Pharmacological and physiological effects of ginseng on actions induced by opioids and psychostimulants

Pharmacological and physiological effects of ginseng on actions induced by opioids and psychostimulants were summarized. Analgesic effects of opioids, such as morphine and U-50,488H, were blocked by ginseng in a non-opioid dependent manner. Furthermore, ginseng inhibited the tolerance to and dependence on morphine, and prevented the suppressive effect on the development of morphine tolerance caused by co-exposure to foot-shock stress, but not psychological stress. On the other hand, behavioral sensitization (reverse tolerance to ambulation-accelerating effect) to morphine, methamphetamine (MAP) and cocaine was also inhibited by ginseng. Interestingly, ginseng also inhibited the appearance of the recurrent phenomenon (reappearance of the sensitized state was observed at the time of readministration of MAP and cocaine even after a 30-day discontinuation of drug administration) of the effect of MAP and cocaine. The conditioned place preference of MAP and cocaine was completely blocked by ginseng. These findings provide evidence that ginseng may be useful clinically for the prevention of abuse and dependence of opioids and psychostimulants.     

Tolerance to the reinforcing effects of cocaine

This study tested the hypothesis that prolonged exposure to high doses of cocaine would produce tolerance to the reinforcing effects of cocaine. We determined the rate of administration of low doses of cocaine in rats and then exposed these subjects to high doses of cocaine (5mg) three-times a day for 1 week. This treatment caused a 2-fold faster intake of cocaine, and the lowest dose of cocaine that would maintain self-administration was double the previous threshold dose. To our knowledge this is the first controlled demonstration of tolerance to the reinforcing effects of cocaine produced by chronic exposure to the drug, and we suggest that this tolerance may be a key marker for the development of drug dependence.     

Pharmacological characterization of almotriptan: an indolic 5-HT receptor agonist for the treatment of migraine

Almotriptan (3-[2-(dimethylamino)ethyl]-5-(pyrrolidin-1-ylsulfonylmethyl )-1H-indo le) has been studied in several models predictive of activity and selectivity at 5-HT receptors. Almotriptan showed low nanomolar affinity for the 5-HT(1B) and 5-HT(1D) receptors in several species, including the human, while affinity for 5-HT receptors other than 5-HT(1B/1D) was clearly less. Affinity for 5-HT(7) and 5-HT(1A) receptors was approximately 40 and 60 times lower than that for 5-HT(1B/1D) receptors, respectively. Almotriptan did not exhibit significant affinity for several non-5-HT receptors studied up to 100 microM. Almotriptan inhibited forskolin-stimulated cyclic AMP accumulation in HeLa cells transfected with 5-HT(1B) or 5-HT(1D) human receptors. In this model, almotriptan had the same efficacy as serotonin and an affinity in the low nanomolar range. It induced vasoconstriction in several vessels in which it was compared with sumatriptan. In isolated dog saphenous veins, almotriptan elicited concentration-dependent contractions with an EC(50) of 394 nM. In both these systems, almotriptan behaved as a full agonist. Infusion of almotriptan into the porcine meningeal vasculature induced vasoconstriction. In contrast, in the pig renal and rabbit mesenteric arteries, it had a very low maximal efficacy even at 100 microM, with similar results obtained in the rabbit renal artery. The results suggest that almotriptan is a potent and selective 5-HT(1B/1D) receptor agonist, with selectivity for the cranial vasculature as compared with peripheral vessels.     

Tic hydantoin sigma-1 agonist: Pharmacological characterization on cocaine-induced stimulant and appetitive effects

Activation of the newly identified σ₁ chaperone protein is involved in several aspects of the psychostimulant and addictive effects of cocaine. The development of ligands that selectively target the σ₁ protein may lead to putative potent anti-cocaine agents. Here, we synthetized substituted hydantoins with high affinity for the σ₁ protein and evaluated their behavioral efficacy. Two pure enantiomers were designed and synthesized: tetrahydroisoquinoleine-hydantoin fused compounds 3 and 4. They increased cocaine-induced locomotor stimulation or sensitization. The most active enantiomer 4, facilitated CPP acquisition but failed to substitute for cocaine. When CPP was acquired with cocaine and then extinguished, 4 provoked reactivation of CPP. These observations showed that compound 4 shows a typical profile of σ₁ protein activator, facilitating cocaine-induced behavioral effects. Preliminary ADME properties are in favour of an optimal therapeutic development. Such Tic-hydantoin compound may serve as a new effective agonist therapy in cocaine addiction.     

Pharmacological activity of amantadine: effect of N-alkyl substitution

Alkyl substitution on the nitrogen atom of the anti-parkinsonian drug amantadine resulted in changes in its pharmacological potency. Greater behavioural stimulation (i.e. increased motor activity) was observed following s.c. injection of several of the analogues, with optimal activity produced by N-n-propyl substitution. These molecular changes did not alter the activity of amantadine on inhibition of dopamine uptake or its weak affinity for dopamine receptors in-vitro. Several of the analogues were more effective than the parent compound in increasing the concentration of dopamine metabolites (suggesting an increase in dopamine utilization) following systemic injection, and these effects generally followed the same pattern as observed in the test of behavioural activity. These results provide further support for the concept that the activity of amantadine may be improved by molecular alterations, although the pharmacological basis for this activity remains obscure.     

Physico-chemical determinants of dermal drug delivery: effects of the number and substitution pattern of polar groups.

The aim of this study was to investigate the effect of number and substitution pattern of -OH groups of a set of phenols on the in vitro permeation of heat-separated human epidermis. The diffusion was calculated from Log(D/x)=logk(p)-0.59logK(oct)+0.024 (D, diffusion coefficient; x, pathlength; k(p), permeability coefficient (cm/h); and K(oct), octanol-water partition coefficient). The main factors reducing D were the dipolar and hydrogen bonding capabilities of the permeants quantified as their Hansen partial solubility parameters delta(p) and delta(h). These parameters are significantly reduced by the degree of symmetry of the molecule, so that phloroglucinol (1,3,5-benzenetriol), with three -OH groups, diffuses more rapidly that phenol. When symmetry is absent, as in 1,2,4-benzenetriol, the number of -OH groups results in very slow diffusion. D/x (cm/h) was related to the combined solubility parameter delta(a) defined as radical(delta(p)(2)+delta(h)(2)) by: (D/x)=0.0024-0.000065delta(a) (n=7, R(2)=0.70, P=0.012).     

Pharmacological and environmental determinants of relapse to cocaine-seeking behavior.

Animal models have been developed that simulate relevant features of relapse to cocaine-seeking behavior in humans. These models have provided valuable information about pharmacological and environmental factors that precipitate reinstatement of extinguished cocaine-seeking in rats and monkeys, as well as new insights about potential pharmacotherapies for relapse prevention. Reinstatement of cocaine-seeking behavior in animals can be induced by cocaine priming or by cocaine-paired environmental stimuli: however, maximum reinstatement of drug-seeking appears to be induced when cocaine priming and cocaine-paired stimuli are combined. Drugs that share cocaine's indirect dopamine agonist properties or that act as direct agonists at D2-like dopamine receptors also induce reinstatement of cocaine-seeking behavior, whereas with some exceptions (e.g., caffeine, morphine) drugs from other pharmacological classes do not. D1-like receptor agonists block rather than mimic the priming effects of cocaine, suggesting different roles for D1- and D2-like receptor mechanisms in cocaine relapse. Although considerable overlap exists, drugs that exhibit cocaine-like discriminative stimulus and/ or reinforcing effects in other situations do not invariably induce cocaine-like reinstatement of drug-seeking and vice versa, implying that these effects are not simply different behavioral expressions of a unitary neurobiological process. Finally, recent findings with D1-like receptor agonists, partial agonists, and antagonists suggest that some of these drugs may be viable candidates for development as antirelapse pharmacotherapies.     

Preclinical evaluation of the reinforcing and discriminative stimulus effects of agomelatine (S-20098), a melatonin agonist

 Agomelatine (S-20098), an analog of melatonin, has shown promise as a chronobiotic in animal models of sleep phase disorders and is being developed for clinical use. Previous research has shown that the pharmacological profile of melatonin-like drugs overlaps that of γ-amino butyric acid (GABA) agonists. Given the potential of drugs within the latter class for recreational abuse in humans, evaluation of this potential for melatonin analogs that target similar therapeutic indications is important. In the present study, agomelatine was tested in animal models of the subjective and reinforcing effects of CNS depressant drugs; i.e., diazepam discrimination in rats and IV methohexital self-administration in rhesus monkeys, respectively. Neither agomelatine nor melatonin substituted for diazepam in rats trained to discriminate 2.5 mg/kg diazepam from vehicle. Further, agomelatine was not self-administered by rhesus monkeys. These results suggest that agomelatine would not produce diazepam-like intoxication in humans, nor would it likely be subject to abuse. Received: 26 March 1998 / Final version: 27 May 1998     

Pharmacological treatment of the cognitive side effects of ECT: a review.

Electroconvulsive therapy (ECT) is an extremely effective treatment for a variety of psychiatric syndromes. However, it is frequently associated with transient cognitive side effects. Recent research has shown that these effects are sensitive to a number of treatment parameters, such as electrode placement and stimulus dosage, that the clinician may manipulate. However there have been relatively few efforts to determine if these cognitive side effects may be reduced or prevented by psychopharmacological intervention. In animals electroconvulsive shock (ECS) has been used frequently to screen for compounds which may improve cognition and memory. This paper reviews basic research studies on such compounds, as well as clinical trials in the treatment of various cognitive disorders. Studies using such compounds to reduce the cognitive side effects of ECT are exhaustively reviewed. The compounds that have been examined include: opioids, vasopressin, adrenocorticotropic hormone, other neuropeptides, cholinergic agents, nootropic agents, ergoloid mesylates, calcium-channel blockers, dexamethasone, thyroid hormone, and stimulants.     

Tolerance to the discriminative stimulus and reinforcing effects of ketamine

In order to examine whether tolerance develops to the discriminative stimulus and reinforcing effects of ketamine, rats were trained either to discriminate ketamine (10mg/kg) from saline or to self-administer ketamine (1.1mg/kg/injection), and then treated with chronic ketamine (32mg/kg), administered i.p. every 8 hours for 7 days. No shift in the dose-response curve for either paradigm was obtained following this chronic regimen. However, following a 2-week rest period in which animals had no exposure to ketamine, the dose-response curve was shifted two-fold to the left, indicating increased sensitivity to the drug. Reinstatement of training shifted the dose-response curve back to the right in both paradigms. These results suggest that tolerance to the discriminative stimulus and reinforcing effects of ketamine develops during training. Examination of the self-administration training data support this assumption, since inter-reinforcer time decreases, reflecting an increase in ketamine intake over training sessions.     

M1胆碱受体激动剂治疗阿尔茨海默病的研究进展

阿尔茨海默病(Alzheimer disease，AD)是一种以胆碱能神经元进行性退变、老年斑和神经元缠结为病理特征的神经退行性疾病。尽管AD发病机制尚未阐明，但β淀粉样肽沉积和tau蛋白磷酸化与胆碱能神经退变的恶性循环(vicious cycle)无疑是造成AD的重要病理机制之一。大量研究表明胆碱能神经突触后膜的M1受体的数目在整个病程中变化不大，M1受体选择性激动剂不但可以直接补偿胆碱能的功能，而且可以调节β淀粉样前体蛋白代谢和降低tau蛋白的过度磷酸化，有助于打破这一恶性循环，改善AD的学习记忆功能并延缓病情的发展。因此M1胆碱受体激动剂被认为是最有前途的治疗AD药物之一。目前Xanomeline、Sabcomeline等具有相对选择性M1受体激动剂业已进入新药临床试验阶段。     

Rapid and persistent sensitization to the reinforcing effects of cocaine.

The development of drug addiction involves a transition from recreational use to compulsive drug seeking and taking, and this progression can occur rapidly with cocaine use. These data highlight the importance of early drug exposure and the development of drug dependence; however, little experimental attention has been paid to this phenomenon in animal models of drug abuse. The present experiments demonstrate a progressive and rapid sensitization to the reinforcing strength of cocaine assessed using a progressive ratio (PR) schedule in rats. The first experiment found that rats show increased breakpoints over a 2-week period following acquisition. Subsequent experiments examined the role of total cocaine intake during the initial exposure period and found that low intakes (20 mg/kg/day x 5 days) resulted in sensitization, whereas relatively higher intake (60 or 100 mg/kg/day x 5 days) suppressed the development of sensitization. In contrast, this higher level of intake (60 mg/kg/day x 5 days) only transiently suppressed the expression of sensitization. Examination of breakpoints maintained by various doses of cocaine revealed an upward and leftward displacement of the cocaine dose-effect curve, relative to nonsensitized animals. These studies describe a form of sensitization that occurs rapidly to the reinforcing effects of cocaine, and provide a model to study the potential impact of initial experience on the development of drug dependence.     

Pretreatment with methylphenidate sensitizes rats to the reinforcing effects of cocaine

Repeated administration of cocaine produces sensitization to its locomotor-activating effects and increases the rate at which cocaine self-administration behavior is acquired. Methylphenidate is administered clinically on a daily basis, predominantly to children and adolescents, for the treatment of attention-deficit hyperactivity disorder (ADHD). It has been demonstrated previously that pretreatment with methylphenidate administered to periadolescent rats decreased the latency to acquisition of cocaine self-administration. Since methylphenidate is often also administered to adults with ADHD, the present study was conducted to determine the effects of prior administration of methylphenidate (5 or 20 mg/kg/day for 9 days) to adult rats on the rate of acquisition for cocaine self-administration (0.25 mg/kg/infusion). The higher dose of methylphenidate significantly decreased the latency for acquisition of this behavior, suggesting that the rats were sensitized to the reinforcing effects of cocaine after treatment with methylphenidate. These findings add to the growing body of evidence suggesting cross-sensitization between the behavioral effects of psychostimulants. Further, insofar as self-administration is a reliable measure of abuse liability, these data suggest that a short-duration pretreatment with a high dose of methylphenidate to adults increases vulnerability to cocaine abuse.     

Self-administration of cocaine-antihistamine combinations: super-additive reinforcing effects

Histamine H1 receptor antagonists have some behavioral effects that predict abuse liability. In the present study, diphenhydramine and cocaine each maintained i.v. self-administration under a progressive-ratio schedule in rhesus monkeys. When cocaine and DPH were combined in a 1:1 ratio of the ED50s, the combination was super-additive in all monkeys. The data predict that the combination of cocaine and histamine H1 receptor antagonists would have enhanced potential for abuse relative to either drug alone.     

Pharmacological approaches to the treatment of diabetic complications

Diabetes is often accompanied by several long-term complications such as neuropathy, nephropathy, retinopathy, cataract and angiopathy; their occurrence has been linked to the modification of the physiological levels of glycaemia. Several interrelated metabolic pathways have been implicated in the toxic effects of glucose; the polyol pathway was one of the first considered. However, while in diabetic animal models the inhibitors of aldose reductase (ALR2, the first enzyme of this pathway) seem to be active, 16 years of clinical trials, based mainly on neuropathy, have been inconclusive; only one drug currently being marketed. Newer potent and selective aldose reductase inhibitors have been discovered in the last few years, but the lack of commercial success has probably led to the very rapid decrease in the number of patents relating to newer aldose reductase inhibitors. Inhibition of the second enzyme of this pathway, sorbitol dehydrogenase (SDH), has been shown to be detrimental. Other approaches for the prevention and the delay of progression of diabetic complications seem to be more promising, namely, the inhibition of the formation of advanced glycated end products (AGEs) or protein kinase C (PKC) β₂ inhibition; compounds acting on these two pathways have proved effective in retarding the development of diabetic complications in animal models and some products are in clinical trials at the moment. Renewed attention has been paid to vascular involvement in the pathogenesis of diabetic neuropathy; the biological activity of C-peptide and the role of endothelin-1 (ET-1) in diabetic vascular disease are emerging as a new research area for the treatment of diabetic complications.