James H. Woods

Behavioral variables affecting the development of amphetamine tolerance

SummaryThe behavioral effects of chronic administration of d-amphetamine in rats at a dosage of 1 mg/kg were studied with baselines involving either food or shock reinforcement. Food reinforcement was assigned according to a fixed interval or on the basis of differential reinforcement of low rate in a multiple schedule of reinforcement. Behavioral tolerance was observed in response to chronic administration of d-amphetamine when the action of drug led to a decrease in frequency of food reinforcement regardless of the schedule of reinforcement. In the second experiment, a shock avoidance situation was employed in which each avoidance response postponed the onset of grid shock. An escape contingency was provided for occasions on which an avoidance response did not occur. The chronic administration of d-amphetamine led to a uniform increase in response rate throughout the drug regimen with the consequence of decreasing rate of shock reinforcement. An hypothesis was put forward on the basis of these results which considers the development of behavioral tolerance to amphetamine administration to be a function of the drugs action in relation to its effects on the organisms behaviour in meeting reinforcement requirements.

Current benzodiazepine issues

This article deals with some of the recent evidence bearing on the issues of the liability of benzodiazepines to lead to abuse, dependence, and adverse behavioral effects. Reviews of epidemiological, clinical and experimental literature indicated that the previous conclusion about abuse of these drugs still holds: the vast majority of the use of benzodiazepines is appropriate. Problems of nonmedical use arise nearly exclusively among people who abuse other drugs. Nevertheless, there are reasons for concern about patients who take benzodiazepines regularly for long periods of time. These drugs can produce physiological dependence when taken chronicaly, and although this does not appear to result in dose escalation or other evidence of “psychological dependence,” physiological dependence can result in patient discomfort if drug use is abruptly discontiniued. Also, physicians are currently prescribing shorter-acting benzodiazepines in preference to longer-acting benzodiazepines. The shorter-acting drugs can produce a more intense withdrawal syndrome following chronic administration. Furthermore, rates of use of benzodiazepines increase with age, and elderly patients are more likely than younger ones to take the drug chronically. The clearest adverse effect of benzodiazepines is impairment of memory. This, too, may be particular concern in older patients whose recall in the absence of drug is typically impaired relative to younger individuals, and who are more compromised following drug administration.

Effects of Buprenorphine Maintenance Dose on μ -Opioid Receptor Availability, Plasma Concentrations, and Antagonist Blockade in Heroin-Dependent Volunteers

The clinical effectiveness of opioid maintenance for heroin dependence is believed to result from a medications ability to decrease μ-opioid receptor (μOR) availability thereby replacing agonist effects, alleviating withdrawal symptoms and attenuating heroin effects. We empirically tested this hypothesis in five heroin-dependent volunteers who were successively maintained on 32, 16, 2, and 0 mg daily buprenorphine (BUP) tablet doses. We predicted and confirmed that higher BUP doses would decrease in vivo μOR availability (measured with PET and [11C]carfentanil), increase plasma levels of BUP and its metabolite nor-BUP, and decrease withdrawal symptoms and hydromorphone (HYD) responses. Relative to placebo, BUP significantly decreased mean (±SEM) whole-brain μOR availability 41±8, 80±2, and 84±2% at 2, 16, and 32 mg, respectively. Regions of interest (ROIs) (prefrontal cortex, anterior cingulate, thalamus, amygdala, nucleus accumbens, caudate) showed similar dose-dependent effects. Changes in μOR availability varied across ROIs (prefrontal cortex, 47% vs amygdala, 27%) at BUP 2 mg, but were more homogeneous across ROIs at BUP 32 mg (94–98%; except thalamus, 88%). Relative to placebo (0 ng/ml), peak plasma levels of BUP and nor-BUP were comparable and dose-dependent (0.5–1, 5–6, and 13–14 ng/ml at 2, 16, and 32 mg, respectively). μOR availability decreases were negatively correlated with BUP plasma level and positively correlated with questionnaire-based opioid withdrawal symptoms and attenuation of HYD symptoms. These findings suggest that high-dose BUP maintenance produces near-maximal μOR occupation, μOR availability correlates well with plasma levels, and BUP-related opioid symptoms and antagonist blockade exhibit concentration–effect relationships.

Nonpeptidic δ-opioid Receptor Agonists Reduce Immobility in the Forced Swim Assay in Rats

The present study examined the effect of opioid receptor agonists in the rat forced swim assay. The δ-opioid receptor agonists SNC80 ((+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide) and (+)BW373U86 ((+)-[1(S*),2α,5β]-4-[[2,5-dimethyl-4-(2-propenyl)-1-piperazinyl] (3-hydroxyphenyl)methyl]-N,N-diethyl-benzamide dihydrochloride) produced a decrease in immobility indicating an antidepressant-like effect. At antinociceptive doses, neither the κ-opioid selective agonist CI977 (5R-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl-1-oxaspiro[4,5]dec-8-yl]-4-benzofuranacetamide) showed a change in immobility that was identifiable by dose, nor were changes in immobility seen with morphine. A δ-opioid mechanism of action in the forced swim assay was likely since naltrindole prevented the effects of both δ-agonists. When compared to desipramine and fluoxetine, SNC80 was more active with a single dose whereas both desipramine and fluoxetine produced greater effects with subchronic dosing (3 doses). All three compounds were active when administered before the initial swim exposure. SNC80 was, however, more effective following a single dose than by subchronic administration demonstrating both a fast onset of activity and potential tolerance. Thus, δ-agonists differ from typical antidepressants in the forced swim assay.

IV. DISCRIMINATIVE STIMULUS EFFECTS OF NARCOTICS: EVIDENCE FOR MULTIPLE RECEPTOR-MEDIATED ACTIONS

Abstract Results of studies on the discriminative stimulus effects of narcotics are consistent with the hypothesis that multiple receptors mediate the effects of these compounds. In the rat, at least three subsets of discriminative effects exist, although some drugs appear to have effects that transcend more than one subset. The discriminative effects of morphine-like narcotics (μ agonists), for example, are often clearly distinguishable from the discriminative effects produced by κ agonists, such as ketazocine, and from those produced by phencyclidine-like agonists, such as SKF-10,047 and cyclazocine. Cyclazocine, however, has been reported to have discriminative effects in common with morphine (45) and fentanyl (17) and appears to have κ-like, in addition to phencyclidine-like, discriminative effects. The relative ability of pure narcotic antagonists to block the discriminative effects of these compounds also provides evidence for distinct pharmacologic actions of these drugs. In the rat, the discriminative effects of morphine are blocked by doses of naloxone that are considerably smaller than those that are needed to block the discriminative effects of cyclazocine (44). The discriminative effects of phencyclidine are not altered at all by naltrexone (63).

Genetic variance in nociception and its relationship to the potency of morphine-induced analgesia in thermal and chemical tests

&NA; The perceived intensity of a painful stimulus is determined in part by the stimulus intensity and environmental conditions. The purpose of this study was to determine the influence of genetic factors in nociception and its contribution to the potency of morphine to produce antinociception. Eight inbred strains of mice were tested across a range of stimulus intensities in thermal (hot plate) and chemical irritant (acetic acid) nociceptive tests. Stimulus intensities in the thermal test included hot plate temperatures of 51, 53, 55, 57 and 59°C. Stimulus intensities in the chemical irritant test included acetic acid concentrations of 0.1, 0.3 and 0.6%. Linear interpolation of stimulus‐effect curves revealed large genotype‐dependent differences in the effective temperature resulting in a 10 s latency on the hot‐plate (ET10″) and the acetic acid concentration resulting in the same number of writhes as determined by the area under the curve (AUC50). There was no genetic correlation between sensitivity to thermal versus chemical stimuli. Morphine dose response curves were then determined at a fixed stimulus intensity in each test (55°C and 0.6% acetic acid) to determine analgesic ED50 doses for each inbred strain. A significant effect of genotype on relative sensitivity to morphine‐induced analgesia in both the thermal and chemical irritant tests was found, however there was no genetic correlation between the potency of morphine in each test. There was an inverse genetic correlation between sensitivity to thermal and chemical stimuli and morphine ED50 values in each respective test. In both tests, strains less sensitive to the nociceptive stimuli were more sensitive to the antinociceptive effects of morphine. Confirmation studies in a separate genetic population confirmed the inverse relationship between hot‐plate sensitivity and antinoceptive potency. In summary, this study demonstrated (i) a large degree of genetically‐determined variability in sensitivity to painful stimuli, (ii) sensitivity to thermal stimuli (hot‐plate) is genetically unrelated to sensitivity to chemical (acetic acid) stimuli, (iii) the mechanism by which morphine produces its antinociceptive effects against thermal stimuli is largely genetically independent of the mechanism by which morphine produces its antinociceptive effects against chemical stimuli, and (iv) inherent differences in sensitivity to painful stimuli may be responsible, in part, for individual differences in the potency of morphines antinociceptive effects.

Most Efficient Cocaine Hydrolase Designed by Virtual Screening of Transition States

Cocaine is recognized as the most reinforcing of all drugs of abuse. There is no anticocaine medication available. The disastrous medical and social consequences of cocaine addiction have made the development of an anticocaine medication a high priority. It has been recognized that an ideal anticocaine medication is one that accelerates cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e., cocaine hydrolysis catalyzed by plasma enzyme butyrylcholinesterase (BChE). However, wild-type BChE has a low catalytic efficiency against the abused cocaine. Design of a high-activity enzyme mutant is extremely challenging, particularly when the chemical reaction process is rate-determining for the enzymatic reaction. Here we report the design and discovery of a high-activity mutant of human BChE by using a novel, systematic computational design approach based on transition-state simulations and activation energy calculations. The novel computational design approach has led to discovery of the most efficient cocaine hydrolase, i.e., a human BChE mutant with an approximately 2000-fold improved catalytic efficiency, promising for therapeutic treatment of cocaine overdose and addiction as an exogenous enzyme in human. The encouraging discovery resulted from the computational design not only provides a promising anticocaine medication but also demonstrates that the novel, generally applicable computational design approach is promising for rational enzyme redesign and drug discovery.

Differential effects of systemically administered nor-binaltorphimine (nor-BNI) on κ-opioid agonists in the mouse writhing assay

The opioid antagonist effects of systemically administered nor-binaltorphimine (nor-BNI) were evaluated against the kappa agonists CI-977, U69,593, U50,488, ethylketocyclazocine (EKC), Mr2034 and bremazocine, the mu agonist morphine and the alkaloid delta agonist BW-373U86 in the acetic acid-induced writhing assay in mice. All eight agonists completely and dose-dependently inhibited writhing. Antagonism of CI-977 was apparent 1 h after administration of 32 mg/kg nor-BNI, peaking after 4 h and was maintained for at least 4 weeks; no antagonist effects of nor-BNI were apparent after 8 weeks. Nor-BNI (32 mg/kg) caused little or no antagonism of morphine or BW-373U86 at 1 h and none at 24 h after nor-BNI administration. Subsequently, dose-effect curves for CI-977, U50,488, U69,593, EKC, Mr2034 and bremazocine were determined 24 h after pretreatment with 3.2, 10 and 32 mg/kg nor-BNI. Pretreatment with 3.2 mg/kg nor-BNI produced significant antagonism of all six kappa agonists, suggesting that their antinociceptive effects were mediated at least in part by nor-BNI-sensitive kappa receptors. At higher doses, nor-BNI dose-depend-ently shifted the agonist dose-effect curves of CI-977, U50,488, U69,593 and bremazocine, but not those of EKC and Mr2034, suggesting that the latter compounds may be producing effects via nor-BNI-insensitive receptors. Mu receptor involvement was demonstrated following a 24 h pretreatment with 32 mg/kgβ-FNA in combination with nor-BNI, which significantly increased the degree of antagonism of Mr2034 and EKC from that seen with nor-BNI alone. Hence, SC administered nor-BNI selectively antagonized agonist activity mediated through kappaopioid receptors without differentiating between kappa subtypes. Nor-BNI also enabled the mu agonist activity of proposed kappa agonists to be measured.

Stereospecific binding of 3H-phencyclidine in brain membranes.

Phencyclidine (PCP) displaceable binding of 3H-PCP to glass-fiber filters was eliminated and total binding markedly reduced by initial treatment of the discs with 0.05% polyethyleneimine. Assessed with treated filters, unlabeled PCP displaced 3H-PCP in both rat and pigeon brain membranes with an EC50 of 1 microM. Of similar high inhibitory potency were dextrorphan, levorphanol, SKF 10047 and ketamine, while morphine, naloxone and etorphine had EC50 values higher then 1 mM. Using the dissociative anesthetic dexoxadrol and its inactive isomer levoxadrol as displacing agents, stereospecific binding of 3H-PCP was obtained in rat and pigeon brain membranes. The markedly higher potency of dexoxadrol, relative to levoxadrol, in displacing bound 3H-PCP is compatible with behavioral data for these enantiomers. However, they were equipotent in displacing 3H-PCP bound to glass-fiber filters in the absence of tissue. Heat denaturation, but not freezing, abolished stereospecific binding of 3H-PCP, which was also absent in rat liver membranes. The stereospecific binding component in brain displayed biphasic saturability at 60-70 nM and 300-400 nM, respectively.

Behavioral and Neurochemical Consequences of Long-Term Intravenous Self-Administration of MDMA and Its Enantiomers by Rhesus Monkeys

The effects of self-administered 3,4-methylenedioxymethamphetamine (MDMA) on behavior and neurochemistry have not been previously studied in laboratory primates. We investigated the capacity of MDMA and its enantiomers to maintain contingent responding over an extended duration, whether any decrements in the reinforcing effects of these compounds would be observed over time, whether such decrements would be MDMA-selective, and whether any neurochemical correlates could be identified. Animals were previously trained to self-administer cocaine, then exposed to periodic substitutions of various doses of racemic MDMA and its enantiomers; full dose–effect curves were generated for each MDMA compound repeatedly over the duration of the study. After approximately 18 months of MDMA self-administration, drug exposure was halted and after at least 2 months drug abstinence, animals were scanned using positron emission tomography (PET) with the vesicular monoamine transporter (VMAT) ligand dihydrotetrabenazine (DTBZ). Shortly thereafter, animals were euthanized, brains were dissected, and samples were assayed for brain monoamines and their metabolites using high-performance liquid chromatography (HPLC), and for VMAT using DTBZ binding. The reinforcing effects of racemic and R(−)-MDMA were reduced over a long series (months) of individual self-administration access periods; the reinforcing effects of S(+)-MDMA were more resistant to this effect, but were attenuated for one animal. The reinforcing effects of cocaine were not altered by chronic MDMA self-administration, nor was the VMAT binding potential as assessed by PET. Further, there were no measurable decrements in serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) or VMAT in any brain regions assayed. The reinforcing effects of MDMA are selectively attenuated by chronic MDMA self-administration, although this behavioral change appears to occur in the absence of any frank neurochemical correlates of toxicity.