Chronic Amphetamine Research Articles

The Impact of Methamphetamine on Liver Injury in Iraqi Male Addicts

Methamphetamine (METH) is a powerful stimulant that affects neurochemical processes controlling heart rate, appetite, blood pressure, body temperature, and wakefulness, making it highly susceptible to abuse. Liver enzymes such as ALT, AST, ALP, and GGT are crucial for liver function. Albumin, a protein synthesized by healthy liver cells, serves as an indicator of chronic liver disease. Additionally, hepatocytes produce bile acids, which are essential for the secretion of bile salts into the bile canaliculi. Disruption in this secretion results in the accumulation of bile salts in the canaliculi, leading to intrahepatic cholestasis. METH-induced liver toxicity involves disruptions in hepatic metabolism, oxidative stress, and increased body temperature, affecting cellular processes such as cell division and the cell cycle and potentially accelerating liver cell apoptosis. The study explores the link between liver toxicity and hepatocyte damage in Iraqi males suffering from addiction. This is a case-control study, conducted at Ibn-Rushed Psychiatric Hospital in Baghdad from July 2023 to February 2024, involved 196 males, with addiction durations exceeding 24 months with varying degrees of methamphetamine (METH) addiction. The study included 187 healthy male controls with no history of drug addiction. Participants were aged 18 to 40 years. Diagnosis was confirmed using a drug test screening card administered by a specialist. The study included liver function tests (ALT, AST, ALP, and GGT), total bilirubin, and albumin concentration assessments. Significant differences were observed between the addicts and controls, particularly a marked decrease in serum albumin concentration in the addicted males. The ROC curve classification model at various thresholds demonstrated that liver enzymes, especially ALT, ALP, and GGT, exhibited increased sensitivity to METH addiction. A histopathological examination was conducted on a deceased 38-year-old male who had a six-year history of chronic amphetamine addiction to confirm liver injury and the resulting elevation of liver enzymes. The findings of this study indicate that METH greatly affects liver function, suggested to the importance of following a preventative measures and effective treatment approaches for monitoring METH addiction progress.

Long-term disruption of tissue levels of glutamate and glutamatergic neurotransmission neuromodulators, taurine and kynurenic acid induced by amphetamine.

Chronic amphetamine (AMPH) use leading to addiction results in adaptive changes within the central nervous system that persist well beyond the drug's elimination from the body and can precipitate relapse. Notably, alterations in glutamatergic neurotransmission play a crucial role in drug-associated behaviours. This study aimed to identify changes induced by amphetamine in glutamate levels and the neuromodulators of glutamatergic neurotransmission (taurine and kynurenic acid) observable after 14 and 28 days of abstinence in key brain regions implicated in addiction: the cortex (Cx), nucleus accumbens (Acb), and dorsolateral striatum (CPu-L). The rats were administered 12 doses of amphetamine (AMPH) intraperitoneally (i.p.) at 1.5mg/kg. The behavioural response was evaluated through ultrasonic vocalizations (USV). High-performance liquid chromatography (HPLC) was used to measure the levels of glutamate, taurine, and kynurenic acid in the Cx, Acb, and CPu-L after 14 and 28 days of abstinence. AMPH administration led to sensitisation towards AMPH's rewarding effects, as evidenced by changes in USV. There was a noticeable decrease in kynurenic acid levels and an increase in both taurine and glutamate in the CPu-L, along with an increase in glutamate levels in the Cx, 28 days following the final AMPH injection. The most significant changes in the tissue levels of glutamate, taurine, and kynurenic acid were seen in the CPu-L 28 days after the last dose of AMPH. The emergence of these changes exclusively after 28 days suggests that the processes initiated by AMPH use and subsequent abstinence take time to become apparent and may be enduring. This could contribute to the incubation of craving and the risk of relapse. Developing pharmacological strategies to counteract the reduction in kynurenic acid induced by psychostimulants may provide new avenues for therapy development.

Chronic administration of glucocorticoid receptor ligands increases anxiety-like behavior and selectively increase serotonin transporters in the ventral hippocampus

Organic cation transporter-3 (OCT3) is widely distributed in the brain with high expression in portions of the stress axis. These high capacity, polyspecific transporters function in monoamine clearance and are sensitive to the stress hormone corticosterone. In rats, withdrawal from chronic amphetamine increases OCT3 expression in specific limbic brain regions involved anxiety and stress responses, including the ventral hippocampus, central nucleus of amygdala (CeA) and dorsomedial hypothalamus. (DMH). Previous studies show that glucocorticoid receptor (GR) agonists increase OCT1 mRNA and OCT2 mRNA expression in non-neural tissues. Thus, we hypothesized that corticosterone increases OCT3 expression in the brain by activating GRs. Male Sprague-Dawley rats were pre-treated daily with the GR antagonist mifepristone (20 mg/kg; sc.) or vehicle followed 45 min later by injections of corticosterone or vehicle for 2 weeks. Corticosterone treatment significantly increased OCT3 expression in the ventral hippocampus and increased anxiety-like behavior. However, these effects were not blocked by mifepristone. Interestingly, treatment with mifepristone alone reduced plasma corticosterone levels and increased serotonin transporter and GR expression in the ventral hippocampus but did not significantly affect OCT3 expression or behavior. No treatment effects on OCT3, serotonin transporter or GR expression were observed in the DMH, CeA or dorsal hippocampus. Our findings suggest that corticosterone increases OCT3 expression in the ventral hippocampus by a mechanism independent of GRs, and that mifepristone and corticosterone can act in an independent manner to affect HPA axis-related physiological and behavioral parameters.

Norepinephrine mediates effects of chronic amphetamine on memory performance in aged rats

Understanding the neural mechanisms of normal and pathological aging is increasingly important as the average lifespan continues to rise. Memory impairment is attributed to normal aging processes, with the hippocampus and the cerebral cortex playing key roles in the encoding and retrieval of memories. Norepinephrine (NE) is an important modulator of memory, especially emotional memory (Tully et al., 2010). Previously, we demonstrated that acute treatment with amphetamine (0.5mg/kg) enhances memory performance on the novel object recognition (NOR) task in aged Fischer 344 rats, with a reversible and short‐term effect (Scognamiglio et al., 2021). The purpose of this study was to investigate whether chronic amphetamine treatment has a more robust and possible long‐term effect on memory performance in aged rats and whether the effect of amphetamine on object recognition memory is NE‐ dependent. To this end, in the first set of experiments we administered amphetamine for 2 weeks via drinking water at doses of 0.25 mg/kg (week 1) and 0.5 mg/kg (week 2) and tested aged Fischer 344 rats on the NOR task. To determine the extent to which NE influences the cognitive effects of amphetamine, we examined the effects of systemic administration of the β‐ and α‐adrenergic antagonists propranolol, metoprolol, and prazosin prior to the NOR test phase in aged rats chronically treated with amphetamine. The present studies found: (a) aged rats chronically treated with amphetamine displayed improved object recognition memory compared to rats treated acutely, (b) memory performance returned to baseline 2 months after chronic amphetamine treatment, (c)all three of the β‐ and α‐ adrenergic antagonists abolished the effect of amphetamine on memory performance in the NOR test. An additional goal of this study was to assess the outcome of chronic amphetamine treatment on a cellular level by analyzing dendritic spines in the cerebral cortex and hippocampus. The results of those studies will be reported.

Flow cytometric analysis of CD4 and T-lymphocytes of chronic amphetamine and alcohol abuse.

Drug and alcohol abuse has significant negative impacts on individuals' life, health status and communities. They have also been implicated immunity system diseases. Therefore we aim to investigate the impact of chronic amphetamine abuse or co-abuse of alcohol with amphetamine on immunity, especially CD3 T cells, as well as the response of CD4 and CD8 T cells. A research sample comprising of 53 individuals younger than 40 years of age was employed to perform a retrospective case study within the setting of the Al-Amal Psychiatric Hospital. Individuals were distributed into 3 groups as the following: group (i) 17 patients abused amphetamine only for five years, group (ii) 17 patients' co-abused alcohol and amphetamine or five years, and group (iii) composed of 19 non-abusers of similar age and sex was selected as control. Flow cytometry was conducted for the collection and analysis of CD3+CD4+ and CD3+CD8+ monoclonal antibodies from blood samples. In contrast to the control group, amphetamine abuser patients showed a significantly decrease of the mean levels of CD3+CD4+ (#Event), CD3+CD8+ (#Event) and CD3+CD8+ (% Total). Meanwhile, levels of CD3+CD4+ (% Parent) was significantly higher in patients versus control (P = 0.001). furthermore, In the amphetamine abuse patient group, there were significant positive correlations between CD3+CD4+ (#Event) and CD3+CD4+ (% Total); CD3+CD8+ (#Event); Between CD3+CD4+ (% Parent) and CD3+CD8+ (% Parent) and CD3+CD8+ (% Total); Between CD3+CD4+ (% Total) and CD3+CD8+ (#Event); Between CD3+CD8+ % Parent) and CD3+CD8+ (% Total). The present work shed light on the reaction of CD4 and CD8 T cells to chronic amphetamine and alcohol abuse, which was found to induce changes in the systemic immune response. Interestingly, amphetamine abuse markedly changes the systemic immune as they diminished CD3+CD4+ and CD3+CD8+ T cells, and amphetamine and co-abuse alcohol affected CD3 cells significantly.

Characterizing the therapeutic application of amphetamine in age‐associated cognitive decline

Memory impairment often accompanies normal aging and is thought to involve hypofunctional glutamatergic systems in the cerebral cortex and hippocampus. Glutamate, the major excitatory neurotransmitter in the brain, plays a fundamental role in functions such as cognition, motor behavior and emotion (Meldrum, 2000). Along with glutamate, norepinephrine (NE) is an important modulator of memory, especially emotional memory (Tully et al., 2010). Our previous study demonstrated a marked deficit in glutamate-stimulated NE release in slices from the cortex and hippocampus of aged (22-24 months old) male Fischer 344 rats, which is rescued by addition of amphetamine (Dezfuli et al., 2019). Thus, amphetamine potentiates glutamate-stimulated NE release (and possibly release of other monoamines). The purpose of our current study was to test the cognitive effects of amphetamine treatment in aged rats. To do this, we investigated whether memory performance as measured in the novel object recognition task (NOR) is enhanced by acute treatment with amphetamine in aged Fischer 344 rats. An additional goal of this study, is to test the effects of chronic amphetamine treatment on the NOR task. Our initial results indicate that in aged Fischer 344 rats, acute treatment with amphetamine (0.5 mg/kg) increases object recognition memory in the NOR task. These results set the stage for our chronic studies, which will be reported.

Fatal and non-fatal health incidents related to recreational ecstasy use.

Background:The recreational drug ecstasy (3,4-methylenedioxymethamphetamine) is currently used world-wide. Severe (including fatal) health incidents related to ecstasy have been reported but a risk assessment of acute non-fatal and fatal ecstasy-related health incidents has never been performed.Methods:In the current risk assessment review, national data of non-fatal health incidents collected in the Netherlands were combined with the nationwide exposure to ecstasy, that is, last-year prevalence of ecstasy use. In addition, the annual number of ecstasy-related deaths in Great Britain (Scotland, Wales and England) was used to assess the risk of fatal ecstasy-related cases.Results:In the Netherlands, the estimated risk of a moderate to severe acute health incident following the use of ecstasy is one in 900 pills (0.11%), whereas for cocaine it is one in 1600 doses (0.06%) and for gamma-hydroxybutyrate one in 95 doses (1.05%). With respect to ecstasy-related deaths in Great Britain, the estimated risk of ecstasy alone per user is 0.01–0.06%, which is close to the range of the fatality risk in chronic alcohol users (0.01–0.02%), amphetamine users (0.005%) and cocaine users (0.05%), but much lower than that of opiate use (heroin and morphine: 0.35%).Conclusion:The current review shows that almost no data are available on the health risks of ecstasy use. The few data that are available show that ecstasy is not a safe substance. However, compared to opiates (heroin, morphine), the risk of acute ecstasy-related adverse health incidents per ecstasy user and per ecstasy use session is relatively low.

Vertebral Artery Dissection Related to Amphetamine Abuse – A Case Report

We report the case of a 37-year-old male patient with chronic amphetamine abuse who presented with vertebral artery dissection. Prior to presentation, he had increased the consumption of amphetamine from 5 times a year to once every week and had used amphetamine on the day of presentation. He attended with neck pain, vertigo and coordinating difficulties of his left arm. Computed tomography angiogram of the neck vessels showed a left vertebral stenosis and cerebral magnetic resonance imaging showed a left vertebral pseudolumen and a medullary stroke. Cervical artery dissection is a major cause of stroke in the young. To the authors’ knowledge, this is the second reported case of vertebral artery dissection in a patient with amphetamine abuse. Amphetamine might contribute to an increased risk of vertebral artery dissection through its vasculopathic properties although more data are needed to establish a causal relationship.

Behavioral sensitization and cellular responses to psychostimulants are reduced in D2R knockout mice.

Repeated cocaine exposure causes long-lasting neuroadaptations that involve alterations in cellular signaling and gene expression mediated by dopamine in different brain regions, such as the striatum. Previous studies have pointed out to the dopamine D1 receptor as one major player in psychostimulants-induced behavioral, cellular, and molecular changes. However, the role of other dopamine receptors has not been fully characterized. Here we used dopamine D2 receptor knockout (D2-/- ) mice to explore the role of D2 receptor (D2R) in behavioral sensitization and its associated gene expression after acute and chronic cocaine and amphetamine administration. We also studied the impact of D2R elimination in D1R-mediated responses. We found that cocaine- and amphetamine-induced behavioral sensitization is deficient in D2-/- mice. The expression of dynorphin, primarily regulated by D1R and a marker of direct-pathway striatal neurons, is attenuated in naïve- and in cocaine- or amphetamine-treated D2-/- mice. Moreover, c-Fos expression observed in D2-/- mice was reduced in acutely but not in chronically treated animals. Interestingly, inactivation of D2R increased c-Fos expression in neurons of the striatopallidal pathway. Finally, elimination of D2R blunted the locomotor and striatal c-Fos response to the full D1 agonist SKF81297. In conclusion, D2R is critical for the development of behavioral sensitization and the associated gene expression, after cocaine administration, and it is required for the locomotor responses promoted by D1R activation.

Commentary on Stockings et al. (2019): The global amphetamine epidemic-a rising tide of mortality.

Amphetamine use disorders are an unrelenting cause of global public health crises. People with regular or dependent amphetamine use are at elevated risk of a range of causes of mortality relative to non-users. As such, interventions to reduce the risks of overdose, suicide and traumatic deaths in this population are clearly warranted—and not yet available. Globally, amphetamine use disorders are an unrelenting cause for public health crises 1. A recent, comprehensive meta-analysis by Stockings and colleagues 2 arrived at an important conclusion: that people with regular or dependent amphetamine use are at elevated risk of a range of causes of mortality—drug poisoning, cardiovascular disease, suicide, accidental injury and homicide—compared with people without regular or dependent amphetamine use. Amphetamine-type stimulants include all substances with a substituted phenylethylamine structure—such as amphetamine, dextroamphetamine and methamphetamine 3—as well as synthetic analogues, including natural cathinones—such as khat—and synthetic cathinones (or ‘bath salts’) 4. While amphetamines are frequently prescribed for the treatment of obesity, attention-deficit/hyperactivity disorder and narcolepsy, prescribed stimulants are often diverted into the illegal market. In the United States, the estimated 12-month prevalence of amphetamine-type stimulant use disorder is 0.2% across all age groups 3. Rates are similar among adult males and females; however, intravenous stimulant use has a male-to-female ratio of 4 : 1 3. Individuals who are exposed to amphetamines can develop amphetamine use disorder as rapidly as within 1 week, regardless of the route of administration 3. Amphetamine withdrawal symptoms, particularly hypersomnia, increased appetite and dysphoria, can occur and can enhance cravings. When injected or smoked, stimulants can produce instantaneous feelings of euphoria, confidence and wellbeing 3. However, acute intoxication with amphetamines may also manifest as pressured speech, paranoia, insomnia, hallucinations, aggression and emotional lability 3. This often creates diagnostic challenges, as amphetamine use disorder is also highly comorbid among those with schizophrenia 5, bipolar disorder 6, attention-deficit/hyperactivity disorder 7 and eating disorders 8. Due to their potent central nervous system stimulant effects and sympathomimetic properties, chronic amphetamine use can lead to myriad medical sequalae, including sinusitis, nasal mucosal bleeds, respiratory problems, elevated risk of HIV and other infections, seizures, as well as cardiovascular disease—including myocardial infarction, palpitations and arrhythmias, sudden death from cardiac arrest and stroke 3. As such, interventions to reduce the risks of overdose, suicide and traumatic deaths in this population are clearly warranted. With the increasing medicalization of addictive disorders as brain-based diseases, their amenability to biological treatments—most commonly pharmacotherapy—has been increasingly explored 9. The efficacy of dopamine agonists and a range of psychostimulant medications have been measured in numerous studies; however, the conclusion of the extant literature examining the potential for pharmacotherapies has been negative 10. As a result, first-line interventions for the treatment of individuals with amphetamine use disorder are primarily psychosocial, including individual and group counselling 11, coping skills training 12, intensive out-patient therapy 13, contingency management 14, cognitive–behavioral therapy 15 and motivational interviewing 16. Increasingly, neurostimulation therapy—particularly repetitive transcranial magnetic stimulation—has been explored for the treatment of amphetamine and other stimulant use disorders, with preliminary evidence of efficacy 17. As Stockings and colleagues identified, mortality among individuals with amphetamine use disorder is high—but unless there are drastic changes in our approaches to the treatment of individuals with amphetamine use disorder, these statistics will not change. Stigma towards people with addictions further estranges those who are in most need of support, and is a large driver of continued morbidity and mortality in this population 18. Anti-methamphetamine campaigns, intended to support those who are interested in quitting or seeking help, are frequently inauthentic, using dramatic imagery that reinforces negative stereotypes of the prototypical ‘white, meth-using zombie’ 19. Taken together, these findings indicate that there is an urgent need for alternative evidence-based strategies to tackle the mounting global amphetamine epidemic. None.

F74. Impaired Fear Extinction in Omega-3 Fatty Acid Deficient Rats is Attenuated by Chronic Amphetamine Treatment

Mood disorders are associated altered prefrontal cortex (PFC) and amygdala (AMY) structural and functional connectivity, and deficits in the omega-3 fatty acid docosahexaenoic acid (DHA). Reciprocal connections between the rat PFC and basolateral AMY mediate conditioned fear acquisition and extinction, and this circuit undergoes robust synaptic pruning during adolescence. DHA promotes synaptogenesis and synaptic pruning, and chronic amphetamine (AMPH) treatment induces synaptic reorganization in the rat PFC. The present study investigated whether developmental deficits in brain DHA accrual and/or chronic AMPH exposure impact fear conditioning in young adulthood.

Questioning the predictive validity of the amphetamine-induced hyperactivity model for screening mood stabilizing drugs

Animal models are critical for the study of disease mechanisms and the screening of potential novel treatments. In the context of bipolar disorder, amphetamine-induced hyperactivity (AIH) is a frequently used screening model for antimanic effects. Yet, the utility of screening models depends on their predictive (or pharmacological) validity and it is expected that such models will respond to effective treatments. Lithium is the prototypic mood stabilizer but previous data regarding the effects of lithium in the AIH model are not clear and most data comes from studies using acute lithium administration that is not relevant to the therapeutic regimen in patients. To evaluate the pharmacological validity of AIH as a model for mania-like behavior we tested the interaction between chronic oral administration of lithium and amphetamine in ICR (CD-1®) mice and in black Swiss mice. We conducted 4 different experiments where chronic lithium was followed by an acute injection of amphetamine and one experiment where chronic amphetamine was combined with chronic lithium. The results show that amphetamine result in hyperactivity (experiments 1–4) and that lithium has no effects. Moreover, chronic amphetamine (experiment 5) result in sensitization that is not attenuated by lithium. The results clearly show that the predictive validity of the AIH model in ICR or black Swiss mice is problematic and possibly cast doubt on the utilization of the AIH as a screening model for novel mood stabilizers in other strains of mice.

Amphetamine Self-Administration and Its Extinction Alter the 5-HT1B Receptor Protein Levels in Designated Structures of the Rat Brain

Manipulation of the serotonin (5-HT)1B receptors can modify the behavioral effects of amphetamine including its reinforcing properties. Focus of this study was to examine changes in 5-HT1B receptor protein expression in several brain structures linked to substance drug disorder in different stages of amphetamine addiction—single session of amphetamine self-administration, 20 consecutive days of amphetamine self-administration, and 3 and 14 days of extinction from chronic drug intake. “Yoked” procedure was employed to set apart pharmacological and motivational effects of amphetamine intoxication. Immunohistofluorescence was performed on brain slices containing the following regions: nucleus accumbens (NAc) shell and core, globus pallidum (GP) lateral and ventral, hippocampus (HIP), substantia nigra (SN), and ventral tegmental area (VTA). Single amphetamine session decreased the amount of 5-HT1B receptors in SN, VTA, and HIP in active and yoked rats. On the contrary, 20 days of chronic amphetamine exposure triggered elevation of 5-HT1B receptors exclusively in animals that voluntarily administered the drug in NAc core, GP ventral, and HIP. Furthermore, 14-day (but not 3-day) extinction from amphetamine increased the 5-HT1B receptor expression in ventral and lateral GP, HIP, and SN. This study is the first to demonstrate that exposure to amphetamine and its extinction alter the expression of 5-HT1B receptors in various rat brain regions, and those changes seem to be transient and region specific. Importantly, since increased expression of 5-HT1B receptor after chronic amphetamine self-administration was limited only to active group of animals, we suggest that 5-HT1B receptor is linked to motivational aspect of addiction.

Chronic amphetamine enhances visual input to and suppresses visual output from the superior colliculus in withdrawal

Heightened distractibility is a core symptom of Attention Deficit Hyperactivity Disorder (ADHD). Effective treatment is normally with chronic orally administered psychostimulants including amphetamine. Treatment prevents worsening of symptoms but the site of therapeutic processes, and their nature, is unknown. Mounting evidence suggests that the superior colliculus (SC) is a key substrate in distractibility and a therapeutic target, so we assessed whether therapeutically-relevant changes are induced in this structure by chronic oral amphetamine. We hypothesized that amphetamine would alter visual responses and morphological measures. Six-week old healthy male rats were treated with oral amphetamine (2, 5 or 10 mg/kg) or a vehicle for one month after which local field potential and multiunit recordings were made from the superficial layers of the SC in response to whole-field light flashes in withdrawal. Rapid Golgi staining was also used to assess dendritic spines, and synaptophysin staining was used to assess synaptic integrity. Chronic amphetamine increased local field potential responses at higher doses, and increased synaptophysin expression, suggesting enhanced visual input involving presynaptic remodelling. No comparable increases in multiunit activity were found suggesting amphetamine suppresses collicular output activity, counterbalancing the increased input. We also report, for the first time, five different dendritic spine types in the superficial layers and show these to be unaffected by amphetamine, indicating that suppression does not involve gross postsynaptic structural alterations. In conclusion, we suggest that amphetamine produces changes at the collicular level that potentially stabilise the structure and may prevent the worsening of symptoms in disorders like ADHD.

Repeated intermittent oral amphetamine administration results in locomotor tolerance not sensitization.

The phenomenon of locomotor sensitization to injected amphetamine is well-characterised. The increased locomotor activity found acutely is enhanced with repeated intermittent treatment. This effect arises due to hypersensitization of the dopaminergic system and is linked to drug addiction. A clinical population exposed to chronic repeated intermittent amphetamine treatment, such as is found for attention deficit hyperactivity disorder (ADHD), may be expected to be more at risk of addiction following this treatment. However, evidence suggests the opposite may be true. This suggests the route of administration may determine the direction of effects. We aimed to establish how an oral amphetamine treatment regimen, similar to that used in ADHD, impacts on locomotor activity, specifically whether tolerance or sensitization would arise. Healthy hooded Lister rats were given amphetamine (2 mg/kg, 5 mg/kg and 10 mg/kg) or a vehicle solution once daily for 4 weeks with a 5 day on, 2 day off schedule. Locomotor activity was measured on the first day of treatment to establish the acute effects and on the final day of treatment to examine the chronic effects. As expected, acute doses of amphetamine increased locomotor activity, although this only reached statistical significance for the 5 mg/kg and 10 mg/kg doses. By contrast, after chronic treatment, animals administered these doses showed reduced activity indicating drug tolerance rather than sensitization had occurred. We suggest that the route of administration used in ADHD, which results in more stable and longer duration drug levels in the blood, results in tolerance rather than sensitization and that this effect could explain the reduced likelihood of substance addiction in those treated with psychostimulants for ADHD.

Involvement of NO/NMDA-R pathway in the behavioral despair induced by amphetamine withdrawal

Abrupt discontinuation of chronic amphetamine consumption leads to withdrawal symptoms including depression, anhedonia, dysphoria, fatigue, and anxiety. These irritating symptoms may result in continuing to take the drug or can lead to suicidal behavior. Past studies have shown the involvement of various biologic systems in depression induced following amphetamine withdrawal (AW). However, there is no evidence about the relation between nitric oxide (NO) with NMDA receptors on depression following AW. In this study, we examined the involvement of the NO/NMDA pathways on depressive-like behaviors after 24 h withdrawal following 5 continuous days of amphetamine administration in male NMRI mice. Behavioral tasks used for depression assessment included the forced swimming test (FST), the Splash test and the open field test (OFT). In order to evaluate the role of NO/NMDA pathways animals treated with MK-801 (NMDA-R antagonist), Aminoguanidine (AG), a selective iNOS inhibitor, Nω-Nitro-l-arginine (L-NNA), a non-selective NOS inhibitor and 7-Nitro indazole (7-NI), a selective nNOS inhibitor. We also measured the level of nitrite in the hippocampus. Our data showed that AW induced the depressive-like effect in the FST and the Splash test. We showed that administration of AG, L-NNA, and MK-801 mitigated AW induced depression, however, 7-NI was failed to decrease depressive-like behaviors. Also, the antidepressant-like effect of co-injection of sub-effective doses of MK-801 with AG suggested that inducible nitric oxide synthase (iNOS) is associated with NMDA-R in AW induced depression. In conclusion, both NO and NMDA-R pathways are involved and related to each other in depression induced following AW.

Chronic amphetamine treatment affects collicular-dependent behaviour

Distractibility can be defined as an attention deficit where orientation toward irrelevant targets cannot be inhibited. There is now mounting evidence that the superior colliculus is a key neural correlate of distractibility, with increased collicular-activity resulting in heightened distractibility. Heightened distractibility is reduced by amphetamine, which acutely suppresses collicular responsiveness. However, when amphetamine is used to treat distractibility, it is given chronically, yet no data exist on whether chronic amphetamine treatment affects the colliculus. Here, the effect of chronic amphetamine treatment was assessed in healthy hooded lister rats on two collicular dependent behaviours following a twenty-eight day treatment period: i) orienting to visual stimuli, and ii) height-dependent modulation of air-righting. We found no significant impact of amphetamine treatment on visual orienting despite showing dose-dependent decreases in orienting to repeated stimuli. However, we did find that treatment with amphetamine significantly reduced the ability to modulate righting according to the height the animal is dropped from – a function known to be dependent on the colliculus. We suggest that the results are in line with previous research showing acute amphetamine suppresses collicular activity and we speculate that the psychostimulant may increase receptive field size, altering time-to-impact calculations carried out by the colliculus during air-righting.

125 Short Duration Monoballismus

AbstractStudy ObjectiveWhile monoballismus has been reported to be associated with hemorrhagic lesions in the subthalamic nucleus (Ohnishi, 2009) and multiple sclerosis (MS) (Rosa, 2011), the duration has been reported to be at least six days (Soysal, 2012). A patient with epochs of monoballismus lasting for 45 minutes is presented.MethodsCase Study: A 57 year old right handed female with attention deficit hereditary disorder predominantly inattentive on amphetamine sulphate, presented with two years of memory loss. For instance, after ordering food in restaurants, by the time the food arrives, she could not recall what she ordered. At the onset of this symptom, she noted three epochs of her left arm jerking for 45 minutes. The jerking would begin with low amplitude and low frequency and rapidly progress to the forearm and arm of greater magnitude and low frequency. With her right hand she would try to hold down her left arm without success. There was no associated paresis, sensory phenomena, headaches, dizziness, presyncope, loss of consciousness, or strong emotions. She admitted to frequent jamais vu.ResultsAbnormalities: Neurological Examination: Mental Status Examination: Memory: Immediate Recall: 5 digits forward and 2 digits backwards. Cranial Nerve (CN) Examination: CN I: Alcohol Sniff Test 8 (hyposmia). CN XII: tongue tremor on protrusion. Motor Examination: Drift Test: positive right pronator drift. Gait Examination: Tandem Gait: unstable. Reflexes: 0-1 throughout. Neuropsychiatric Examination: Go-No-Go Test: 6/6 (normal). Animal Fluency Test: 15 (normal). Clock Drawing Test: 3 (abnormal). Center for Neurologic Study Lability Scale: 16 (pseudobulbar affect). Other: MRI with and without infusion: normal.ConclusionTransient tonic-clonic movements of one limb have been described with focal epilepsy associated with diabetic non-ketotic hyperglycemia (Grant, 1985). A metabolic abnormality such as transient hypoglycemia or hyperkalemia can cause a focal dystonia (Soysal, 2012), which theoretically could manifest with monoballismus. This could be a somatic manifestation of underlying conflict, conversion disorder, or as a result of a physical manifestation of panic attack with hyperventilation and tetany (Mihai, 2008). This may be the first manifestation of a generalized cerebral disorder associated with chorea or ballismus such as Wilson’s disease, or Huntington’s Chorea (Mihai, 2008). It is possible that this is a variant of Alien Hand Syndrome with parietal lobe involvement (Shrestha, 2015). But this is unlikely given the absence of hemineglect or hemiagnosia. It is possible that amphetamines may have induced a monochorea. Chronic amphetamine use has been demonstrated to cause chorea (Klawans, 1974) and it theoretically could have caused ballismus movements in this case. In patients who present with short duration monoballismus, evaluation for subthalamic nuclei function, seizure disorders and other origins of ballismus are warranted.Funding AcknowledgementsSmell & Taste Treatment and Research Foundation

Neuroprotective effects of melatonin on amphetamine-induced dopaminergic fiber degeneration in the hippocampus of postnatal rats.

Chronic amphetamine (AMPH) abuse leads to damage of the hippocampus, the brain area associated with learning and memory process. Previous results have shown that AMPH-induced dopamine neurotransmitter release, reactive oxygen species formation, and degenerative protein aggregation lead to neuronal death. Melatonin, a powerful antioxidant, plays a role as a neuroprotective agent. The objective of this study was to investigate whether the protective effect of melatonin on AMPH-induced hippocampal damage in the postnatal rat acts through the dopaminergic pathway. Four-day-old postnatal rats were subcutaneously injected with 5-10mg/kg AMPH and pretreated with 10mg/kg melatonin prior to AMPH exposure for seven days. The results showed that melatonin decreased the AMPH-induced hippocampal neuronal degeneration in the dentate gyrus, CA1, and CA3. Melatonin attenuated the reduction in the expression of hippocampal synaptophysin, PSD-95, α-synuclein, and N-methyl-D-aspartate (NMDA) receptor protein and mRNA caused by AMPH. Melatonin attenuated the AMPH-induced reduction in dopamine transporter (DAT) protein expression in the hippocampus and the reduction in mRNA expression in the ventral tegmental area (VTA). Immunofluorescence demonstrated that melatonin not only prevented the AMPH-induced loss of DAT and NMDA receptor but also prevented AMPH-induced α-synuclein overexpression in the dentate gyrus, CA1, and CA3. Melatonin decreased the AMPH-induced reduction in the protein and mRNA of the NMDA receptor downstream signaling molecule, calcium/calmodulin-dependent protein kinase II (CaMKII), and the melatonin receptors (MT1 and MT2). This study showed that melatonin prevented AMPH-induced toxicity in the hippocampus of postnatal rats possibly via its antioxidative effect and mitochondrial protection.

Naltrexone modulates dopamine release following chronic, but not acute amphetamine administration: a translational study

The opioid antagonist naltrexone has been shown to attenuate the subjective effects of amphetamine. However, the mechanisms behind this modulatory effect are currently unknown. We hypothesized that naltrexone would diminish the striatal dopamine release induced by amphetamine, which is considered an important mechanism behind many of its stimulant properties. We used positron emission tomography and the dopamine D2-receptor radioligand [11C]raclopride in healthy subjects to study the dopaminergic effects of an amphetamine injection after pretreatment with naltrexone or placebo. In a rat model, we used microdialysis to study the modulatory effects of naltrexone on dopamine levels after acute and chronic amphetamine exposure. In healthy humans, naltrexone attenuated the subjective effects of amphetamine, confirming our previous results. Amphetamine produced a significant reduction in striatal radioligand binding, indicating increased levels of endogenous dopamine. However, there was no statistically significant effect of naltrexone on dopamine release. The same pattern was observed in rats, where an acute injection of amphetamine caused a significant rise in striatal dopamine levels, with no effect of naltrexone pretreatment. However, in a chronic model, naltrexone significantly attenuated the dopamine release caused by reinstatement of amphetamine. Collectively, these data suggest that the opioid system becomes engaged during the more chronic phase of drug use, evidenced by the modulatory effect of naltrexone on dopamine release following chronic amphetamine administration. The importance of opioid-dopamine interactions in the reinforcing and addictive effects of amphetamine is highlighted by the present findings and may help to facilitate medication development in the field of stimulant dependence.