Showing papers in "Behavioural Pharmacology in 2013"
TL;DR: Several commonly marketed cathinones produce discriminative stimulus effects comparable with those of cocaine and methamphetamine, which suggests that these compounds are likely to have similar abuse liabilities.
Abstract: A number of psychostimulant-like cathinone compounds are being sold as 'legal' alternatives to methamphetamine or cocaine. The purpose of these experiments was to determine whether cathinone compounds stimulate motor activity and have discriminative stimulus effects similar to those of cocaine and/or methamphetamine. 3,4-Methylenedioxypyrovalerone (MDPV), methylone, mephedrone, naphyrone, flephedrone, and butylone were tested for locomotor stimulant effects in mice and subsequently for substitution in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally) or methamphetamine (1 mg/kg, intraperitoneally) from saline. All compounds fully substituted for the discriminative stimulus effects of cocaine and methamphetamine. Several commonly marketed cathinones produce discriminative stimulus effects comparable with those of cocaine and methamphetamine, which suggests that these compounds are likely to have similar abuse liabilities. MDPV and naphyrone produced locomotor stimulant effects that lasted much longer than those of cocaine or methamphetamine and therefore may be of particular concern, particularly because MDPV is one of the most commonly found substances associated with emergency room visits because of adverse effects of taking 'bath salts'. Language: en
160 citations
TL;DR: It is argued here that drug-escalated animals represent a comprehensive model of addiction according to the manifestations of behavioral neuroadaptations resulting directly or indirectly from excessive drug consumption, as well as mechanisms and therapeutic interventions for reversing the aberrant neuroplasticity underlying addiction.
Abstract: Drug addiction is a progressive, relapsing disease comprised of interlocking stages of disordered motivation. Numerous animal models describing various stages of the addiction process have been developed over the past few decades, providing considerable advantages for the modeling of drug addiction compared with other complex psychiatric disease states. Escalation of drug self-administration has emerged as a widely accepted operant conditioning model of excessive drug intake. We further argue here that drug-escalated animals represent a comprehensive model of addiction according to the manifestations of behavioral neuroadaptations resulting directly or indirectly from excessive drug consumption. In particular, drug-escalated animals exhibit a host of symptoms in line with multiple Diagnostic and Statistical Manual of Mental Disorders criteria for substance dependence, which can be summarized as an emergence of uncontrollable drug-taking and drug-seeking behaviors as a consequence of within-circuit and between-circuit neuroadaptations. Such a transition from impulsive drug sampling to compulsive intake represents a highly valid conceptualization of the addiction timeline in humans, and further investigation of persistent or near-permanent (e.g. epigenetic) neuroadaptations generated by operant drug intake escalation models will continue to provide mechanisms and therapeutic interventions for reversing the aberrant neuroplasticity underlying addiction.
119 citations
TL;DR: The present paper summarizes the different self-Administration techniques that are commonly used today and the application of other procedures that may complement interpretation of the drug self-administration findings.
Abstract: Drug self-administration procedures in laboratory settings allow us to closely model drug-taking behavior in real-world settings. This review provides an overview of many of the common self-administration methods used in human laboratory research. Typically, self-administration studies provide a quantifiable measure of the reinforcing effect of a drug, which is believed to be predictive of its potential for abuse. Several adaptations of the self-administration paradigm exist, the simplest of which allows participants free access to the drug under investigation. Free-access procedures allow investigators to observe patterns of drug self-administration and drug effects in a controlled setting. Allowing participants to choose between two simultaneously available reinforcers (choice procedures) is another well-established method of assessing the reinforcing effects of a drug. Offering a choice between two reinforcers (e.g. two different doses of the same drug, two different drugs, or drug and nondrug reinforcers) provides researchers with a point of comparison (e.g. between a drug of known abuse potential and a novel drug). When combined with other endpoints, such as subjective effects ratings, physiological responses, and cognitive performance, human self-administration paradigms have contributed significantly to our understanding of the factors that contribute to, maintain, and alter drug-taking behavior including: craving, positive subjective effects, toxicity, drug interactions and abstinence. This area of research has also begun to incorporate other techniques such as imaging and genetics to further understand the multifaceted nature of substance abuse. The present paper summarizes the different self-administration techniques that are commonly used today and the application of other procedures that may complement interpretation of the drug
50 citations
TL;DR: Data from 100 small molecules was analyzed to compare the predictive validity for drug scheduling status of a number of models that typically contribute to the abuse potential assessment package and the impact of combining information from multiple models was examined.
Abstract: Within the drug development industry the assessment of abuse potential for novel molecules involves the generation and review of data from multiple sources, ranging from in-vitro binding and functional assays through to in-vivo nonclinical models in mammals, as well as collection of information from studies in humans. This breadth of data aligns with current expectations from regulatory agencies in both the USA and Europe. To date, there have been a limited number of reviews on the predictive value of individual models within this sequence, but there has been no systematic review on how each of these models contributes to our overall understanding of abuse potential risk. To address this, we analyzed data from 100 small molecules to compare the predictive validity for drug scheduling status of a number of models that typically contribute to the abuse potential assessment package. These models range from the assessment of in-vitro binding and functional profiles at receptors or transporters typically associated with abuse through in-vivo models including locomotor activity, drug discrimination, and self-administration in rodents. Data from subjective report assessments in humans following acute dosing of compounds were also included. The predictive value of each model was then evaluated relative to the scheduling status of each drug in the USA. In recognition of the fact that drug scheduling can be influenced by factors other than the pharmacology of the drug, we also evaluated the predictive value of each assay for the outcome of the human subjective effects assessment. This approach provides an objective and statistical assessment of the predictive value of many of the models typically applied within the pharmaceutical industry to evaluate abuse potential risk. In addition, the impact of combining information from multiple models was examined. This analysis adds to our understanding of the predictive value of each model, allows us to critically evaluate the benefits and limitations of each model, and provides a method for identifying opportunities for improving our assessment and prediction of abuse liability risk in the future.
50 citations
TL;DR: The present data suggest the need to consider dopaminergic mechanisms in the mesolimbic circuit as novel targets for the pharmacological treatment of fear-related disorders, especially post-traumatic stress disorder.
Abstract: Although dopaminergic systems are more commonly associated with the reinforcing effects of various stimuli, numerous reports have demonstrated a relationship between changes in dopaminergic transmission and aversive situations. In the present study, we examined the involvement of D1-like and D2-like receptors in the expression of conditioned freezing using the context as the conditioned stimulus. Intraperitoneal injections of the D1 agonist SKF38393 or the D1 antagonist SCH23390 did not change the conditioned freezing in rats subjected to the contextual fear paradigm. In contrast, intraperitoneal injections of the D2 agonist quinpirole and the D2 antagonist sulpiride caused a significant dose-dependent reduction in the expression of contextual conditioned freezing. As these data may reflect that the systemic manipulations acted on dopaminergic receptors in different brain areas, the effects of administration of quinpirole and sulpiride into the ventral tegmental area (VTA) and the basolateral amygdala complex (BLA) on the expression of contextual conditioned freezing were also evaluated. Intra-VTA quinpirole and intra-BLA sulpiride injections reduced the conditioned freezing response; intra-VTA sulpiride and intra-BLA quinpirole injections had no significant effects. These data suggest that D2-like receptors, but not D1-like receptors, play an important role in the expression of contextual conditioned freezing. Quinpirole may act at D2 presynaptic receptors located in the VTA, decreasing dopamine levels in the terminal fields of the mesolimbic pathway. The effects of sulpiride, in contrast, appear to be triggered by an action on postsynaptic dopaminergic receptors located in the BLA. However, it cannot be totally excluded that the injected solutions did not also affect neighboring amygdalar regions. Together with previous findings, the present data suggest the need to consider dopaminergic mechanisms in the mesolimbic circuit as novel targets for the pharmacological treatment of fear-related disorders, especially post-traumatic stress disorder.
47 citations
TL;DR: The increased potency of systemic morphine to produce a CPP in animals with neuropathic pain suggests that the motivation for opioid-induced reward is different in the two states, and may be reflected as altered sensitivity to rewarding stimuli.
Abstract: In addition to sensory disturbances, neuropathic pain is associated with an ongoing and persistent negative affective state. This condition may be reflected as altered sensitivity to rewarding stimuli. We examined this hypothesis by testing whether the rewarding properties of morphine are altered in a rat model of neuropathic pain. Neuropathic pain was induced by chronic constriction of the common sciatic nerve. Drug reward was assessed using an unbiased, three-compartment conditioned place preference (CPP) paradigm. The rats underwent two habituation sessions beginning 6 days after surgery. Over the next 8 days, they were injected with drug or vehicle and were confined to one CPP compartment for 30 min. On the following test day, the rats had access to all three compartments for 30 min. Consistent with the literature, systemic administration of morphine dose-dependently increased the CPP in pain-naive animals. In rats with neuropathic pain, however, the dose-dependent effects of morphine were in a bell-shaped curve, with a low dose of morphine (2 mg/kg) producing a greater CPP than a higher dose of morphine (8 mg/kg). In a separate group of animals, acute administration of morphine reversed mechanical allodynia in animals with neuropathic pain at the same doses that produced a CPP. The increased potency of systemic morphine to produce a CPP in animals with neuropathic pain suggests that the motivation for opioid-induced reward is different in the two states.
46 citations
TL;DR: A discussion on the merits, advantages, and limitations of the zebrafish model and its utility in relation to conditioned place preference is presented.
Abstract: Substance abuse is a significant public health concern both domestically and worldwide. The persistent use of substances regardless of aversive consequences forces the user to give higher priority to the drug than to normal activities and obligations. The harmful and hazardous use of psychoactive substances can lead to a dependence syndrome. In this regard, the genetic and neurobiological underpinnings of reward-seeking behavior need to be fully understood in order to develop effective pharmacotherapies and other methods of treatment. Animal models are often implemented in preclinical screening for testing the efficacy of novel treatments. Several paradigms exist that model various facets of addiction including sensitization, tolerance, withdrawal, drug seeking, extinction, and relapse. Self-administration and, most notably, conditioned place preference (CPP) are relatively simple tests that serve as indicators of the aforementioned aspects of addiction by means of behavioral quantification. CPP is a commonly used technique to evaluate the motivational effects of compounds and experiences that have been associated with a positive or negative reward, which capitalizes on the basic principles of Pavlovian conditioning. During training, the unconditioned stimulus is consistently paired with a neutral set of environmental stimuli, which obtain, during conditioning, secondary motivational properties that elicit approach behavior in the absence of the unconditioned stimulus. For over 50 years, rodents have been the primary test subjects. However, the zebrafish (Danio rerio) is gaining favor as a valuable model organism in the fields of biology, genetics, and behavioral neuroscience. This paper presents a discussion on the merits, advantages, and limitations of the zebrafish model and its utility in relation to CPP.
46 citations
TL;DR: It is suggested that sodium butyrate may be a potential mood stabilizer in depression and mania because it reversed the depressive-like and manic-like behaviors evaluated in the animal models.
Abstract: Bipolar disorder is a severe mood disorder with high morbidity and mortality. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, and functional impairment. Some preclinical studies have shown that histone deacetylase inhibitors may act on depressive-like and manic-like behaviors. Therefore, the aim of the present study was to evaluate the effects of sodium butyrate (SB) on behavioral changes in animal models of depression and mania. The animals were submitted to protocols of chronic mild stress or maternal deprivation for induction of depressive-like behaviors and subjected to amphetamine, or ouabain administration for induction of manic-like behaviors. SB reversed the depressive-like and manic-like behaviors evaluated in the animal models. From these results we can suggest that SB may be a potential mood stabilizer.
45 citations
TL;DR: Results reveal a unique antagonistic action of H2S in depressive-like and anxiety-like behaviors and suggest that elevating H 2S signaling in the brain may represent a novel approach for the treatment of depressive and anxiety disorders.
Abstract: Depression is a common and debilitating mental illness and is often comorbid with anxiety disorders. Altered synaptic plasticity is considered to be an important mechanism underlying antidepressant drug action. It has been reported that hydrogen sulfide (H2S), the third gaseous transmitter, facilitates the induction of hippocampal long-term potentiation and augments synaptic neurotransmission, involved in the regulation of synaptic plasticity. The aim of this study was to clarify the antidepressant-like and anxiolytic-like effects of H2S. H2S (NaHS, 1.68 or 5.6 mg/kg, intraperitoneally, for 7 days) exerts a specific antidepressant-like effect in the forced swimming test of mice and rats and the tail suspension test of mice, and reduces the anxiety-like behaviors of both mice and rats in the elevated plus-maze test. These results reveal a unique antagonistic action of H2S in depressive-like and anxiety-like behaviors and suggest that elevating H2S signaling in the brain may represent a novel approach for the treatment of depressive and anxiety disorders.
43 citations
TL;DR: It is argued that the discussion of drug reward only may be insufficient in accounting for drug taking and evidence is presented for the theoretical position that both the rewarding and the aversive effects of drugs should be taken into consideration in ongoing attempts to model drug-taking behavior.
Abstract: Since the first experimental demonstration that a drug of abuse supports instrumental behavior, drugs have been discussed in the context of their rewarding effects, which are assumed to drive and maintain drug-taking behavior. Indeed, drug reward has been fundamental in the formulation of most models of drug use, abuse, and addiction. Over the last several decades, however, drugs of abuse have been increasingly recognized as complex pharmacological compounds producing multiple stimulus effects, not all of which are rewarding. The aversive effects of such drugs, for example, have been described by a number of researchers working in the field, although few attempts have been made to investigate the role of these aversive effects in drug taking. The present paper offers a historical perspective on the view that drugs of abuse are complex pharmacological compounds with multiple stimulus effects. In doing so, we argue that the discussion of drug reward only may be insufficient in accounting for drug taking and we present evidence for the theoretical position that both the rewarding and the aversive effects of drugs should be taken into consideration in ongoing attempts to model drug-taking behavior. The present review summarizes several decades of research characterizing the aversive effects of major drugs of abuse, as well as more recent studies seeking to assess directly the role of drug aversion in drug taking.
43 citations
TL;DR: It is suggested that orexin signaling within the dHPC is necessary for the development of morphine CPP and modification of hippocampal c-Fos and cyclic AMP response element-binding protein (CREB) levels.
Abstract: In this study, we evaluated the role of orexin receptors in the dorsal hippocampus (dHPC) in the development of morphine-induced conditioned place preference (CPP) and modification of hippocampal c-Fos and cyclic AMP response element-binding protein (CREB) levels. Orexin-A (0.5, 5, and 50 pmol) and the orexin-1 receptor antagonist, SB334867 (10, 20, and 40 nmol), were bilaterally infused into the dHPC immediately before conditioning with morphine (0.5 or 7.5 mg/kg) using the CPP task. Western blotting was then used to measure the protein levels of c-Fos, total CREB, and phosphorylated CREB (pCREB) in the hippocampus. Orexin did not enhance the rewarding efficacy of morphine (0.5 mg/kg), but caused a reduction in hippocampal c-Fos. Successful conditioning with morphine (7.5 mg/kg) was associated with increased levels of hippocampal c-Fos and CREB, but with decreased CREB phosphorylation. Intrahippocampal administration of SB334867 before conditioning sessions disrupted the rewarding effect of morphine (7.5 mg/kg) and blocked morphine-induced increases in hippocampal CREB protein levels. The results suggest that orexin signaling within the dHPC is necessary for the development of morphine CPP. Morphine reward is related to altered levels of hippocampal c-Fos and CREB. Inhibition of morphine-induced increases in CREB levels might be the underlying mechanism for the disruption of morphine CPP.
TL;DR: The data suggest that the presence of an abstaining peer decreases the reinforcing strength of cocaine, thus supporting the development of social interventions in drug abuse prevention and treatment programs.
Abstract: Social-learning theories of substance use propose that members of peer groups influence the drug use of other members by selectively modeling, reinforcing, and punishing either abstinence-related or drug-related behaviors. The objective of the present study was to examine the social influences on cocaine self-administration in isolated and socially housed rats, under conditions where the socially housed rats were tested simultaneously with their partner in the same chamber. To this end, male rats were obtained at weaning and housed in isolated or pair-housed conditions for 6 weeks. Rats were then implanted with intravenous catheters and cocaine self-administration was examined in custom-built operant conditioning chambers that allowed two rats to be tested simultaneously. For some socially housed subjects, both rats had simultaneous access to cocaine; for others, only one rat of the pair had access to cocaine. An econometric analysis was applied to the data, and the reinforcing strength of cocaine was measured by examining consumption (i.e. quantity demanded) and elasticity of demand as a function of price, which was manipulated by varying the dose and ratio requirements on a fixed ratio schedule of reinforcement. Cocaine consumption decreased as a function of price in all groups. Elasticity of demand did not vary across groups, but consumption was significantly lower in socially housed rats paired with a rat without access to cocaine. These data suggest that the presence of an abstaining peer decreases the reinforcing strength of cocaine, thus supporting the development of social interventions in drug abuse prevention and treatment programs.
TL;DR: Although 8-OH-DPAT and quinpirole can induce compulsive checking in a large open field, the results suggest that they do so differently, and it is suggested that they probably produce compulsive behavior by acting on different parts of a security motivation circuit underlying obsessive–compulsive disorder.
Abstract: This study investigated whether the serotonin 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) can induce compulsive checking in a large open field, as does the dopamine D2/D3 receptor agonist quinpirole. To induce compulsive checking, male rats were exposed to eight injections of either 8-OH-DPAT (1 mg/kg), quinpirole (0.2 mg/kg), or saline. Subsequently, to assess cross-sensitization, rats received an acute challenge of 8-OH-DPAT or quinpirole. The results showed that treatment with 8-OH-DPAT induces compulsive checking and may have a stronger effect on this behavior compared with quinpirole. However, there was no cross-sensitization between 8-OH-DPAT and quinpirole on measures of compulsive checking and locomotion. Moreover, the spatial distribution of locomotor paths in 8-OH-DPAT animals was more confined and invariant than in quinpirole rats; their rate of locomotor sensitization was also faster than that in quinpirole animals. Thus, although 8-OH-DPAT and quinpirole can induce compulsive checking in a large open field, the results suggest that they do so differently. It is suggested that 8-OH-DPAT and quinpirole probably produce compulsive behavior by acting on different parts of a security motivation circuit underlying obsessive-compulsive disorder. Quinpirole may induce compulsive checking behavior by directly driving dopaminergic activity mediating the motivational drive to check. Conversely, 8-OH-DPAT may perpetuate the activated motivational state by inhibiting the serotonergic-negative feedback signals that normally deactivate the obsessive-compulsive disorder circuit.
TL;DR: Findings provide further evidence for a selective role of epinephrine in contextual-fear learning and support its potential role in acoustic startle in PNMT-KO mice.
Abstract: Norepinephrine and epinephrine signaling is thought to facilitate cognitive processes related to emotional events and heightened arousal, however, the specific role of epinephrine in these processes is less known. To investigate the selective impact of epinephrine on arousal and fear-related memory retrieval, mice unable to synthesize epinephrine (phenylethanolamine N-methyltransferase knockout, PNMT-KO) were tested in context and cued fear conditioning. To assess the role of epinephrine in other cognitive and arousal-based behaviors these mice were also tested for acoustic startle, prepulse inhibition, novel object recognition and open field activity. Our results show that compared to wild-type (WT) mice, PNMT-KO mice displayed reduced context fear but normal cued fear. Mice exhibited normal memory performance in the short-term version of the novel object recognition task suggesting PNMT mice exhibit more selective memory effects on highly emotional and/or long term memories. Similarly, open field activity was unaffected by epinephrine deficiency, suggesting differences in freezing are not related to changes in overall anxiety or exploratory drive. Startle reactivity to acoustic pulses was reduced in PNMT-KO mice while prepulse inhibition was increased. These findings provide further evidence for a selective role of epinephrine in contextual fear learning, and support its potential role in acoustic startle.
TL;DR: CoQ10 dose-dependently antagonized CRS-induced depressive behavior by increasing sucrose preference (reversal of anhedonia), body weight, and food intake and reducing adrenal gland weight and support the hypothesis that brain energy impairment is involved in the pathophysiology of depression.
Abstract: Several recent studies suggest a close link between mitochondrial dysfunction and depression. Coenzyme Q10 (CoQ10) is a mobile electron carrier in the mitochondrial respiratory chain (MRC) with antioxidant and potential neuroprotective activities. This study investigated the effect of chronic administration of CoQ10 (50, 100, and 200 mg/kg/day, intraperitoneally, for 4 weeks) on anhedonia and on the activities of MRC complexes and creatine kinase in the frontal cortex and hippocampus of Wistar rats subjected to chronic restraint stress (CRS, 6 h × 28 days). Exposure to CRS-induced anhedonic-like behavior (decreased sucrose preference), reduced body weight gain and food intake, increased adrenal gland weight, and altered the activity of the MRC complexes in the brain areas tested. CoQ10 dose-dependently antagonized CRS-induced depressive behavior by increasing sucrose preference (reversal of anhedonia), body weight, and food intake and reducing adrenal gland weight. CoQ10 also enhanced the activities of MRC complexes (I-IV) and creatine kinase in the frontal cortex and hippocampus. Thus, the reversal of CRS-induced anhedonia may be partially mediated by amelioration of brain mitochondrial function. The findings also support the hypothesis that brain energy impairment is involved in the pathophysiology of depression and enhancing mitochondrial function could provide an opportunity for development of a potentially more efficient drug therapy for depression.
TL;DR: It is found that PACAP-deficient mice showed impairments in the novel object recognition test and these impairments were improved by MGS0028 (0.1 mg/kg), and the results suggest that M GS0028 may be a potential, novel treatment for psychiatric disorders.
Abstract: Previous studies suggest that metabotropic glutamate 2/3 receptors are involved in psychiatric disorders. In this study, we examined the effects of the selective metabotropic glutamate 2/3 (mGlu2/3) receptor agonist MGS0028 on behavioral abnormalities in mice lacking the pituitary adenylate cyclase-activating polypeptide (PACAP), an experimental model of psychiatric disorders such as schizophrenia and attention-deficit/hyperactivity disorder. We found that PACAP-deficient mice showed impairments in the novel object recognition test and these impairments were improved by MGS0028 (0.1 mg/kg). Similarly, MGS0028 improved hyperactivity and jumping behaviors, but did not reverse increased immobility times in the forced swim test in PACAP-deficient mice. These results suggest that MGS0028 may be a potential, novel treatment for psychiatric disorders.
TL;DR: The present demonstration that cocaine-induced locomotor activation is enhanced by prior MEPH exposure suggests that MEPH cross-sensitizes to cocaine and increases cocaine efficacy, suggesting that the phenomenon is sensitive to specific psychostimulants.
Abstract: Concurrent use of mephedrone (4-methylmethcathinone; MEPH) and established drugs of abuse is now commonplace, but knowledge about interactions between these drugs is sparse. The present study was designed to test the hypothesis that prior MEPH exposure enhances the locomotor-stimulant effects of cocaine and methamphetamine (METH). For cocaine experiments, rats pretreated with saline, cocaine (15 mg/kg), or MEPH (15 mg/kg) for 5 days were injected with cocaine after 10 days of drug absence. For METH experiments, rats pretreated with saline, METH (2 mg/kg), or MEPH (15 mg/kg) were injected with METH after 10 days of drug absence. Cocaine challenge produced greater locomotor activity after pretreatment with cocaine or MEPH than after pretreatment with saline. METH challenge produced greater locomotor activity after METH pretreatment than after saline pretreatment; however, locomotor activity in rats pretreated with MEPH or saline and then challenged with METH was not significantly different. The locomotor response to MEPH (15 mg/kg) was not significantly affected by pretreatment with cocaine (15 mg/kg) or METH (0.5, 2 mg/kg). The present demonstration that cocaine-induced locomotor activation is enhanced by prior MEPH exposure suggests that MEPH cross-sensitizes to cocaine and increases cocaine efficacy. Interestingly, MEPH cross-sensitization was not bidirectional and did not extend to METH, suggesting that the phenomenon is sensitive to specific psychostimulants.
TL;DR: The beneficial effects of Noni fruit against STZ-induced memory impairment are shown, which may be attributed to improved brain energy metabolism, cholinergic neurotransmission, BDNF, and antioxidative action.
Abstract: This study evaluated the effects of a standardized ethyl acetate extract of Morinda citrifolia L. (Noni) fruit on impairment of memory, brain energy metabolism, and cholinergic function in intracerebral streptozotocin (STZ)-treated mice. STZ (0.5 mg/kg) was administered twice at an interval of 48 h. Noni (50 and 100 mg/kg, postoperatively) was administered for 21 days following STZ administration. Memory function was evaluated using Morris Water Maze and passive avoidance tests, and brain levels of cholinergic function, oxidative stress, energy metabolism, and brain-derived neurotrophic factor (BDNF) were estimated. STZ caused memory impairment in Morris Water Maze and passive avoidance tests along with reduced brain levels of ATP, BDNF, and acetylcholine and increased acetylcholinesterase activity and oxidative stress. Treatment with Noni extract (100 mg/kg) prevented the STZ-induced memory impairment in both behavioral tests along with reduced oxidative stress and acetylcholinesterase activity, and increased brain levels of BDNF, acetylcholine, and ATP level. The study shows the beneficial effects of Noni fruit against STZ-induced memory impairment, which may be attributed to improved brain energy metabolism, cholinergic neurotransmission, BDNF, and antioxidative action.
TL;DR: The data suggest that the presence of alcohol-associated stimuli attenuates cognitive control processes in social drinkers, an effect that was associated with the participants’ average weekly alcohol intake.
Abstract: Alcohol-related stimuli attract social drinkers’ attention (attentional bias). We devised a dual task to test whether attentional biases to alcohol-related stimuli are modulated by cognitive control mechanisms. Sixteen nondependent healthy social drinkers were required to respond to the direction of
TL;DR: PEBT significantly ameliorated the scopolamine-induced impairment of long-term memory, as indicated by a decrease in escape latency and an increase in the number of crossings of the platform location when compared with the amnesic mice.
Abstract: Taking into account the memory-enhancing properties of 2-phenylethynyl-butyltellurium (PEBT) and the constant search for drugs that improve cognitive performance, the present study was designed to investigate the effect of PEBT on cognitive impairment induced by scopolamine in mice. PEBT (10 mg/kg,
TL;DR: The study demonstrated that a 3 : 1 oral dose ratio of morphine : oxycodone was not equipotent in buprenorphine-dependent individuals, and both self-administration procedures were effective for assessing the relative reinforcing effects of drugs.
Abstract: This double-blind, placebo-controlled study investigated effects of oral morphine (0, 45, 135 mg/70kg) and oral oxycodone (0, 15, 45 mg/70kg) in buprenorphine-maintained opioid addicts. Since a 3:1 morphine:oxycodone dose ratio had yielded equivalent subjective and physiological effects in non-dependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures, i.e. a drug vs. money and a drug vs. drug procedure, were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater compared to high-dose morphine. The study demonstrated that a 3:1 dose ratio of morphine:oxycodone was not equipotent in buprenorphine-dependent subjects. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest.
TL;DR: A positive allosteric modulator of mGlu7 receptor AMN082 reduced immobility in the forced swim test and tail suspension test (TST) in both C57BL/6j and CD1 mice, and administration of MMPIP partially attenuated the antidepressant-like effect of AMN072, however, this effect was absent from the CD1 strain.
Abstract: There is increasing evidence suggesting a role of the neurotransmitter glutamate in depression. The metabotropic glutamate (mGlu) receptors are G-protein coupled receptors, which mediate a slow modulatory response to glutamate signalling. mGlu₇ receptor is a presynaptic inhibitory autoreceptor showing great promise as a potential therapeutic target for the treatment of depression. Selective pharmacological modulators of mGlu₇ receptor have been developed; the positive allosteric modulator AMN082 and the negative modulator 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP). They remain to be extensively characterized in behavioural models sensitive to antidepressant action. Therefore, we assessed the effects of these compounds on behaviour in two different mouse strains using several preclinical tests sensitive to antidepressant pharmacological action. AMN082 (6 mg/kg) reduced immobility in the forced swim test and tail suspension test (TST) in both C57BL/6j and CD1 mice. In CD1 mice, MMPIP (10 and 30 mg/kg) significantly increased the time spent immobile in the TST, whereas this effect was restricted to a dose of 30 mg/kg in C57BL/6j mice. Administration of MMPIP with AMN082 partially attenuated the antidepressant-like effect of AMN082 in C57BL/6j mice in the forced swim test and the TST. However, this effect was absent from the CD1 strain. This further adds to the growing corpus of data promoting the targeting of mGlu₇ receptor with the aim of achieving an antidepressant effect.
TL;DR: Data show that bilobalide is a potent anti-inflammatory and antihyperalgesic agent, the therapeutic effects of which are mediated in part through a central site of action, and may account for the therapeutic action of the whole extract G. biloba.
Abstract: Standardized Ginkgo biloba extract EGb 761 has been shown to inhibit inflammatory hyperalgesia in rats; however, the mechanism of action is not known. This study set out to investigate the anti-inflammatory and analgesic potential of bilobalide, a unique G. biloba constituent, in three well-characterized models of acute inflammatory pain. The effect of oral, intraplantar or intrathecal administration of bilobalide or drug-vehicle (0.25% agar; 10% ethanol in H2O) on responses to noxious thermal and mechanical stimulation of the hindpaw, and paw oedema were assessed in adult male Wistar rats before and after intradermal hindpaw injection of carrageenan (3%; 50 μl) or capsaicin (10 μg; 50 μl) or after hindpaw incision (n=6-8/group). Oral administration of bilobalide (10-30 mg/kg) significantly inhibited thermal hyperalgesia in response to carrageenan, capsaicin and paw incision, independent of dose, with an efficacy similar to that of diclofenac. In the carrageenan model, mechanical hypersensitivity and paw oedema were also significantly reduced after treatment with bilobalide (10-30 mg/kg). Intrathecal administration of bilobalide (0.5-1 μg) inhibited carrageenan-induced thermal hyperalgesia, but had no effect on mechanical hypersensitivity or paw oedema (application≥2 μg induced adverse effects, precluding testing of higher doses). Intraplantar administration of bilobalide (30-100 μg) had no effect. These data show that bilobalide is a potent anti-inflammatory and antihyperalgesic agent, the therapeutic effects of which are mediated in part through a central site of action, and may account for the therapeutic action of the whole extract G. biloba.
TL;DR: It is shown that naltrexone improves BDL-induced memory deficit in rats and the observation that the procognitive effect of naltrezone is counteracted either by general inhibition of NOS enzymes or by selective inhibition of inducible NOS suggests the nitrergic pathway as a probable mechanism involved in the amelioration of spatial recognition memory by nALTrexone in BDL rats.
Abstract: Recent studies suggest an augmentation of endogenous opioids following bile duct ligation (BDL) and their pivotal role in the pathophysiology of cholestasis. In this study, the effect of naltrexone, an opioid receptor antagonist, was determined on cholestasis-induced memory impairment and the possible involvement of nitric oxide (NO) in this effect. Male Albino-Wistar rats were randomized to sham-operated and BDL-operated groups. In each group, animals were treated for up to 28 days with saline; naltrexone (10 mg/kg); naltrexone and N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective nitric oxide synthase (NOS) inhibitor (3, 10 mg/kg); naltrexone and aminoguanidine, an inducible NOS inhibitor (100 mg/kg); or methylnaltrexone, a peripherally acting opioid receptor antagonist (3 mg/kg, intraperitoneal). Spatial recognition memory was determined in a Y-maze task on the day before surgery and days 7, 14, 21, and 28 after surgery. Memory performance was impaired 14 days after BDL in cholestatic rats and was significantly reversed by chronic treatment with naltrexone at days 14, 21, and 28 after BDL. On day 21 after BDL, chronic L-NAME produced only a nonsignificant decrease in the beneficial effect of naltrexone, whereas on day 28, chronic administration of both L-NAME and aminoguanidine significantly reversed this effect of naltrexone. It is therefore shown in this study that naltrexone improves BDL-induced memory deficit in rats. We conclude that the memory impairment in cholestatic rats might be because of an increase in the level of endogenous opioids and that naltrexone improved the spatial recognition memory by antagonizing opioid receptors. The observation that the procognitive effect of naltrexone is counteracted either by general inhibition of NOS enzymes or by selective inhibition of inducible NOS suggests the nitrergic pathway as a probable mechanism involved in the amelioration of spatial recognition memory by naltrexone in BDL rats.
TL;DR: The results demonstrate that WSE was devoid of motivational properties, and point to WSE as an interesting alternative tool, worthy of further investigation, to study opiate addiction.
Abstract: Previous studies have reported that some of the central effects of morphine are counteracted by the administration of the methanolic extract of the root of Indian ginseng, Withania somnifera Dunal (WSE). The present study sought to determine whether WSE affects acquisition and expression of morphine-elicited conditioned place preference (CPP) in CD-1 mice. In CPP acquisition experiments, WSE (0, 25, 50, and 100 mg/kg) was administered, during conditioning, 30 min before morphine (10 mg/kg), whereas in expression experiments, WSE (0, 25, 50, and 100 mg/kg) was administered 30 min before the postconditioning test. The results demonstrate (i) that WSE was devoid of motivational properties; (ii) that WSE (100 mg/kg) was devoid of effects on spontaneous and morphine-stimulated motor activity and on spatial memory; and (iii) that WSE (50 and 100 mg/kg) significantly prevented the acquisition and expression of CPP. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for µ-opioid and γ-aminobutyric acid B receptors. These experiments revealed a higher affinity of WSE for γ-aminobutyric acid B than for µ-opioid receptors. Overall, these results point to WSE as an interesting alternative tool, worthy of further investigation, to study opiate addiction.
TL;DR: It is suggested that µ-agonist exposure increases the expression of abuse-related ICSS facilitation by µ agonists with a broad range of efficacies at µ receptors.
Abstract: Intracranial self-stimulation (ICSS) is an operant procedure in which responding is maintained by electrical brain stimulation. Stimulation frequency can be varied rapidly to maintain a wide range of baseline response rates, and drugs' effects can be evaluated simultaneously on both low ICSS rates maintained by low stimulation frequencies and high ICSS rates maintained by high stimulation frequencies. ICSS 'facilitation' indicates drug-induced increases in low ICSS rates and is often considered an abuse-related effect, whereas ICSS 'depression' indicates decreases in high ICSS rates and may indicate abuse-limiting effects. This study examined the roles of µ-agonist efficacy and of previous µ-agonist exposure as determinants of µ-agonist effects on ICSS in rats with electrodes implanted into the medial forebrain bundle. The high-efficacy, intermediate-efficacy, and low-efficacy µ agonists methadone, fentanyl, and nalbuphine were tested during escalating regimens of morphine exposure (vehicle, 3.2, and 18 mg/kg/day). During vehicle treatment, methadone and fentanyl primarily depressed ICSS, whereas nalbuphine produced weak facilitation that was not dose dependent. Chronic morphine produced tolerance to ICSS depression and increased expression of ICSS facilitation. These results suggest that µ-agonist exposure increases the expression of abuse-related ICSS facilitation by µ agonists with a broad range of efficacies at µ receptors.
TL;DR: Results suggest that selectively inhibiting G&bgr;&ggr;-mediated signaling may selectively increase &mgr;-opioid receptor-mediated antinociception without matching increases in adverse physiological effects.
Abstract: Inhibition of Gβγ-subunit signaling to phospholipase C β3 has been shown to potentiate morphine-mediated antinociception while attenuating the development of tolerance and dependence in mice. The objective of this study was to determine the effect of Gβγ-subunit inhibition on antinociception and other pharmacological effects, such as respiratory depression, constipation, and hyperlocomotion, mediated by the μ-opioid receptor. The Gβγ-subunit inhibitor, gallein, was administered to C57BL/6J mice by intraperitoneal injection before morphine, and data were compared with mice treated with vehicle, morphine, or gallein alone. Morphine-induced antinociception was measured using the 55°C warm-water tail-withdrawal test. Pretreatment with gallein produced a dose-dependent potentiation of morphine-mediated antinociception, producing up to a 10-fold leftward shift in the morphine dose-response curve and extending the duration of antinociception induced by a single dose of morphine. Gallein pretreatment also prevented acute antinociceptive tolerance induced by morphine. In contrast, the dose-dependent respiratory depression and hyperlocomotion induced by morphine were not potentiated by gallein pretreatment. Similarly, gallein pretreatment did not potentiate morphine-conditioned place preference responses or morphine-induced constipation, as measured as a reduction in excreta. These results suggest that selectively inhibiting Gβγ-mediated signaling may selectively increase μ-opioid receptor-mediated antinociception without matching increases in adverse physiological effects.
TL;DR: There appears to be a synergistic effect between opioidergic and nitrergic systems on memory acquisition and exploratory behaviors in cholestatic mice.
Abstract: Bile duct ligation (BDL) is an animal model used in cholestatic disease research. Both opioidergic and nitrergic systems are known to be involved in cholestasis. The aim of this study was to investigate the possible interaction between these two systems in BDL-induced memory formation and exploratory behaviors in mice. Male mice weighing 25-30 g were divided into nonoperated controls, sham-operated, and BDL groups. One-trial step-down and hole-board paradigms were used to assess memory acquisition and exploratory behaviors, respectively. Cholestasis did not alter memory acquisition while increasing exploratory behaviors 7 days after BDL. A pretraining intraperitoneal injection of L-arginine (50, 100, and 200 mg/kg), L-NG-nitroarginine methyl ester (L-NAME) (5, 10, 20, and 40 mg/kg), or naloxone (0.125, 0.25, and 0.5 mg/kg) did not alter memory acquisition or exploratory behaviors, whereas morphine (5 and 7.5 mg/kg) decreased memory acquisition in sham-operated animals. Moreover, although injection of L-NAME and naloxone exerted no effect on memory acquisition in the 7 days post-BDL mice, L-arginine (100 and 200 mg/kg) and morphine (2.5, 5, and 7.5 mg/kg) injection reduced it. In contrast, L-NAME and naloxone, but not morphine or L-arginine, reduced the BDL-induced exploratory behaviors. Coadministration of subthreshold doses of morphine (1.25 mg/kg) and L-arginine (50 mg/kg) caused a memory deficit in 7 days post-BDL mice. However, the memory deficit induced by the effective doses of morphine (2.5 mg/kg) or L-arginine (200 mg/kg) in these mice was restored by the administration of either naloxone (0.5 mg/kg) or L-NAME (40 mg/kg). In addition, naloxone and L-NAME reduced the exploratory behaviors in L-arginine-pretreated mice but not in morphine-pretreated mice. We conclude that there appears to be a synergistic effect between opioidergic and nitrergic systems on memory acquisition and exploratory behaviors in cholestatic mice.
TL;DR: The results of the present study confirm that 50-kHz calls elicited by several tickling sessions in rats can be reduced by acute administration of PCP, and that this effect can be reversed by previous administration of compounds with 5-HT1A receptor agonist properties.
Abstract: The objective of the present study was to examine the idea that the decrease in 50-kHz ultrasonic vocalizations elicited by tickling in juvenile rats following the administration of the psychotomimetic drug phencyclidine (PCP) may represent a valid model of the negative symptoms of schizophrenia. Fifty-kilohertz calls in rodents have been suggested to represent an archaic model of human laughter. Our results showed that daily tickling sessions produced a gradual increase in 50-kHz vocalizations, an effect that reached statistical significance from day 3. Administration of PCP (1 mg/kg, intraperitoneally) attenuated the 50-kHz calls induced by 4 consecutive days of tickling. The ability of several clinically effective or potential antipsychotics to reverse the effects of PCP was investigated. The 5-HT1A receptor partial agonist, buspirone (0.3 and 1 mg/kg, intraperitoneally), the dual D2/5-HT1A receptor ligand, SSR181507 (0.5-0.75 mg/kg, intraperitoneally), but not the atypical antipsychotic, aripiprazole (0.1-1 mg/kg, intraperitoneally), the 5-HT2A receptor antagonist, eplivanserin (0.3-3 mg/kg, intraperitoneally), and the GlyT1 inhibitor, SSR103800 (0.3-3 mg/kg, intraperitoneally) significantly attenuated the effects of PCP on 50-kHz calls. Importantly, in animals not treated with PCP, none of the drugs affected 50-kHz calls elicited by a first handling-tickling session, indicating that the action of buspirone and SSR181507 cannot be explained by an intrinsic effect. To investigate further the specificity of these drug effects, we tested the anxiolytic and antidepressant agents, diazepam (0.1-1 mg/kg, intraperitoneally) and fluoxetine (1-10 mg/kg, intraperitoneally), respectively, in this procedure. Neither drug affected tickling-induced 50-kHz calls in naive or PCP-treated rats. In conclusion, the results of the present study confirm that 50-kHz calls elicited by several tickling sessions in rats can be reduced by acute administration of PCP, and that this effect can be reversed by previous administration of compounds with 5-HT1A receptor agonist properties. As evidence for clinical efficacy of both agents on the negative symptoms of schizophrenia is weak or lacking, the current findings do not allow a definite conclusion to be drawn on the validity of this procedure as a model of this aspect of schizophrenia.
TL;DR: The results suggest that chronic neonatal NMDA receptor blockade causes changes in glutamatergic and cholinergic transmission in adulthood long after the cessation of treatment.
Abstract: This study investigated the effects of chronic neonatal blockade of N-methyl-D-aspartate (NMDA) receptors on NMDA and muscarinic acetylcholine receptor-mediated neurotransmission in adulthood. Rats neonatally treated chronically with MK-801/saline were tested for 40 min, at the age of 14-16 weeks, for locomotor activity in an open field immediately after acute administration of MK-801 (0.2 mg/kg) or scopolamine (0.4-2.0 mg/kg). Rats neonatally treated with MK-801 showed significantly higher locomotor activity than those treated with saline. Acute MK-801 administration caused hyperlocomotion regardless of neonatal treatment, but the effect was more potent in rats neonatally treated with MK-801. In contrast, acute scopolamine administration did not cause hyperlocomotion in rats neonatally treated with saline, but significantly increased locomotion in those neonatally treated with MK-801. The results suggest that chronic neonatal NMDA receptor blockade causes changes in glutamatergic and cholinergic transmission in adulthood long after the cessation of treatment.