is estimated to determine how much filtering is needed in the temporal-domain, and the amount of motion is taken into consideration to determine the degree of similarity between consecutive frames. The similarity affects how much noise removal is possible using temporal-domain processing. Using motion and noise level estimates, a video denoising technique is established which is robust to various levels of noise corruption and various levels of motion.
Neural basis of inhalant abuse Balster, Robert L
Drug and alcohol dependence,
06/1998, Letnik:
51, Številka:
1
Journal Article
Recenzirano
It should be apparent from this review that far less is known about the neural basis for inhalant abuse than for other forms of drug abuse. This reflects a lack of research interest in this area ...(Balster, 1997). Indeed, conclusions are difficult to draw. In the case of the volatile alkyl nitrites, the most reasonable hypothesis at this time is that the cellular basis for their abuse resides in their actions on smooth muscles to produce vasodilation and relaxation, however, direct effects on the brain cannot be ruled out. Although there is some evidence that analgesic effects of nitrous oxide may involve opiate systems, even this conclusion is controversial. There is no evidence that opiate systems play a role in nitrous oxide intoxication or reinforcement. The mechanisms for these effects are unknown. They may reflect the same actions on lipid membranes or on hydrophobic sites on unspecified proteins that have been proposed as mechanisms for nitrous oxide anesthesia. In the case of the volatile solvents, fuels and anesthetics we are faced with a wide variety of specific chemicals which may produce different profiles of pharmacological effects. There is evidence that the prototypic abused solvents toluene and trichloroethane produce acute effects similar to subanesthetic concentrations of general anesthetics, as well as to the effects of classical CNS depressant drugs, such as alcohol and the barbiturates. For the anesthetics, evidence suggests that enhancement of GABAergic inhibition may be an important cellular target for their acute effects, just as it is for alcohol and other depressant drugs. For toluene, as with alcohol, recent evidence suggests a possible role for inhibition of glutamatergic neurotransmission involving NMDA receptors. Toluene has also been shown to have some dopaminergic effects which may be important to its abuse. As for the large number of other abused vapors, practically no information can be found on their cellular actions, and certainly not on actions that may be relevant to their abuse. This entire area would seem an important direction for future research.
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