Acute D-amphetamine Research Articles

Detecting Pharmacologically Induced Serotonin Release in Depression With Positron Emission Tomography Imaging: A New Approach

In the current issue of Biological Psychiatry, Erritzoe et al. ( 1 Erritzoe D. Godlewska B.R. Rizzo G. Searle G.E. Agnorelli C. Lewis Y. et al. Brain serotonin release is reduced in patients with depression: A [11C]Cimbi-36 positron emission tomography study with a d-amphetamine challenge. Biol Psychiatry. 2023; 93: 1089-1098 Abstract Full Text Full Text PDF Scopus (5) Google Scholar ) used positron emission tomography (PET) imaging of the 5-HT2A receptor agonist [11C]Cimbi-36 in combination with a d-amphetamine challenge to demonstrate for the first time lower, on average, capacity for serotonin release in the frontal cortex of participants with major depressive disorder or comorbid depression with Parkinson’s disease compared with demographically similar healthy control subjects. There has been some recent controversy regarding the role of serotonin in depression, with an umbrella analysis, a meta-analysis of meta-analyses, disputing the serotonin hypothesis of depression ( 2 Moncrieff J. Cooper R.E. Stockmann T. Amendola S. Hengartner M.P. Horowitz M.A. The serotonin theory of depression: A systematic umbrella review of the evidence [published online Jul 20]. Mol Psychiatry. 2022; Crossref Scopus (105) Google Scholar ), generating discussion, pro and con, in both the scientific community and the general media. The umbrella analysis cites data from many studies using many modalities, but no studies that include in vivo PET imaging of the brain to infer capacity for serotonin release. This is not because such data were ignored, but rather because they didn’t exist, as a method for reliably and robustly quantifying serotonin release with PET had not yet been developed at the time the literature search was performed in that study. In 2020, Erritzoe et al. ( 3 Erritzoe D. Ashok A.H. Searle G.E. Colasanti A. Turton S. Lewis Y. et al. Serotonin release measured in the human brain: A PET study with [11C]Cimbi-36 and d-amphetamine challenge. Neuropsychopharmacology. 2020; 45: 804-810 Crossref PubMed Scopus (20) Google Scholar ) published a demonstration, for the first time, of an approach to reliably detect pharmacologically induced cortical serotonin release in humans. In their new article ( 1 Erritzoe D. Godlewska B.R. Rizzo G. Searle G.E. Agnorelli C. Lewis Y. et al. Brain serotonin release is reduced in patients with depression: A [11C]Cimbi-36 positron emission tomography study with a d-amphetamine challenge. Biol Psychiatry. 2023; 93: 1089-1098 Abstract Full Text Full Text PDF Scopus (5) Google Scholar ), they’ve applied this approach in a sample of participants with depression. This methodological breakthrough did not come about by implementation of new technology but rather from combining existing methods and ideas in a novel way. SEE CORRESPONDING ARTICLE ON PAGE 1089 SEE CORRESPONDING ARTICLE ON PAGE 1089 Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine ChallengeBiological PsychiatryVol. 93Issue 12PreviewThe serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT2A receptor agonist positron emission tomography (PET) radioligand [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression. Full-Text PDF

Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge

BackgroundThe serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT2A receptor agonist positron emission tomography (PET) radioligand [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression. MethodsSeventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16–30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [11C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region. ResultsFollowing d-amphetamine administration, frontal nondisplaceable binding potential (BPND) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p < .001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ΔBPND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041). ConclusionsThis first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE.

GPR52 agonists attenuate ropinirole-induced preference for uncertain outcomes.

Dopamine D2/3 receptor agonists are less likely to trigger dyskinesias than L-dopa while still offering relief from the motor symptoms of Parkinson's disease (PD). However, these drugs can cause serious impulse control problems and gambling disorders. Adjunctive therapies capable of blocking these side effects without impacting the antiparkinsonian effect would be clinically useful. G-protein-coupled receptor 52 (GPR52) is an orphan Gs-protein-coupled receptor that is coexpressed with striatal D₂ receptors. Activating GPR52 attenuates behaviors associated with increased striatal dopamine release without altering basal function. Iatrogenic gambling disorder may be mediated, at least partly, by striatal dopamine signaling. We therefore investigated whether 2 potent small-molecule GPR52 agonists (BD442618, BD502657) could block the increase in preference for uncertain outcomes caused by acute d-amphetamine and chronic ropinirole, without altering baseline choice patterns. In the rat betting task (rBT), subjects choose between a guaranteed reward (the "wager") versus the 50:50 chance of double the wager or nothing. Although wager size varies across trial blocks, both options are constantly matched for expected value. The effects of BD442618 on the rBT were acutely assessed alone or in combination with d-amphetamine and subsequently in combination with chronic ropinirole. The latter experiment was then repeated with BD502657. BD442618 did not alter baseline decision making but attenuated the increase in preference for uncertainty caused by both acute amphetamine and chronic ropinirole administration. Similarly, BD502657 abrogated chronic ropinirole's effects. These data provide the first evidence that GPR52 agonists may be useful in treating iatrogenic gambling disorder or other conditions hallmarked by hyperdopaminergic states. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Methylmercury, attention, and memory: baseline-dependent effects of adult d-amphetamine and marginal effects of adolescent methylmercury

Methylmercury (MeHg) is an environmental neurotoxicant known to disrupt behavior related to dopamine neurotransmission in experimental models. Such disruptions are sensitive to dopamine agonists when administered acutely after exposure to MeHg has ended or when administered concurrently with MeHg exposure. Sustained attention and short-term remembering, components of attention-deficit/hyperactivity disorder (ADHD), are partially mediated by dopamine neurotransmission. In order to observe MeHg-related alterations in sustained attention and short-term memory, as well as determine sensitivity of MeHg exposed animals to dopamine agonists commonly used in the treatment of ADHD symptoms, rats were exposed to 0, 0.5, or 5 ppm MeHg throughout adolescence and trained in a hybrid sustained attention/short term memory visual signal detection task in adulthood. Behavior was then probed with acute i.p. injections of the dopamine agonist, d-amphetamine, which improves impaired attention and inhibits short-term memory in clinical syndromes like ADHD. Acute d-amphetamine dose-dependently decreased short-term memory as well as sustained attention. While MeHg alone did not impair accuracy or memory, it did interact with d-amphetamine to produce baseline-dependent inhibition of behavior. These findings further show that changes in behavior following low-level exposure to MeHg during adolescence are augmented by dopamine agonists. Observed impairments in memory following acute d-amphetamine are consistent with previous findings.

Development of a Semimechanistic Pharmacokinetic-Pharmacodynamic Model Describing Dextroamphetamine Exposure and Striatal Dopamine Response in Rats and Nonhuman Primates following a Single Dose of Dextroamphetamine.

Acute central nervous system exposure to dextroamphetamine (d-amphetamine) elicits a multitude of effects, including dual action on the dopamine transporter (DAT) to increase extracellular dopamine, and induction of a negative feedback response to limit the dopamine increase. A semimechanistic pharmacokinetic and pharmacodynamic (PK/PD) model with consideration of these multiple effects as a basis was developed. Integrated pharmacokinetics of d-amphetamine in plasma, brain extracellular fluid (ECF) via microdialysis, and cerebrospinal fluid were characterized using a population approach. This PK model was then linked to an indirect-response pharmacodynamic model using as a basis the measurement of extracellular striatal dopamine, also via microdialysis. In both rats and nonhuman primates (NHPs), d-amphetamine stimulation of dopamine outflow (reverse transport) through DAT was primarily responsible for the dose-linear increase in dopamine. As well, in both species a moderator function was needed to account for loss of the dopamine response in the presence of a relatively sustained d-amphetamine ECF exposure, presumptive of an acute tolerance response. PK/PD model structure was consistent between species; however, there was a 10-fold faster return to baseline dopamine in NHPs in response to an acute d-amphetamine challenge. These results suggest preservation from rodents to NHPs regarding the mechanism by which amphetamine increases extracellular dopamine, but a faster system response in NHPs to tolerate this increase. This microdialysis-based PK/PD model suggests greater value in directing preclinical discovery of novel approaches that modify reverse transport stimulation to treat amphetamine abuse. General value regarding insertion of an NHP model in paradigm rodent-to-human translational research is also suggested.

Response-inhibition capacity in spontaneously hypertensive and Wistar rats: acquisition of fixed minimum interval performance and responsiveness to D-amphetamine.

Reduced response-inhibition capacity is a defining feature of attention-deficit hyperactivity disorder. The fixed minimum interval (FMI) schedule has been systematically validated to assess such capacity in rats. On each FMI trial, the first lever press initiates an inter-response time (IRT); a potentially consummatory response terminates the IRT; only IRTs longer than a target interval result in access to food. Despite task validity, steady-state FMI performance in the most common animal model of attention-deficit hyperactivity disorder, the spontaneously hypertensive rat (SHR), is similar to normotensive control performance, even though SHR performs at lower levels, especially during acquisition, in similar response-withholding tasks. To determine whether such limitations of the model are specific to stable-state performance, this experiment compared FMI 6-s performance in SHR and Wistar rats during acquisition and in steady state, and assessed the effect of acute D-amphetamine (AMP) administration (0.1, 0.5, and 1.0 mg/kg) on steady-state performance. Median latencies to first lever press were consistently shorter in SHR than in Wistar rats; IRTs were shorter for SHR than for Wistar rats during acquisition, but substantially less so during asymptotic performance. AMP dose-dependently reduced latencies, shortened IRTs, and, at the highest dose, increased the proportion of IRTs under schedule control. These results suggest that, relative to Wistar rats, SHR have a reduced capacity to learn to withhold a reinforced response; once the FMI is acquired, high doses of D-AMP disrupt withholding performance in both strains, but they also enhance the responsiveness of both strains to reinforcement contingencies.

BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine.

Background:One of the most devastating consequences of methamphetamine abuse is increased risk of psychosis. Brain-derived neurotrophic factor has been implicated in both psychosis and neuronal responses to methamphetamine. We therefore examined persistent psychosis-like behavioral effects of methamphetamine in brain-derived neurotrophic factor heterozygous mice.Methods:Mice were chronically treated with methamphetamine from 6 to 9 weeks of age, and locomotor hyperactivity to an acute D-amphetamine challenge was tested in photocell cages after a 2-week withdrawal period.Results:Methamphetamine-treated wild-type mice, but not brain-derived neurotrophic factor heterozygous mice, showed locomotor sensitization to acute 3mg/kg D-amphetamine. Qualitative analysis of exploration revealed tolerance to D-amphetamine effects on entropy in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice, but not wild-type mice.Conclusions:Chronic methamphetamine exposure induces contrasting profiles of behavioral changes in wild-type and brain-derived neurotrophic factor heterozygous mice, with attenuation of behaviors relevant to psychosis in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice. This suggests that brain-derived neurotrophic factor signalling changes may contribute to development of psychosis in methamphetamine users.

Effect of environmental enrichment on dopamine and serotonin transporters and glutamate neurotransmission in medial prefrontal and orbitofrontal cortex

Recent studies have reported that rats raised in an enriched condition (EC) have decreased dopamine transporter (DAT) function and expression in medial prefrontal cortex (mPFC), as well as increased d-amphetamine-induced glutamate release in nucleus accumbens compared to rats raised in an isolated condition (IC). In these previous studies, DAT function and expression were evaluated using mPFC pooled from four rats for each condition to obtain kinetic parameters due to sparse DAT expression in mPFC. In contrast, accumbal glutamate release was determined using individual rats. The current study extends the previous work and reports on the optimization of DAT and serotonin transporter (SERT) functional assays, as well as cell surface expression assays using both mPFC and orbitofrontal cortex (OFC) from individual EC or IC rats. In addition, the effect of d-amphetamine on glutamate release in mPFC and OFC of EC and IC rats was determined using in vivo microdialysis. Results show that environmental enrichment decreased maximal transport velocity (Vmax) for [3H]dopamine uptake in mPFC, but increased Vmax for [3H]dopamine uptake in OFC. Corresponding changes in DAT cell surface expression were not found. In contrast, Vmax for [3H]serotonin uptake and cellular localization of SERT in mPFC and OFC were not different between EC and IC rats. Further, acute d-amphetamine (2mg/kg, s.c.) increased extracellular glutamate concentrations in mPFC of EC rats only and in OFC of IC rats only. Overall, these results suggest that enrichment produces long-lasting alterations in mPFC and OFC DAT function via a trafficking-independent mechanism, as well as differential glutamate release in mPFC and OFC. Rearing-induced modulation of DAT function and glutamate release in prefrontal cortical subregions may contribute to the known protective effects of enrichment on drug abuse vulnerability.

Social stress and escalated drug self-administration in mice II. Cocaine and dopamine in the nucleus accumbens.

Social defeat stress results in escalation of cocaine taking and long-term neural adaptations in rats. How the intensity and timing of social defeat stress determine these effects, particularly in mice, have not been well characterized. This study investigated the effects of mild vs. moderate intensities and durations of social stress on intravenous cocaine self-administration as well as on dopamine (DA) release in the nucleus accumbens shell (NAcSh) by using in vivo microdialysis. Adult male Swiss Webster (CFW) mice experienced 10 days of social defeat stress, either mild (15 attack bites in ca. 1.8 min) or moderate (30 attack bites in ca. 3.6 min), and compared to controls that were handled daily. Subsequently, the socially stressed mice were assessed for either (1) intravenous cocaine self-administration, using several unit doses (0, 0.3, 0.6, 1.0 mg/kg/infusion) under limited access conditions, or (2) neural sensitization, as determined by in vivo microdialysis of DA in the NAcSh in response to acute d-amphetamine challenge. Social defeat stress resulted in escalated cocaine self-administration in both mild and moderate socially stressed groups. In addition, social defeat stress led to increased DA release after d-amphetamine challenge. These data suggest that both mild and moderate socially stressed mice exhibit increased cocaine taking compared to controls, and this increase is associated with escalated dopaminergic responses in the NAcSh.

Emotions and motivated behavior converge on an amygdala-like structure in the zebrafish.

The brain reward circuitry plays a key role in emotional and motivational behaviors, and its dysfunction underlies neuropsychiatric disorders such as schizophrenia, depression and drug addiction. Here, we characterized the neuronal activity pattern induced by acute amphetamine administration and during drug-seeking behavior in the zebrafish, and demonstrate the existence of conserved underlying brain circuitry. Combining quantitative analyses of cfos expression with neuronal subtype-specific markers at single-cell resolution, we show that acute d-amphetamine administration leads to both increased neuronal activation and the recruitment of neurons in the medial (Dm) and the lateral (Dl) domains of the adult zebrafish pallium, which contain homologous structures to the mammalian amygdala and hippocampus, respectively. Calbindin-positive and glutamatergic neurons are recruited in Dm, and glutamatergic and γ-aminobutyric acid (GABAergic) neurons in Dl. The drug-activated neurons in Dm and Dl are born at juvenile stage rather than in the embryo or during adulthood. Furthermore, the same territory in Dm is activated during both drug-seeking approach and light avoidance behavior, while these behaviors do not elicit activation in Dl. These data identify the pallial territories involved in acute psychostimulant response and reward formation in the adult zebrafish. They further suggest an evolutionarily conserved function of amygdala-like structures in positive emotions and motivated behavior in zebrafish and mammals.

Cannabinoids negatively modulate striatal glutamate and dopamine release and behavioural output of acute d-amphetamine

The cannabinoid system plays a regulatory role in neurotransmission and is involved in the central actions of psychostimulants. This complex interaction between the cannabinoid system and psychostimulants represents a potential pharmacological target for psychosis and addiction. However, most studies have focused on cocaine, therefore, it is unclear whether these findings can be extended to other psychostimulants such as the amphetamines. The present study investigated the effects of WIN55,212-2, a synthetic cannabinoid and SR141716A, a CB1 receptor antagonist, on d-amphetamine-induced locomotor activity and extracellular dopamine and glutamate release in the striatum. Rats were either observed for locomotor activity or glutamate and dopamine neurotransmitter release in the striatum using in vivo microdialysis following intraperitoneal co-administration of d-amphetamine with WIN55,212-2 or SR141716A. Our results demonstrated that d-amphetamine per se induced hyperlocomotion and enhanced dopamine and glutamate release, as expected. WIN55,212-2 dampened these effects when co-administered with d-amphetamine, while alone it displayed its characteristic biphasic motor profile coupled with increases in dopamine and decreases in glutamate release. SR141716A at high doses reduced d-amphetamine-induced hyperlocomotion and completely reversed enhanced dopamine and glutamate release but alone had no effect. These findings validate the capacity of the cannabinoid system to modulate amphetamine-induced behaviour and its neurochemical output, in a state-dependent manner, providing insight into aspects of the neurobiological substrate that underlies amphetamines’ psychotogenic and addictive properties.

Attenuation of acute d-amphetamine-induced disruption of conflict resolution by clozapine, but not α-flupenthixol in rats

Previous research demonstrates that disruption of forebrain dopamine systems impairs the use of high-order information to guide goal-directed performance, and that this deficit may be related to impaired use of task-setting cues in patients with schizophrenia. Such deficits can be interrogated through conflict resolution, which has been demonstrated to be sensitive to prefrontal integrity in rodents. We sought to examine the effects of acute systemic d-amphetamine administration on the contextual control of response conflict in rats, and whether deficits were reversed through pre-treatment with clozapine or the D₁/D₂ antagonist α-flupenthixol. Acute d-amphetamine (1.5 mg/kg) disrupted the utilisation of contextual cues; therefore rats were impaired during presentation of stimulus compounds that require conflict resolution. Evidence suggested that this effect was attenuated through pre-treatment with the atypical antipsychotic clozapine (5.0 mg/kg), but not the typical antipsychotic α-flupenthixol (0.25 mg/kg), at doses previously shown to attenuate d-amphetamine-induced cognitive deficits. These studies therefore demonstrate a potentially viable model of disrupted executive function such as that seen in schizophrenia.

α3β4 nicotinic acetylcholine receptors in the medial habenula modulate the mesolimbic dopaminergic response to acute nicotine in vivo

Habenulo-interpeduncular nicotinic receptors, particularly those containing α3, β4 and α5 subunits, have recently been implicated in the reinforcing effects of nicotine. Our laboratory has shown that injection of α3β4 nicotinic receptor antagonists into the medial habenula (MHb) decreases self-administration of multiple abused drugs, including nicotine (Glick et al., 2006, 2008; 2011). However, it is unclear whether blockade of MHb nicotinic receptors has a direct effect on mesolimbic dopamine. Here, we performed in vivo microdialysis in female rats. Microdialysis probes were implanted into the nucleus accumbens (NAcc) and α3β4 nicotinic receptor antagonists (18-methoxycoronaridine; 18-MC or α-conotoxin AuIB; AuIB), were injected into the ipsilateral MHb, just prior to systemic nicotine (0.4 mg/kg, s.c.). Dialysate samples were collected before and after drug administration and levels of extracellular dopamine and its metabolites were measured using HPLC. Acute nicotine administration increased levels of extracellular dopamine and its metabolites in the NAcc. Pre-treatment with intra-habenular AuIB or 18-MC prevented nicotine-induced increases in accumbal dopamine. Neither drug had an effect on nicotine-induced increases in dopamine metabolites, suggesting that α3β4 receptors do not play a role in dopamine metabolism. The effect of intra-habenular blockade of α3β4 receptors on NAcc dopamine was selective for acute nicotine: neither AuIB nor 18-MC prevented increases in NAcc dopamine stimulated by acute d-amphetamine or morphine. These results suggest the mesolimbic response to acute nicotine, but not to acute administration of other drugs of abuse, is directly modulated by α3β4 nicotinic receptors in the MHb, and emphasize a critical role for habenular nicotinic receptors in nicotine's reinforcing effects.

A preclinical assessment of d.l-govadine as a potential antipsychotic and cognitive enhancer

Tetrahydroprotoberberines (THPBs) are compounds derived from traditional Chinese medicine and increasing preclinical evidence suggests efficacy in treatment of a wide range of symptoms observed in schizophrenia. A receptor-binding profile of the THPB, d.l-govadine (d.l-Gov), reveals high affinity for dopamine and noradrenaline receptors, efficacy as a D2 receptor antagonist, brain penetrance in the 10-300 ng/g range, and thus motivated an assessment of the antipsychotic and pro-cognitive properties of this compound in the rat. Increased dopamine efflux in the prefrontal cortex and nucleus accumbens, measured by microdialysis, is observed following subcutaneous injection of the drug. d.l-Gov inhibits both conditioned avoidance responding (CAR) and amphetamine-induced locomotion (AIL) at lower doses than clozapine (CAR ED50: d.l-Gov 0.72 vs. clozapine 7.70 mg/kg; AIL ED50: d.l-Gov 1.70 vs. clozapine 4.27 mg/kg). Catalepsy is not detectable at low biologically relevant doses, but is observed at higher doses. Consistent with previous reports, acute d-amphetamine disrupts latent inhibition (LI) while a novel finding of enhanced LI is observed in sensitized animals. Treatment with d.l-Gov prior to conditioned stimulus (CS) pre-exposure restores LI to levels observed in controls in both sensitized animals and those treated acutely with d-amphetamine. Finally, possible pro-cognitive properties of d.l-Gov are assessed with the spatial delayed win-shift task. Subcutaneous injection of 1.0 mg/kg d.l-Gov failed to affect errors at a 30-min delay, but decreased errors observed at a 12-h delay. Collectively, these data provide the first evidence that d.l-Gov may have antipsychotic properties in conjunction with pro-cognitive effects, lending further support to the hypothesis that THPBs are a class of compounds which merit serious consideration as novel treatments for schizophrenia.

Effects of olanzapine on extracellular concentrations and tissue content of neurotensin in rat brain regions

We have previously shown that both the psychostimulant d-amphetamine and the antipsychotics haloperidol and risperidone affect extracellular concentrations and tissue content of neurotensin (NT) in distinct brain regions. This study investigated the effects of acute olanzapine (1, 5mg/kg, s.c.) on extracellular NT-like immunoreactivity (−LI) concentrations in the ventral striatum (vSTR) and the medial prefrontal cortex (mPFC), and the effects of acute d-amphetamine (1.5mg/kg, s.c.) on extracellular NT-LI in these brain regions after a 30-day olanzapine (15mg/kg, p.o.) administration in rats. The effects of a 30-day olanzapine (3, 15mg/kg, p.o.) administration and d-amphetamine (1.5mg/kg, s.c.) coadministration during either the last day (acute) or the last 8days (chronic) on NT-LI tissue content in distinct rat brain regions were also studied. Acute olanzapine increased extracellular NT-LI, in both the vSTR and the mPFC. Chronic olanzapine increased and decreased basal extracellular NT-LI in the vSTR and the mPFC, respectively, and abolished the stimulatory effects of acute d-amphetamine on extracellular NT-LI in these brain regions. Chronic olanzapine as well as acute and chronic d-amphetamine affected NT-LI tissue content in a brain region-dependent manner. Chronic olanzapine prevented the effects of acute and chronic d-amphetamine on NT-LI tissue content in certain brain regions. The fact that olanzapine and d-amphetamine affected extracellular NT-LI in the vSTR and mPFC as well as NT-LI tissue content in distinct brain regions further supports the notion that NT plays a role in the therapeutic actions of antipsychotic drugs and possibly also in the pathophysiology of schizophrenia.

Effects of asenapine, olanzapine, and risperidone on psychotomimetic-induced reversal-learning deficits in the rat

Background Asenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and α 2-adrenergic than dopaminergic D 2 receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats. Methods After operant training, rats were treated acutely with d-amphetamine (0.75 mg/kg intraperitoneally [i.p.]) or phencyclidine (PCP; 1.5 mg/kg i.p.) or subchronically with PCP (2 mg/kg i.p. for 7 days). We assessed the effects of acute coadministration of asenapine, risperidone, or olanzapine on acute d-amphetamine- and PCP-induced deficits and the effects of long-term coadministration of these agents (for 28 additional days) on the deficits induced by subchronic PCP. Results Deficits in reversal learning induced by acute d-amphetamine were attenuated by risperidone (0.2 mg/kg i.p.). Acute PCP-induced impairment of reversal learning was attenuated by acute asenapine (0.025 mg/kg subcutaneously [s.c.]), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.). Subchronic PCP administration induced an enduring deficit that was attenuated by acute asenapine (0.075 mg/kg s.c.) and by olanzapine (1.5 mg/kg i.p.). Asenapine (0.075 mg/kg s.c.), risperidone (0.2 mg/kg i.p.), and olanzapine (1.0 mg/kg i.p.) all showed sustained efficacy with chronic (29 days) treatment to improve subchronic PCP-induced impairments. Conclusion These data suggest that asenapine may have beneficial effects in the treatment of cognitive symptoms in schizophrenia. However, this remains to be validated by further clinical evaluation.

Use of an acute challenge with d‐amphetamine to model cognitive improvement in chronic schizophrenia

There is general agreement that pharmacologic improvement of cognition in chronic schizophrenia is a worthwhile therapeutic goal. Accordingly, there has been careful consideration about how neuropsychological methods can be used to detect improvement in cognition in people with schizophrenia. However, little data are available on the nature and magnitude of cognitive improvement that can occur with adjunctive therapeutic interventions.This double-blind, placebo-controlled crossover study examined the nature and magnitude of cognitive enhancement associated with a single-dose administration of d-amphetamine in 32 adult men with schizophrenia using a set of tasks developed specifically for detecting treatment-related change in cognitive function. Relative to placebo, acute d-amphetamine administration was associated with clinically meaningful improvement on measures of executive function and visual attention and vigilance, and with modest improvements on a measure of speed of processing. These results suggest that a brief computerized cognitive test battery designed for repeat administration, in combination with a statistical approach that emphasizes individual-level change, provides a sensitive approach to detecting the effect of cognitive-enhancing medications in people with chronic schizophrenia.

Efficacy of the atypical antipsychotic aripiprazole in d-amphetamine-based preclinical models of mania

The atypical antipsychotic aripiprazole has been demonstrated to reduce symptoms of bipolar mania. To further profile the antimanic-like properties of aripiprazole in relevant preclinical models, we examined its efficacy in d-amphetamine-based behavioural models of acute mania in rats. The effects of acute and repeated administration of aripiprazole were assessed in the facilitation of intracranial self-stimulation (ICSS) and hyperlocomotion after acute d-amphetamine, and in the sensitized facilitation of ICSS function and hyperlocomotion after repeated d-amphetamine. Acutely, aripiprazole (0.75, 1.5 and 2.5 mg/kg i.p.) increased ICSS thresholds, attenuated the reward-facilitating effects of d-amphetamine (0.5 mg/kg i.p.), decreased motor activity and prevented d-amphetamine-induced hyperlocomotion. Co-administration of aripiprazole and d-amphetamine for 7 d resulted in aripiprazole counteracting the d-amphetamine-induced sensitization in facilitation of brain reward function and hyperlocomotion. These results indicate the efficacy of aripiprazole in d-amphetamine-based preclinical models of acute mania that are characterized by increased motivational drive and/or hyperfunction of brain reward.

Effects of acute and chronic d-amphetamine on two variations of a temporal discrimination procedure

This study assessed temporal discrimination using a procedure in which pigeons classified temporal intervals as short or long based on different responses following visually presented stimulus durations. For the Location group, response alternatives were defined by the location of response keys, whereas for the Color group response alternatives were defined by key color. Temporal parameters were derived from psychophysical curves for time, and the impact of d-amphetamine was determined during acute and chronic dosing. Results showed that classification of temporal intervals was disrupted dose dependently during the acute drug assessment, regardless of the procedural variation. During the chronic drug assessment, differences in one of the psychophysical parameters, Range, were found between groups, as well as a significant effect of Dose on Standard Deviation values in the Color group. These data suggest that procedural variation does not lead to differential effects of d-amphetamine when administered in an acute regimen; however, differences found during chronic administration suggest that procedural variations may influence the development of tolerance as evidenced by differing Range values between groups and marked disruption of Standard Deviation values at the low dose in the Color group. The influence exerted on temporal behavior and tolerance by procedural variations during acute and chronic regimens of d-amphetamine should be explored further.

Chronic d-amphetamine depresses an imaging marker of arachidonic acid metabolism in rat brain.

Acute d-amphetamine (d-Amph) administration to rats leads to the release of arachidonic acid (AA, 20:4n-6) as a second messenger following indirect agonism at dopamine D2-like receptors in the brain. We hypothesized that chronically administered d-Amph in rats also would alter brain AA metabolism and signalling. To test this, adult male rats were injected i.p. daily for 2 wk with saline or 2.5 mg/kg d-Amph. After a 1-d washout, the unanaesthetized rats were injected acutely with i.v. saline, 1 mg/kg quinpirole (a D2-like receptor agonist) or 5.0 mg/kg SKF-38393 (a D1-like receptor agonist), followed by i.v. [1-14C]AA. The AA incorporation coefficient k* (brain radioactivity/integrated plasma radioactivity), a marker of AA signalling and metabolism, was quantified using autoradiography in each of 62 brain regions. Compared with chronic saline, chronic d-Amph widely decreased baseline values of k* in brain regions having D2-like receptors. On the other hand, chronic amphetamine did not alter the k* responses to quinpirole seen in chronic saline-treated rats. SKF-38393 had minimal effects on k* in both chronic saline-treated and amphetamine-treated rats, consistent with D1-like receptors not being coupled to AA signalling. The ability of chronic d-Amph after 1-d washout to down-regulate baseline values of k* probably reflects neuroplastic changes in brain AA signalling, and may correspond to depressive behaviours noted following withdrawal from chronic amphetamine in humans and in rats.