Administration Of D-amphetamine Research Articles

Further evidence of association between amphetamine response and SLC6A2 gene variants

We previously found that the intronic norepinephrine transporter gene (SLC6A2) polymorphism rs36017 modulates feelings of elation after administration of 20 mg D-amphetamine in healthy volunteers. In this study, we further investigated the association between D-amphetamine response and 11 SLC6A2 single-nucleotide polymorphisms (SNPs), including rs36017, in an extended sample of Caucasian young adults. One hundred fifty-nine healthy volunteers participated in a three-session double-blind crossover design receiving either placebo or oral D-amphetamine (10 and 20 mg). Based on our previous results, we examined the associations between levels of self-reported elation and vigor after D-amphetamine administration and SNPs and SNP haplotypes in SLC6A2. Consistent with our previous findings, SNPs rs36017 and rs1861647 were associated with significantly higher ratings of elation and vigor after 20 mg Damphetamine. Ratings of vigor after 20 mg D-amphetamine were also associated with a two-SNP haplotype formed with rs1861647 and rs5569 and a three-SNP haplotype formed with rs36017, rs10521329, and rs3785155. These results provide further evidence that genetic variants in the SLC6A2 gene are involved in acute response to D-amphetamine, which may influence progression to amphetamine abuse. Identifying sources of variation in acute drug responses could lead to better prevention and treatment of psychostimulant abuse and may be valuable in the therapeutic use of stimulants.

Effects of variable training, signaled and unsignaled delays, and d-amphetamine on delay-discounting functions

One common procedure for obtaining delay-discounting functions consists of a choice between a larger reinforcer that is presented after an increasing delay and a smaller reinforcer that is always presented immediately within session. Repeating the same context of delay presentation (e.g. ascending delay order) in a discrete-choice paradigm, however, may lead to a perseverative response pattern when rats are used as subjects. The purpose of this study was to increase the variability in delay presentation (i.e. ascending and descending delays) in an attempt to reduce a perseverative response pattern and gain tighter control over choice by reinforcer amount and delay. For one group of rats (n = 8), delays to reinforcer presentation were differentially signaled by a flashing houselight and for one group of rats (n = 8) the delays were unsignaled. Effects of delay signal and d-amphetamine on choice were evaluated in both groups. Similar rates of delay discounting and area under the curve (AUC) were observed with both ascending and descending delay presentations and with signaled and unsignaled delays to reinforcement. Increasing the variability in delay order resulted in differences in the choice pattern during 0-s probe sessions. d-Amphetamine had little or no effect on AUC at low doses, but decreased AUC at the highest doses tested, that is, 1.0 and 1.7 mg/kg. Some of the changes in AUC after d-amphetamine administration may have been because of disruption in discrimination of the different food amounts.

Effects of acute treatment with amphetamine in locomotor activity in sepsis survivor rats

We here evaluated the central dopaminergic response in sepsis survivor rats using the administration of d-amphetamine. Male Wistar rats underwent cecal ligation and perforation (CLP) or were sham-operated. After 10 days of recovery, rats received an intraperitoneal injection of d-amphetamine 0.5, 1 and 2 mg/kg or saline, and were subjected to the open field test. We did not observe alterations in locomotor and exploratory activities in CLP compared to sham group. Treatment with amphetamine 0.5 mg/kg did not have effect in sham and CLP groups; d-amphetamine 1 mg/kg increased locomotor and exploratory activities only in sham group, and d-amphetamine 2 mg/kg increased in both sham and CLP groups. We suggest that, in part, dopamine pathway may be altered in sepsis.

Dopaminergic activity in depressed smokers: A positron emission tomography study

Tobacco dependence is highly prevalent in depressed patients. We assessed changes in [(11)C]-raclopride binding potential (BP) using positron emission tomography (PET) before and after the oral administration of d-amphetamine in healthy controls and unmedicated patients with current depression with and without current tobacco dependence. Over a single study day 2 [(11)C]-raclopride positron emission tomography scans were taken in 38 subjects: at baseline and 2 h following oral d-amphetamine 30 mg. Twenty controls (9 smokers, 11 nonsmokers) and 18 subjects with current major depressive episode (8 smokers, 10 non-smokers). Striatal [(11)C]-raclopride binding potential was measured before and after d-amphetamine administration. Depressed smokers had a lower baseline [(11)C]-raclopride binding potential compared with both control non-smokers (P < 0.007) and depressed non-smokers (P < 0.001). There was a main effect of smoking status on amphetamine-induced change in [(11)C]-raclopride binding potential (P < 0.02), but no main effect of depression. This may be due to a floor effect because of the low BP at baseline. Depressed subjects reported significant increase of positive mood after d-amphetamine administration compared with controls (depressed smokers vs. control smokers: P < 0.05; depressed non-smokers vs. controls: P < 0.055). Tobacco dependence appears to decrease d-amphetamine-induced changes in [(11)C]-raclopride binding potential as measured by positron emission tomography. Comorbid major depression and tobacco dependence exacerbates this effect, suggesting an altered dopamine system in comorbid patients.

Effects of co-administration of bupropion and nicotine or D-amphetamine on the elevated plus maze test in mice

A variety of abused drugs, including psychostimulants, can modulate the expression of anxiety. Although the effect of nicotine and D-amphetamine on anxiety-related behaviour in animal models has been investigated, the mechanisms underlying the anxiogenic or anxiolytic actions of these drugs have not been clarified. Bupropion is an antidepressant drug which may alleviate some symptoms of nicotine withdrawal, although its effects on anxiety are not clear. We have investigated the effect of nicotine and D-amphetamine on anxiety in the elevated plus maze test in mice. We examined the influence of acute administration of nicotine (0.1 mg/kg, s.c.) and D-amphetamine (2 mg/kg, i.p.) on anxiety level. We then evaluated the anxiety-related response after subchronic injection of both psychostimulants, including crossover effects. For this purpose, nicotine (0.1 mg/kg, s.c.) was administered daily for six days, and on the seventh day mice were challenged with nicotine (0.1 mg/kg, s.c.) or D-amphetamine (2 mg/kg, i.p.). A distinct group of mice was pretreated with D-amphetamine (2 mg/kg, i.p., 8 days), and subjected to D-amphetamine (2 mg/kg, i.p.) or nicotine (0.1 mg/kg, s.c.) challenge on the ninth day. Moreover, we investigated acute and subchronic effects of coadministration of bupropion (5, 10 and 20 mg/kg; i.p.) and nicotine or D-amphetamine. We observed that acute anxiogenic effects of nicotine and D-amphetamine as well as the development of tolerance and cross-tolerance to their effects were blunted by a pretreatment with a nonactive dose of bupropion (5 mg/kg, i.p.). These results demonstrated that similar neural mechanisms were involved in the regulation of nicotine and D-amphetamine anxiety-like behaviour in mice. The results have provided new findings to support the use of bupropion in the treatment of nicotine and/or amphetamine addiction.

Deficits of mesolimbic dopamine neurotransmission in rat dietary obesity

Increased caloric intake in dietary obesity could be driven by central mechanisms that regulate reward-seeking behavior. The mesolimbic dopamine system, and the nucleus accumbens in particular, underlies both food and drug reward. We investigated whether rat dietary obesity is linked to changes in dopaminergic neurotransmission in that region. Sprague–Dawley rats were placed on a cafeteria-style diet to induce obesity or a laboratory chow diet to maintain normal weight gain. Extracellular dopamine levels were measured by in vivo microdialysis. Electrically evoked dopamine release was measured ex vivo in coronal slices of the nucleus accumbens and the dorsal striatum using real-time carbon fiber amperometry. Over 15 weeks, cafeteria-diet fed rats became obese (>20% increase in body weight) and exhibited lower extracellular accumbens dopamine levels than normal weight rats (0.007±0.001 vs. 0.023±0.002 pmol/sample; P<0.05). Dopamine release in the nucleus accumbens of obese rats was stimulated by a cafeteria-diet challenge, but it remained unresponsive to a laboratory chow meal. Administration of d-amphetamine (1.5 mg/kg i.p.) also revealed an attenuated dopamine response in obese rats. Experiments measuring electrically evoked dopamine signal ex vivo in nucleus accumbens slices showed a much weaker response in obese animals (12 vs. 25×10 6 dopamine molecules per stimulation, P<0.05). The results demonstrate that deficits in mesolimbic dopamine neurotransmission are linked to dietary obesity. Depressed dopamine release may lead obese animals to compensate by eating palatable “comfort” food, a stimulus that released dopamine when laboratory chow failed.

Dopamine transporters, D2receptors, and dopamine release in generalized social anxiety disorder

Dopamine D2 receptor and dopamine transporter (DAT) availability in the striatum (STR) have each been reported abnormal in generalized social anxiety disorder (GSAD) in studies using single photon emission computerized tomography (SPECT). D2 receptors and DAT have not previously been studied within the same GSAD subjects, however, and prior GSAD studies have not assessed dopamine release or subdivided the STR into functional subregions. Unmedicated adults with GSAD (N=17) and matched healthy comparison (HC) subjects (N=13) participated in this study. Of these, 15 GSAD and 13 HC subjects completed baseline assessment of D2 receptor availability using positron emission tomography (PET) with the radiotracer [11C]raclopride. Twelve GSAD and 13 HC subjects completed a repeat scan after intravenous administration of d-amphetamine to study dopamine release. Twelve of the GSAD subjects and 10 of the HC subjects also completed SPECT with the radiotracer [123I] methyl 3beta-(4-iodophenyl) tropane-2beta-carboxylate ([123I]beta-CIT) to assess DAT availability. GSAD and HC groups did not differ significantly in striatal DAT availability, the overall striatal or striatal subregion D2 receptor availability at baseline, or change in D(2) receptor availability after d-amphetamine. Receptor availability and change after d-amphetamine were not significantly associated with severity of social anxiety or trait detachment. These findings do not replicate previous findings of altered striatal DAT and D2 receptor availability in GSAD subjects assessed with SPECT. The differences from results of prior studies may be due to differences in imaging methods or characteristics of samples.

Discriminative-stimulus and time-course effects of kava-kava ( Piper methysticum) in rats

Kava is a widely available and used herbal medicine that is not regulated in many countries. There are many questions concerning kava's stimulus properties, potential for therapeutic use, and potential for abuse. Although there is evidence that kava may possess some anxiolytic properties, kava's mechanism of action and the extent to which it may serve as an alternative to pharmaceutical anxiolytics are not fully known. The current study was designed to evaluate whether kava shares discriminative-stimulus properties with the anxiolytic chlordiazepoxide (CDP). Effects of different doses of kava extract were evaluated in two groups of rats trained to discriminate either a high or low training dose of CDP (i.p.). In order to assess time-course effects, two tests were conducted/session at 60 (Test One) and 90 (Test Two) min following oral administration of kava, CDP, or d-amphetamine. Dose-dependent substitution of CDP was found in both training groups in both tests. Kava (560 mg/kg, p.o.) occasioned responding indicative of partial substitution in both groups during Test One and only the low-dose group during Test Two. Partial substitution of kava extract for CDP suggests that the herbal compound may share a mechanism of action similar to CDP, but is less potent.

Poststroke Treatment

See related article, pages 294–302. Stroke research has primarily focused on prevention and acute treatment. Yet, there is a window of opportunity to provide treatments that will increase functional recovery by capitalizing on the brain’s neural plastic responses during postacute and chronic periods.1,2 Papadopoulos and colleagues’ study in this issue of Stroke is consistent with decades of research demonstrating that coupling of D-amphetamine administration with motor practice can enhance motor recovery after brain injury in animal models.3,4 This study elegantly shows that short-term, postacute administration of D-amphetamine sulfate combined with focused physical activity and housing in an “enriched” environment improves motor recovery markedly. These improvements are associated with increased axonal sprouting in corticoefferent pathways to the red nucleus and cervical spinal cord from …

Electrophysiological correlates of sleep disturbance induced by acute and chronic administration of d-amphetamine

Sleep disturbance is the strongest predictor of manic relapse and is considered one of the most important objective measures of treatment response in bipolar disorder (BD). However, the neurobiological mechanisms underlying sleep disturbance in BD are poorly understood. The administration of psychostimulants to rodents can trigger a number of manic-like behaviors. Therefore, the present study aims to investigate the effects of single and repeated d-amphetamine (AMPH) administration on sleep patterns in rats. Sleep was continuously monitored during light periods after single and repeated (7 days) injections of AMPH (2 mg/kg, i.p.) or saline in adult Wistar rats using electrocorticogram and electromyographic recordings. Acute injections of AMPH suppressed sleep for the first 2 h, and were followed by a gradual increase in the amount of sleep. Both slow wave sleep (SWS) and paradoxical sleep (PS) were compromised. Repeated exposure to AMPH led to a drastic disruption of the sleep–wake cycle that was mainly characterized by a decrease of PS during all time-points recorded in comparison to the saline group. Furthermore, both acute and chronic AMPH administration induced longer latencies to both SWS and PS. These findings suggest that AMPH produces profound sleep disturbances and decreases PS sleep. Given that some of these abnormalities are observed in individuals with BD, this animal model can provide a means to investigate neurobiological aspects of sleep disturbance in BD, as well as their response to mood stabilizers.

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.

Impulsive choice and environmental enrichment: Effects of d-amphetamine and methylphenidate

Individual differences in impulsive choice and rearing in differential environments are factors that predict vulnerability to drug abuse. The present study determined if rearing influences impulsive choice, and if d-amphetamine or methylphenidate alters impulsive choice in differentially reared rats. Male Sprague-Dawley rats were raised from 21 days of age in either an enriched condition (EC) or an isolated condition (IC) and were tested as young adults on an adjusting delay task. In this task, two levers were available and a response on one lever yielded one 45 mg food pellet immediately, whereas a response on the other yielded three pellets after an adjusting delay. The delay was initially set at 6 s, and it decreased or increased by 1 s following responses on the immediate or delayed levers, respectively. A mean adjusted delay (MAD) was calculated upon completion of each daily session, and it served as the quantitative measure of impulsivity. Once MADs stabilized, rats were injected with saline, d-amphetamine (0.5, 1.0, or 2.0 mg/kg, s.c.), or methylphenidate (2.5, 5.0, or 10.0 mg/kg, s.c.) 15 min prior to adjusting delay sessions. EC rats had higher baseline MADs (were less impulsive) than IC rats. Additionally, administration of d-amphetamine, but not methylphenidate, dose-dependently increased impulsive choice (decreased MADs) in EC rats. In IC rats, d-amphetamine and methylphenidate dose-dependently decreased impulsivity (increased MADs). These results indicate that rearing environment influences impulsive choice and moderates the effect of psychostimulants on impulsive choice. Specifically, psychostimulants may decrease environment-dependent impulsive choice in individuals with high levels of impulsivity (e.g., those with ADHD), whereas they may increase impulsive choice in individuals with low levels of impulsivity.

Small effect of dopamine release and no effect of dopamine depletion on [18F]fallypride binding in healthy humans

Molecular imaging has been used to estimate both drug-induced and tonic dopamine release in the striatum and most recently extrastriatal areas of healthy humans. However, to date, studies of drug-induced and tonic dopamine release have not been performed in the same subjects. This study performed positron emission tomography (PET) with [18F]fallypride in healthy subjects to assess (1) the reproducibility of [18F]fallypride and (2) both D-amphetamine-induced and alpha-methyl-p-tyrosine (AMPT)-induced changes in dopamin release on [(18)F]fallypride binding in striatal and extrastriatal areas. Subjects underwent [18F]fallypride PET studies at baseline and following oral D-amphetamine administration (0.5 mg/kg) and oral AMPT administration (3 g/70 kg/day over 44 h). Binding potential (BP) (BP(ND)) of [18F]fallypride was calculated in striatal and extrastriatal areas using a reference region method. Percent change in regional BP(ND) was computed and correlated with change in cognition and mood. Test-retest variability of [18F]fallypride was low in both striatal and extrastriatal regions. D-Amphetamine significantly decreased BP(ND) by 8-14% in striatal subdivisions, caudate, putamen, substantia nigra, medial orbitofrontal cortex, and medial temporal cortex. Correlation between change in BP(ND) and verbal fluency was seen in the thalamus and substantia nigra. In contrast, depletion of endogenous dopamine with AMPT did not effect [18F]fallypride BP(ND) in both striatum and extrastriatal regions. These findings indicate that [18F]fallypride is useful for measuring amphetamine-induced dopamine release, but may be unreliable for estimating tonic dopamine levels, in striatum and extrastriatal regions of healthy humans.

Effect of N-acetylcysteine and/or deferoxamine on oxidative stress and hyperactivity in an animal model of mania

Studies have consistently reported the participation of free radicals in Bipolar Disorder. Administration of d-amphetamine (d-AMPH) is a relevant animal model of mania and it increases oxidative stress in rat brain. Evidences indicate that the antioxidants N-acetylcysteine (NAC) and Deferoxamine (DFX) exert protective effects in the brain. The present study was designed to evaluate the effects of NAC, DFX or their combination on AMPH-induced hyperactivity. The protein oxidation levels were analyzed in prefrontal cortex and hippocampus. In the first animal model (reversal treatment), adult male Wistar rats received saline or d-AMPH for 14 days, and from the 8th to the 14th day, they were treated with saline, NAC, DFX, or NAC plus DFX. In the second animal model (prevention treatment), rats were pretreated with saline or antioxidant regime, and from the 8th to the 14th day, they also received saline or d-AMPH. In the prefrontal cortex, the protein carbonyls were not affected by the treatment with antioxidants alone but it was increased by treatment with NAC plus DFX. At the same model, NAC plus DFX reversed the protein damage in the hippocampus, but NAC alone increased this damage. In the prevention treatment, it was observed that the protein damage in the prefrontal cortex was prevented by DFX or NAC plus DFX. In the hippocampus, the pretreatment with all antioxidant regime prevented protein damage induced by d-AMPH. At both treatments (reversal or prevention) the antioxidants did not present any effect against d-AMPH-induced hyperactivity. In conclusion, NAC or DFX and the combination of NAC plus DFX reverse and protect against d-AMPH-induced oxidative protein damage. Using these protocols we could not observe affects on locomotion, however this effect varies depending on the brain region and the treatment regime.

Pharmacological treatment of neurobehavioural sequelae of traumatic brain injury

Neurobehavioural sequelae of traumatic brain injuries require an appropriate/effective pharmacological response in that they represent an important cause of disability. In this field, there is no evidence that reaches the level of a standard: there are guidelines on the use of methylphenidate, donepezil and bromocriptine for the treatment of cognitive disturbances, for the non-use of phenytoin and for the use of beta-blockers for controlling aggressiveness. Resolving a single symptom is not relevant in a rehabilitation project if it is not in the context of a more complex picture of neurobehavioural recovery, in which the positive and negative effects of every therapeutic choice are considered. For example, phenytoin could be used for the positive control of epileptic crises but is not advised since it impedes the recovery of cognitive functions in general. Analogous effects not yet identified may concern benzodiazepine, neuroleptics and other sedatives usually prescribed in cases of cranial trauma. Psychotropic drugs are considered to be able to influence the neuronal plasticity processes. Studies on animals have shown that the administration of D-amphetamine combined with sensorial-motor exercise produces the steady acceleration of motor recovery, which acts as a catalyst to the neurological recovery process. On the other hand, alpha1-NA receptor antagonist drugs produce negative effects; these include clonidine (antihypertension) and haloperidol (neuroleptic). Studies need to be carried out to evaluate the effectiveness of particular drugs. These studies need to focus not only on the disappearance of symptoms but also on the positive and negative effects on overall rehabilitation and on the neurobiological recovery of the patient.

Differential effects of D‐amphetamine on red and blue light‐induced photic activation: A novel BOLD fMRI assay of human dopamine function

The neurotransmitter dopamine (DA) is implicated in the pathophysiology of central nervous system (CNS) illnesses including Parkinson's disease, attention deficit disorder, schizophrenia, and substance abuse. A better understanding of CNS DA function would be of importance in improving our understanding of these conditions. Several lines of evidence suggest that exploring visual system function may be a useful paradigm for examining DA function. Clinical and basic science findings suggest that the visual response to blue light might prove a useful assay of CNS DA tone. To test this hypothesis, we used the functional magnetic resonance imaging (fMRI) BOLD method to measure visual cortical activation in human subjects (N = 6) in response to 8 Hz flashing red and blue light stimuli during placebo conditions and during the oral administration of 2.5 mg of D-amphetamine, a drug known to increase synaptic concentrations of DA and other monoamine neurotransmitters. There was no effect of D-amphetamine administration on the percent BOLD signal change to red or blue light. However, there was a specific augmentation of the spatial extent of activation (as measured by the number of activated pixels; P = 0.018) to blue, but not red light following D-amphetamine administration. This finding is consistent with our hypothesis that blue light function may have utility as an assay of CNS DA tone. However, several limitations to the study, including the small sample size, low dosage of D-amphetamine, and the fact that D-amphetamine increases synaptic concentrations of DA and other monoamine neurotransmitters do not permit a conclusion regarding a specific role for DA in the observed increase in spatial activation to blue light in the amphetamine condition.

Acute prefrontal rTMS increases striatal dopamine to a similar degree as d-amphetamine

Prefrontal repetitive transcranial magnetic stimulation (rTMS) has been shown to increase striatal dopaminergic activity. Here we investigated dopaminergic neurotransmission using single photon emission computed tomography (SPECT) and [ 123I]IBZM to indirectly assess the change in endogenous striatal dopamine concentration upon rTMS as compared with d-amphetamine challenge. SPECT imaging was performed twice each in five patients during rTMS, and in two patients who received 0.3 mg/kg d-amphetamine. Administration of rTMS led to a mean relative decrease in striatal IBZM binding by 9.6 ± 6.2%, and d-amphetamine challenge ( n = 4) induced a mean relative reduction by 8 ± 2.95% (difference not statistically significant). Acute rTMS challenge showed similar striatal dopaminergic effects to those associated with the administration of d-amphetamine, a substance known to increase synaptic dopamine.

Behavioral and biochemical responses to d‐amphetamine in MCH1 receptor knockout mice

The melanin-concentrating hormone (MCH) system is anatomically and functionally interlaced with the mesocorticolimbic dopamine system. Therefore, we investigated whether MCH(1) receptor knockout (KO) mice are more susceptible than wild-type (WT) mice to psychostimulant-induced locomotor stimulation and sensitization, dopamine receptor-mediated phosphorylation events and c-fos expression within the frontal cortex and ventral striatum. MCH(1) receptor KO mice have 20% higher basal locomotor activity, are hypersensitive to the locomotor activating effects of d-amphetamine (1 mg/kg), and develop behavioral sensitization to a regimen of repeated d-amphetamine administration that does not induce sensitization in WT mice. In addition, d-amphetamine-mediated regulation of p44-mitogen activated protein kinase (MAPK) phosphorylation within the frontal cortex was significantly enhanced in MCH(1) receptor KO mice, when compared with WT mice. No significant genotype difference in the effects of d-amphetamine on MAPK phosphorylation events within the ventral striatum, phosphorylation at Ser(897) of the NR1 subunit of the NMDA receptor or Ca(2+) and cyclic AMP response-element binding-protein (CREB) at Ser(133) in the frontal cortex was detected. d-Amphetamine (3 mg/kg) increased c-fos expression within the frontal cortex in MCH(1) receptor KO mice, but not WT mice. There were no d-amphetamine-induced changes in c-fos expression within the ventromedial striatum in KO or WT mice. Overall, MCH(1) receptor KO mice are hypersensitive to the behavioral and molecular effects of the dopaminergic psychostimulant d-amphetamine. Increased frontal cortical MAPK phosphorylation and c-fos expression in MCH(1) receptor KO mice indicates that the MCH(1) receptor may be an important target for treating neuropsychiatric disorders characterized by frontal cortex dysfunction, including depression, attention deficit hyperactivity disorder (ADHD) and schizophrenia.

Enhanced apomorphine sensitivity and increased binding of dopamine D2 receptors in nucleus accumbens in prepubertal rats after neonatal blockade of the dopamine D3 receptors by (+)‐S14297

The role of dopamine (DA) D3 receptors is controversial in early developmental stages of specially locomotor activity. Past studies have only tested behavioral changes induced by neonatal administration of nonselective dopamine antagonist such as haloperidol or sulpiride in adult rats. We investigated the role of neonatal blockade of DA D3 receptors at (postnatal day, P1 to P12) using the DA D3 receptor antagonist (+)-S14297 on paradigms related to DA behaviors including locomotor activity in novel environment and after administration of the DA nonspecific agonists d-amphetamine, and apomorphine. Additionally, autoradiographic studies were performed to correlate behavioral alterations with DA D1-like, D2-like, and D3 receptors. All studies were performed at two critical ages, prepubertal (P35) and postpubertal (P60). The quantitative autoradiogaphic study revealed increases in the expression of DA D2-like receptor expression in the nucleus accumbens (NAcc) in prepubertal animals that received the DA D3 antagonist (+)-S14297 at neonatal age. In addition, novel environment and apomorphine administration (0.5 mg/kg, s.c.), induced increases of locomotor activity in prepubertal animals that received the DA D3 antagonist (+)-S14297. Autoradiographic and behavioral results suggest that blockade of DA D3 receptors after birth may mediate different neurodevelopmental aspects of the dopaminergic pathway before and after puberty.

Acute prefrontal rTMS increases striatal dopamine to a similar degree as d-amphetamine

Prefrontal repetitive transcranial magnetic stimulation (rTMS) has been shown to increase striatal dopaminergic activity; however, the magnitude of these effects compared with other dopaminergic stimuli is unknown. We have investigated dopaminergic neurotransmission in patients with major depressive episodes using single photon emission computed tomography (SPECT) and [123I] iodobenzamide (IBZM) under a bolus and constant infusion paradigm to indirectly assess the change in endogenous striatal dopamine concentration upon rTMS and d-amphetamine challenge. SPECT imaging was performed twice each in five patients during rTMS, and in two patients who received 0.3mg/kg d-amphetamine. The change in striatal IBZM binding upon challenge was assessed with a region of interest technique. Data sets of 13 SPECT imaging sessions were available for analysis. TMS (9 SPECT assessments) led to a mean relative decrease in striatal IBZM binding by 9.6±6.2%, d-amphetamine challenge (n=4) induced a mean relative reduction by 8±2.95% (difference not statistically significant). The decrease of IBZM binding upon challenge is suggestive of an increase in endogenous dopaminergic stimulation. Acute rTMS challenge showed similar striatal dopaminergic effects as compared to administration of d-amphetamine, a substance known to increase synaptic dopamine.