Showing papers in "Psychopharmacology in 2006"

Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance.

Abstract: Rationale Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects. Objectives This double-blind study evaluated the acute and longer-term psychological effects of a high dose of psilocybin relative to a comparison compound administered under comfortable, supportive conditions. Materials and methods The participants were hallucinogennaive adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-month intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six additional volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers’ behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 months after sessions. Community observers rated changes in the volunteer’s attitudes and behavior. Results Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 months, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior consistent with changes rated by community observers. Conclusions When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.

Nicotinic effects on cognitive function : behavioral characterization, pharmacological specification, and anatomic localization

Abstract: Nicotine has been shown in a variety of studies in humans and experimental animals to improve cognitive function. Nicotinic treatments are being developed as therapeutic treatments for cognitive dysfunction. Critical for the development of nicotinic therapeutics is an understanding of the neurobehavioral bases for nicotinic involvement in cognitive function. Specific and diverse cognitive functions affected by nicotinic treatments are reviewed, including attention, learning, and memory. The neural substrates for these behavioral actions involve the identification of the critical pharmacologic receptor targets, in particular brain locations, and how those incipient targets integrate with broader neural systems involved with cognitive function. Nicotine and nicotinic agonists can improve working memory function, learning, and attention. Both α4β2 and α7 nicotinic receptors appear to be critical for memory function. The hippocampus and the amygdala in particular have been found to be important for memory, with decreased nicotinic activity in these areas impairing memory. Nicotine and nicotinic analogs have shown promise for inducing cognitive improvement. Positive therapeutic effects have been seen in initial studies with a variety of cognitive dysfunctions, including Alzheimer's disease, age-associated memory impairment, schizophrenia, and attention deficit hyperactivity disorder. Discovery of the behavioral, pharmacological, and anatomic specificity of nicotinic effects on learning, memory, and attention not only aids the understanding of nicotinic involvement in the basis of cognitive function, but also helps in the development of novel nicotinic treatments for cognitive dysfunction. Nicotinic treatments directed at specific receptor subtypes and nicotinic cotreatments with drugs affecting interacting transmitter systems may provide cognitive benefits most relevant to different syndromes of cognitive impairment such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder. Further research is necessary in order to determine the efficacy and safety of nicotinic treatments of these cognitive disorders.

Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure.

Abstract: The reinstatement model is widely used to study relapse to drug addiction. However, the model’s validity is open to question. We assess the reinstatement model in terms of criterion and construct validity. We find that the reinstatement model has adequate criterion validity in the broad sense of the term, as evidenced by the fact that reinstatement in laboratory animals is induced by conditions reported to provoke relapse in humans. The model’s criterion validity in the narrower sense, as a medication screen, seems promising for relapse to heroin, nicotine, and alcohol. For relapse to cocaine, criterion validity has not yet been established primarily because clinical studies have examined medication’s effects on reductions in cocaine intake rather than relapse during abstinence. The model’s construct validity faces more substantial challenges and is yet to be established, but we argue that some of the criticisms of the model in this regard may have been overstated.

The acute effects of cannabinoids on memory in humans: a review

Abstract: Cannabis is one of the most frequently used substances. Cannabis and its constituent cannabinoids are known to impair several aspects of cognitive function, with the most robust effects on short-term episodic and working memory in humans. A large body of the work in this area occurred in the 1970s before the discovery of cannabinoid receptors. Recent advances in the knowledge of cannabinoid receptors’ function have rekindled interest in examining effects of exogenous cannabinoids on memory and in understanding the mechanism of these effects. The literature about the acute effects of cannabinoids on memory tasks in humans is reviewed. The limitations of the human literature including issues of dose, route of administration, small sample sizes, sample selection, effects of other drug use, tolerance and dependence to cannabinoids, and the timing and sensitivity of psychological tests are discussed. Finally, the human literature is discussed against the backdrop of preclinical findings. Acute administration of Δ-9-THC transiently impairs immediate and delayed free recall of information presented after, but not before, drug administration in a dose- and delay-dependent manner. In particular, cannabinoids increase intrusion errors. These effects are more robust with the inhaled and intravenous route and correspond to peak drug levels. This profile of effects suggests that cannabinoids impair all stages of memory including encoding, consolidation, and retrieval. Several mechanisms, including effects on long-term potentiation and long-term depression and the inhibition of neurotransmitter (GABA, glutamate, acetyl choline, dopamine) release, have been implicated in the amnestic effects of cannabinoids. Future research in humans is necessary to characterize the neuroanatomical and neurochemical basis of the memory impairing effects of cannabinoids, to dissect out their effects on the various stages of memory and to bridge the expanding gap between the humans and preclinical literature.

Mesocortical dopamine modulation of executive functions: beyond working memory

Abstract: Dopamine (DA) neurotransmission in the prefrontal cortex (PFC) is known to play an essential role in mediating executive functions such as the working memory. DA exerts these effects by acting on D1 receptors because blockade or stimulation of these receptors in the PFC can impair performance on delayed response tasks. However, comparatively less is known about dopaminergic mechanisms that mediate other executive functions regulated by the PFC. Furthermore, the functional importance of other DA receptor subtypes that reside on PFC neurons (D2 and D4) is unclear. This review will summarize previous findings and previously unpublished data addressing the contribution of PFC DA to higher-order cognition. We will compare the DA receptor mechanisms, which regulate executive functions such as working memory, behavioral flexibility, and decision-making. Whereas PFC D1 receptor activity is of primary importance in working memory, D1 and D2 receptors act in a cooperative manner to facilitate behavioral flexibility. We note that the principle of the “inverted U-shaped” function of D1 receptor activity mediating working memory does not necessarily apply to other PFC functions. DA in different subregions of the PFC also mediates decision-making assessed with delay discounting or effort-based procedures, and we report that D1, D2, and D4 receptors in the medial PFC contribute to decision-making when animals must bias the direction of behavior to avoid aversive stimuli, assessed with a conditioned punishment procedure. Thus, mesocortical DA modulation of distinct executive functions is subserved by dissociable profiles of DA receptor activity in the PFC.

Nicotine and nonnicotine factors in cigarette addiction.

Abstract: A great deal of research supports the role of nicotine in cigarette addiction However, the effectiveness of nicotine replacement therapy (NRT) as a smoking cessation treatment has fallen short of initial hopes A key reason may be that NRT does not address nonnicotine components of smoking reinforcement These include constituents that provide reinforcing sensory stimulation, components that minimize excessive irritation from inhaled nicotine and other pharmacologically active compounds in cigarette smoke Studies using various paradigms to dissociate nicotine from other components of smoking are summarized Nonnicotine components provide many rewarding effects, often surpassing the direct effects of nicotine Substitutes for the sensory effects of smoking may be effective in relieving craving for cigarettes and in facilitating smoking cessation Moreover, techniques for devaluing smoking-related cues may decrease craving and enhance subsequent abstinence Promising approaches for devaluing smoke cues include extinction-based treatments employing denicotinized cigarettes and the use of nicotinic agonist and/or antagonist treatment during the weeks leading up to a quit attempt Recent studies suggest that incorporating these approaches into a treatment program may significantly increase smoking abstinence rates Preliminary findings also suggest that replacement of the effects of monoamine oxidase inhibitors contained in cigarette smoke may enhance quit rates While current NRT methods have been the mainstay of smoking cessation treatment and will likely continue to serve a useful role, the next stage of progress will likely entail the development of tools designed with recognition of the importance of nonnicotine components of cigarette smoking

Dysfunction of ventral striatal reward prediction in schizophrenic patients treated with typical, not atypical, neuroleptics

Abstract: Rational Clinical studies in patients with schizophrenia suggest that atypical neuroleptics are more effective than typical neuroleptics in reducing negative symptoms including apathy and anhedonia. Dysfunction of the dopaminergic reward system may contribute to negative symptoms in schizophrenia.

Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications

Abstract: Oxytocin (OT) acts as a neuromodulator/neurotransmitter within the central nervous system (CNS) and regulates a diverse range of CNS functions. Notably, evidence from studies in females has revealed an important role for OT in regulating anxiety behavior. The objective of this study was to examine the effects of OT on both behavioral and autonomic parameters of the anxiety response in male mice using three pharmacologically validated preclinical models of anxiety: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH). In the FPT, both peripherally (3–30 mg/kg i.p.) and centrally (1–10 μg i.c.v.) administered OT produced dose-dependent increases in punished crossings, indicating an anxiolytic-like effect. The effects of centrally administered OT in the FPT were blocked with peripheral administration of a brain-penetrant OT receptor (OTR) antagonist WAY-162720 (30 mg/kg i.p.), and the effects of peripherally administered OT were blocked with central administration of a non-penetrant OTR antagonist L-371,257, suggesting OT acts centrally. In the EZM, centrally administered OT (0.1–1.0 μg, i.c.v.) produced significant increases in the percentage time spent in the open quadrants of the maze, comparable to alprazolam (0.5–1.0 μg, i.c.v.). In SIH, OT (1–10 mg/kg i.p.) dose-dependently attenuated stress-induced increases in core body temperature, comparable to the reference anxiolytic chlordiazepoxide (CDP) (10 mg/kg i.p.). These results provide specific behavioral and autonomic evidence of anxiolytic-like effects for oxytocin in males and, together with previously reported observations in females, suggest the potential utility of OTR agonism as a therapeutically relevant mechanism of action for novel anxiolytics in both sexes.

Neuropsychological function and delay discounting in methamphetamine-dependent individuals.

Abstract: Rationale Methamphetamine (MA) dependence accounts for substantial neuropsychiatric morbidity. Furthermore, there is evidence in the literature of psychiatric and cognitive impairment in chronic users.

Acute and chronic effects of ketamine upon human memory: a review.

Abstract: Introduction Ketamine is attracting increasing research interest not only because of its powerful amnestic effects but also as a putative model of schizophrenia and as a substance with an expanding following of recreational users.

Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement

Abstract: Although considerable progress has been made, we do not yet fully understand the behavioral and neurobiological basis of nicotine reinforcement, and without this knowledge, treatment strategies aimed at reducing smoking remain deficient. This review describes an original perspective on nicotine reinforcement, which arises from substantial evidence of complex interactions between nicotine and nonpharmacological stimuli. We hypothesize that nicotine reinforcement derives from at least two sources: (1) primary reinforcement, an action that requires response-dependent drug administration and is capable of conveying secondary reinforcing effects on associated stimuli, and (2) the reinforcement-enhancing effect of nicotine, which directly enhances behavior maintained by salient nonnicotine stimuli and does not require a contingent relationship between drug administration and reinforced operant responding. Although novel for nicotine, this hypothesis has origins in an extensive literature on the reinforcing effects of psychostimulants. Empirical support for this hypothesis, based largely on animal models of reinforcement, will be presented. Animal models of drug reinforcement have evolved to reflect our growing awareness of the multidimensional nature of drug dependence in humans. Investigating the interaction between nicotine and nonpharmacological stimuli within the context of the drug self-administration paradigm in rats has generated new insights into the paradox of how nicotine, an apparently weak primary reinforcer, can sustain the robust behavior observed in self-administration and in smoking. The hypothesis presented in this paper—that nicotine acts as both a primary reinforcer and an enhancer of other nonnicotine reinforcers—provides important direction for future investigations into the neurobiology of nicotine reinforcement and treatments for smoking cessation.

Behavioral disinhibition requires dopamine receptor activation

Abstract: Behavioral disinhibition is a manifestation of impulsive behavior that is prominent in the psychopathology of various psychiatric disorders, but the underlying neural mechanisms are unclear. Behavioral disinhibition can be investigated by measuring premature responding in the 5-choice serial reaction time task (5-CSRTT) in which attentional parameters can be measured as well. The objective of the study was to investigate the involvement of dopamine neurotransmission in behavioral disinhibition using the 5-CSRTT in rats. The effects of amphetamine, cocaine, nicotine, the dopamine reuptake inhibitor GBR 12909, the noradrenaline reuptake inhibitor desipramine, the dopamine D1 receptor antagonist SCH 23390, and the dopamine D2 receptor antagonist eticlopride were studied in rats that were well-trained in the 5-CSRTT. Subsequently, the effects of amphetamine, cocaine, and nicotine were tested after pretreatment with SCH 23390 or eticlopride. What amphetamine, cocaine, and nicotine had in common is that they increased premature responding. However, these drugs had distinct effects on attentional parameters. GBR 12909 also enhanced premature responding, whereas desipramine reduced it. Eticlopride by itself had no effect on premature responding but it attenuated the increases in this parameter evoked by amphetamine, cocaine, or nicotine. SCH 23390 reduced premature responding on its own and also reduced its drug-induced enhancement. The present data show that behavioral disinhibition, i.e., the inability to withhold a premature response, is a common effect of drugs of abuse and that this effect is the result of enhanced dopaminergic neurotransmission. In addition, dopamine D1 and D2 receptors play important, but perhaps distinct roles, in inhibitory control of behavior.

Delay discounting and the behavioural economics of cigarette purchases in smokers: the effects of nicotine deprivation.

Abstract: In smokers, nicotine deprivation may increase impulsive decision-making and the demand for cigarettes. To investigate the effects of acute nicotine deprivation on (a) the delay discounting of monetary and cigarette rewards, and (b) the behavioural economics of hypothetical cigarette purchases. A repeated measures design was employed, with participants (daily cigarette smokers, N=30) repeating experimental tasks in two different sessions, once after at least 13 h of abstinence from smoking and once after ad lib smoking. Participants completed measures of cigarette craving, impulsivity, delay discounting and a behavioural economic simulation in which participants made hypothetical purchases of cigarettes and other commodities as the price of cigarettes was systematically varied. Participants showed more pronounced delay discounting of both cigarette and monetary rewards after abstinence compared to after ad lib smoking. In the behavioural economic simulation, nicotine deprivation had no influence on hypothetical cigarette purchases. However, spending on some commodities (alcohol, clothing, household goods, leisure activities and long-distance travel) was reduced as the price of cigarettes increased in order to fund increased spending on cigarettes, although the number of packs of cigarettes purchased actually decreased. Nicotine deprivation increases impulsive choices for both cigarette and monetary rewards in a delay-discounting task. Results from a behavioural economic simulation suggest that increases in the price of cigarettes may increase smokers’ spending on cigarettes, while also reducing the number of cigarettes purchased.

Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake

Abstract: It has recently become more clearly understood that in human brain pathophysiology, neurosteroids play a role in anxiety disorders, premenstrual syndrome, postpartum depression, posttraumatic stress disorder, and depression. In the treatment of major depression, recent clinical studies indicate that the pharmacological profiles of fluoxetine and fluvoxamine are correlated with the ability of these drugs to increase the brain and cerebrospinal fluid content of allopregnanolone (Allo), a potent positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors. Thus, the neurosteroid-induced positive allosteric modulation of GABA action at GABAA receptors is facilitated by fluoxetine or its congeners (i.e., paroxetine, fluvoxamine, sertraline), which may not block 5-HT reuptake at the doses currently prescribed in the clinic. However, these doses are effective in the treatment of premenstrual dysphoria, anxiety, and depression. In socially isolated mice, we tested the hypothesis that fluoxetine, norfluoxetine, and other specific serotonin reuptake inhibitor (SSRI) congeners stereoselectively upregulate neurosteroid content at doses insufficient to inhibit 5-HT reuptake; although they potentiate pentobarbital-induced sedation and exert antiaggressive action. Very importantly, the inhibition of 5-HT reuptake lacks stereospecificity and requires fluoxetine and norfluoxetine doses that are 50-fold greater than those required to increase brain Allo content, potentiate the action of pentobarbital, or antagonize isolation-induced aggression. Based on these findings, it could be inferred that the increase of brain Allo content elicited by fluoxetine and norfluoxetine, rather than the inhibition selective of 5-HT reuptake, may be operative in the fluoxetine-induced remission of the behavioral abnormalities associated with mood disorders. Therefore, the term "SSRI" may be misleading in defining the pharmacological profile of fluoxetine and its congeners. To this extent, the term "selective brain steroidogenic stimulants" (SBSSs) could be proposed.

Severity of nicotine dependence modulates cue-induced brain activity in regions involved in motor preparation and imagery

Abstract: In nicotine-dependent subjects, cues related to smoking elicit activity in brain regions linked to attention, memory, emotion and motivation Cue-induced brain activation is associated with self-reported craving but further correlates are widely unknown This study was conducted to investigate whether brain activity elicited by smoking cues increases with severity of nicotine dependence and intensity of cue-elicited craving Ten healthy male smokers whose degree of nicotine dependence ranged from absent to severe were investigated Visual smoking cues and neutral stimuli were presented in a block design during functional magnetic resonance imaging (fMRI) Using multiple linear regression analysis, the blood oxygen level dependent (BOLD) response to smoking cues was correlated with severity of nicotine dependence assessed with the Fagerstrom Test of Nicotine Dependence (FTND) and with cue-induced craving Significant positive correlations between the BOLD activity and FTND scores were found in brain areas related to visuospatial attention (anterior cingulate cortex, parietal cortex, parahippocampal gyrus and cuneus) and in regions involved in motor preparation and imagery (primary and premotor cortex, supplementary motor area) Intensity of cue-induced craving was significantly associated with greater BOLD activation in mesocorticolimbic areas engaged in incentive motivation and in brain regions related to episodic memory Our study suggests that severity of nicotine dependence and intensity of craving are independently associated with cue-induced brain activation in separate neuronal networks The observed association between severity of dependence and brain activity in regions involved in allocation of attention, motor preparation and imagery might reflect preparation of automated drug taking behavior thereby facilitating cue-induced relapse

Nicotinic modulation of neuronal networks: from receptors to cognition.

Abstract: Rationale Nicotine affects many aspects of human cognition, including attention and memory. Activation of nicotinic acetylcholine receptors (nAChRs) in neuronal networks modulates activity and information processing during cognitive tasks, which can be observed in electroencephalograms (EEGs) and functional magnetic resonance imaging studies.

The early time course of smoking withdrawal effects

Abstract: Rationale There has been little study of the very early time course of the smoking withdrawal syndrome, despite its relevance to the maintenance of both smoking and postcessation abstinence. The literature contains a range of estimates about the early appearance of withdrawal symptoms, but without reference to empirical data.

Subjective, behavioral, and physiological effects of acute caffeine in light, nondependent caffeine users.

Abstract: Caffeine produces mild psychostimulant effects that are thought to underlie its widespread use. However, the direct effects of caffeine are difficult to evaluate in regular users of caffeine because of tolerance and withdrawal. Indeed, some researchers hypothesize that the psychostimulant effects of caffeine are due largely to the reversal of withdrawal and question whether there are direct effects of caffeine consumption upon mood, alertness, or mental performance in nondependent individuals. This study investigated the physiological, subjective, and behavioral effects of 0, 50, 150, and 450 mg caffeine in 102 light, nondependent caffeine users. Using a within-subjects design, subjects participated in four experimental sessions, in which they received each of the four drug conditions in random order under double blind conditions. Participants completed subjective effects questionnaires and vital signs were measured before and at repeated time points after drug administration. Forty minutes after the capsules were ingested, subjects completed behavioral tasks that included tests of sustained attention, short-term memory, psychomotor performance, and behavioral inhibition. Caffeine significantly increased blood pressure, and produced feelings of arousal, positive mood, and high. Caffeine increased the number of hits and decreased reaction times in a vigilance task, but impaired performance on a memory task. We confirm that acute doses of caffeine, at levels typically found in a cup of coffee, produce stimulant-like subjective effects and enhance performance in light, nondependent caffeine users. These findings support the idea that the drug has psychoactive effects even in the absence of withdrawal.

Inhibition of neuronal nitric oxide synthase in the rat hippocampus induces antidepressant-like effects

Abstract: Systemic inhibition of neuronal nitric oxide synthase (nNOS) induces antidepressant-like effects in rodents. The mechanisms and brain regions mediating this effect are still unknown. The hippocampus is a brain region proposed to mediate adaptation to stress and antidepressant behavioral effects. Therefore, it could be involved in the antidepressant effects of NOS inhibitors. To test the hypothesis that nNOS inhibition in the dorsal hippocampus will induce antidepressant-like effects in the forced swimming test (FST) in rats. Rats implanted with cannulas aimed at the dorsal hippocampus were submitted to 15 min of forced swimming (pretest). Immediately before or after pretest they received bilateral microinjections of the nNOS inhibitor 7-nitroindazole (7-NI; 50, 100, or 200 nmol/0.5 μl) or vehicle, alone or combined with l-arginine. Additional groups received SIN-1 (125 or 250 nmol/0.5 μl), a NO donor, either before or after the pretest. Twenty-four hours later, immobility time was registered for 5 min in the FST. 7-NI (100 nmol) significantly decreased immobility time when administered either before or after pretest. Pretreatment with l-arginine (100 nmol/0.5 μl) prevented these effects but produced no significant effects per se. SIN-1 did not induce any significant effect. These data suggest that the reduction of NO levels within the hippocampus can induce antidepressant-like effects; thus implicating endogenous hippocampal NO in the neurobiology of stress and depression.

Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers

Abstract: Preclinical investigations have established that methamphetamine (MA) produces long-term changes in dopamine (DA) neurons in the striatum. Human studies have suggested similar effects and correlated motor and cognitive deficits. The present study was designed to further our understanding of changes in brain function in humans that might result from chronic high dose use of MA after at least 3 months of abstinence. Brain function in abstinent users was compared to controls using neuroimaging of monoamine transporters and cognitive assessment. Striatal levels of DA transporter (DAT) and vesicular monoamine transporter type-2 (VMAT2) were determined using [11C]methylphenidate and [11C]dihydrotetrabenazine positron emission tomography, respectively. Cognitive function was evaluated using tests of motor function, memory, learning, attention, and executive function. Striatal DAT was approximately 15% lower and VMAT2 was 10% lower in MA abusers across striatal subregions. The MA abusers performed within the normal range but performed more poorly compared to controls on three of the 12 tasks. Failure to find more substantial changes in transporter levels and neurocognitive function may be attributed to the length of time that MA users were abstinent (ranging from 3 months to more than 10 years, mean 3 years), although there were no correlations with length of abstinence. Persistent VMAT2 reductions support the animal literature indicating a toxic effect of MA on nigrostriatal nerve terminals. However, the magnitude of the MA effects on nigrostriatal projection integrity is sufficiently small that it is questionable whether clinical signs of DA deficiency are likely to develop.

The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats.

Abstract: Rationale Previous studies demonstrated that pharmacological blockade of CB1 cannabinoid receptors decreases the extinction of conditioned fear and spatial memory in rodents. However, the effects of CB1 cannabinoid receptor activation in this response remain unclear. Objectives To evaluate the effects of the cannabinoid agonist WIN 55,212-2 (WIN) and the cannabinoid antagonist SR 147778 (SR) on the extinction of contextual fear memory in rats 24 h or 30 days after fear conditioning. Methods For fear conditioning, rats were placed in the conditioning chamber for 3 min and received a 1-s electric foot shock (1.5 mA). Retrieval testing consisted of a 3-min exposure to the conditioning chamber and extinction training consisted of successive 9-min exposures at 24-h intervals. Rats were also evaluated in the open field and water maze reversal task. Results The administration of SR (1.0 mg/kg, i.p.) and WIN (0.25 mg/kg, i.p.) before extinction training disrupted and facilitated, respectively, the extinction of 24 h contextual fear memory. These effects were not related to any disturbance in memory retrieval, unconditioned freezing expression, or locomotor activity. WIN (0.25 mg/kg, i.p.) also facilitated the extinction of 30-day-old contextual fear memory, while the prior administration of SR (0.2 mg/kg, i.p.) antagonized this response. The facilitative effect of WIN on memory extinction does not seem to be specific for contextual fear memory because it was also observed in the water maze reversal task. Conclusions These results suggest cannabinoid receptor agonists as potential drugs to treat anxiety disorders related to the retrieval of aversive memories.

N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder.

Abstract: Dysfunction of glutamatergic neurotransmission has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and recent clinical reports suggest that some glutamate modulating agents are efficacious in the treatment of this disorder. N-acetylcysteine (NAC) is a readily available amino acid compound that is thought to attenuate glutamatergic neurotransmission. NAC may be useful in treating psychiatric disorders involving glutamatergic dysfunction such as OCD. To examine the efficacy of augmentation with NAC in a patient with serotonin reuptake inhibitor (SRI)-refractory OCD. A patient with SRI-refractory OCD was treated with an off-label use of NAC augmentation of fluvoxamine over several weeks. NAC augmentation of fluvoxamine resulted in a marked decrease in Yale-Brown Obsessive Compulsive Scale (Y-BBOCS) score and a clinically significant improvement in OCD symptoms. NAC augmentation was effective in treating SRI-refractory OCD in this single case. Further research is warranted to investigate the use of NAC and other glutamate modulating agents in the treatment of OCD.

The β2 but not α7 subunit of the nicotinic acetylcholine receptor is required for nicotine-conditioned place preference in mice

Abstract: Rationale Tobacco use is implicated in approximately 440,000 deaths per year, making it the leading cause of preventable death in the United States. Although it is generally recognized that tobacco use is correlated with a variety of health-related complications, many smokers are unsuccessful in their efforts to stop smoking using current cessation therapies.

Increased frontal and paralimbic activation following ayahuasca, the pan-Amazonian inebriant.

Abstract: Ayahuasca is a South American psychoactive plant tea which contains the serotonergic psychedelic N,N-dimethyltryptamine (DMT) and monoamine-oxidase inhibitors that render DMT orally active. Previous investigations with ayahuasca have highlighted a psychotropic effect profile characterized by enhanced introspective attention, with individuals reporting altered somatic perceptions and intense emotional modifications, frequently accompanied by visual imagery. Despite recent advances in the study of ayahuasca pharmacology, the neural correlates of acute ayahuasca intoxication remain largely unknown. To investigate the effects of ayahuasca administration on regional cerebral blood flow. Fifteen male volunteers with prior experience in the use of psychedelics received a single oral dose of encapsulated freeze-dried ayahuasca equivalent to 1.0 mg DMT/kg body weight and a placebo in a randomized double-blind clinical trial. Regional cerebral blood flow was measured 100–110 min after drug administration by means of single photon emission tomography (SPECT). Ayahuasca administration led to significant activation of frontal and paralimbic brain regions. Increased blood perfusion was observed bilaterally in the anterior insula, with greater intensity in the right hemisphere, and in the anterior cingulate/frontomedial cortex of the right hemisphere, areas previously implicated in somatic awareness, subjective feeling states, and emotional arousal. Additional increases were observed in the left amygdala/parahippocampal gyrus, a structure also involved in emotional arousal. The present results suggest that ayahuasca interacts with neural systems that are central to interoception and emotional processing and point to a modulatory role of serotonergic neurotransmission in these processes.

Escalation of methamphetamine self-administration in rats: a dose–effect function

Abstract: The transition from stable to escalated drug intake has been demonstrated in rats self-administrating cocaine and heroin using a single dose of drug. To investigate the prolonged exposure to methamphetamine self-administration and the effect of various training doses of methamphetamine on the changes of methamphetamine intake over a 21-day period. Two groups of rats were trained in 1-h daily sessions of methamphetamine self-administration [0.033 mg/infusion (inf); approximately 0.066 mg/kg/inf]. Methamphetamine access was increased to 6 h in one group [Long Access (LgA)] or maintained at 1 h in another [Short Access (ShA)]. The same procedure was repeated in rats exposed to different training doses of methamphetamine (0.05, 0.1, and 0.2 mg/kg/inf). In LgA rats, total and first hour intake of methamphetamine significantly increased compared to ShA rats at various methamphetamine doses. LgA animals, at all doses in the second study, escalated intake to 8–9 mg/kg per 6-h session, with the most rapid escalation occurring at 3–5 days at a methamphetamine dose of 0.1 mg/kg/inf. The escalation of drug intake observed with extended access is produced at multiple doses of methamphetamine. The rapidity of escalation depends on the dose. Ultimately, all doses in the dose-response study engendered self-administration of the same amount of total drug in a 6-h session in the extended-access group. Results suggest that the rapidity of escalation is dependent on dose and has an upper limit of intake over a period of 21 days.

Periadolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine.

Abstract: Initiation of tobacco use typically begins during adolescence, and the nature of these first experiences with nicotine may affect the probability of continued use. In rodents, a number of studies suggest that periadolescents are more responsive to the rewarding effects of nicotine compared to adults. This study was designed to determine if there are age differences in the rewarding and aversive effects of nicotine by using the conditioned place preference (CPP) and conditioned taste avoidance (CTA) paradigms, respectively. We also examined age differences in locomotor responses to nicotine. In the CPP paradigm, male periadolescent and adult Wistar rats received nicotine (0.2, 0.4, or 0.8 mg/kg, s.c.) or vehicle prior to place conditioning trials. In the CTA paradigm, in separate groups of rats, periadolescents and adults were exposed to a 0.1% saccharin solution, followed by the administration of nicotine (0.2, 0.4, or 0.8 mg/kg, s.c.) or vehicle. Four saccharin–nicotine pairings were followed by a preference test and three extinction sessions. In the CPP paradigm, nicotine produced a dose-dependent place preference in periadolescent, but not in adult, rats. In the CTA paradigm, adult rats expressed a dose-dependent avoidance of saccharin after pairings with nicotine, whereas periadolescents were resistant to CTA formation. With regard to locomotor activity, adults and periadolescents showed comparable locomotor responses to nicotine. These results suggest that periadolescent rats find nicotine more rewarding and less aversive, compared to adult rats. This shift in the balance between the rewarding and aversive effects of nicotine may make adolescents more susceptible to continued nicotine use.

The group II metabotropic glutamate receptor agonist, LY379268, inhibits both cocaine- and food-seeking behavior in rats.

Abstract: Group II metabotropic glutamate receptor (mGluR2/3) agonists are proposed to serve as potential treatment for addiction. The present study examined the hypothesis that mGluR2/3 agonists exert inhibitory effects on cocaine-induced reinstatement of cocaine-seeking. Rats were trained to self-administer either cocaine or control reinforcer (food), then responding on the reinforcer-paired lever was extinguished. Reinstatement of responding was induced by a noncontingent presentation of the self-administered reinforcer (10 mg/kg cocaine, i.p. or 765 mg of food). In one experiment, rats were systemically pretreated with vehicle (Veh) or the mGluR2/3 agonist LY379268 (0.3, 1, or 3 mg/kg, i.p.) 30 min before the reinstatement test session. In a second experiment, Veh or LY379268 (0.05, 0.5, or 5 nmol/side) was microinjected into the nucleus accumbens core (NAc core) 5 min before the reinstatement test session. The effects of LY379268 on cocaine- and food-induced reinstatement on reward seeking were assessed. Both systemic and intra-NAc core pretreatment with LY379268 inhibited both cocaine- and food-seeking behavior. However, the effect of LY379268 appeared somewhat more effective for cocaine-seeking than food-seeking. These results support a potential therapeutic role for mGluR2/3 agonists on relapse of cocaine-seeking. However, doses that inhibited cocaine-seeking were only threefold lower than those inhibiting food-seeking, indicating possible unacceptable nonspecific effects. In addition, the NAc core is one site of action where the mGluR2/3 agonists elicit effects on reward-seeking behavior.

Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes

Abstract: Rationale Corticotropin-releasing factor (CRF) produces anxiety-like and aversive effects when infused directly into the various regions of the brain, including the bed nucleus of the stria terminalis (BNST). However, the CRF receptor subtypes within the BNST mediating these phenomena have not been established.

Long-term effects of frequent cannabis use on working memory and attention: an fMRI study

Abstract: Excessive use of cannabis may have long-term effects on cognitive abilities. Mild impairments have been found in several cognitive domains, particularly in memory and attention. It is not clear, however, whether these effects also occur with moderate, recreational use of cannabis. Furthermore, little is known about underlying brain correlates. The aim of this study is to assess brain function in frequent but relatively moderate cannabis users in the domains of working memory and selective attention. Functional magnetic resonance imaging was used to examine verbal working memory and visuo-auditory selective attention in ten frequent cannabis users (after 1 week of abstinence) and ten non-using healthy controls. Groups were similar in age, gender and estimated IQ. Cannabis users and controls performed equally well during the working memory task and the selective attention task. Furthermore, cannabis users did not differ from controls in terms of overall patterns of brain activity in the regions involved in these cognitive functions. However, for working memory, a more specific region-of-interest analysis showed that, in comparison to the controls, cannabis users displayed a significant alteration in brain activity in the left superior parietal cortex. No evidence was found for long-term deficits in working memory and selective attention in frequent cannabis users after 1 week of abstinence. Nonetheless, frequent cannabis use may affect brain function, as indicated by altered neurophysiological dynamics in the left superior parietal cortex during working memory processing.

Dissociating the primary reinforcing and reinforcement-enhancing effects of nicotine using a rat self-administration paradigm with concurrently available drug and environmental reinforcers.

Abstract: Rationale Nicotine has two effects on reinforcement in traditional self-administration paradigms. It serves as a primary reinforcer by increasing the probability of behaviors that result in nicotine delivery. However, nicotine also potently enhances behaviors that result in the delivery of nonpharmacological reinforcers.