Chronic Amphetamine Research Articles

Treatment for amphetamine psychosis

Chronic amphetamine users may have experience of paranoia and hallucination. It has long been believed that dopamine antagonists, such as chlorpromazine, haloperidol, and thioridazine, are effective for the treatment of amphetamine psychosis. To evaluate risks, benefits, costs of treatments for amphetamine psychosis. MEDLINE (1966-2007), EMBASE (1980-2007), CINAHL (1982-2007), PsychINFO (1806-2007), CENTRAL (Cochrane Library 2008 issue 1), references of obtained articles. All randomised controlled and clinical trials (RCTs, CCTs) evaluating treatments (alone or combined) for people with amphetamine psychosis Two authors evaluated and extracted the data independently. Dichotomous data were extracted on an intention-to-treat basis in which the dropouts were assigned as participants with the worst outcomes. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess the dichotomous data. The Weighted Mean Difference (WMD) with 95% CI was used to assess the continuous data. The comprehensive searches found one randomised controlled trial of treatment for amphetamine psychosis meeting the criteria for considering studies. The study involved 58 participants and compared the efficacy and tolerability of two antipsychotic drugs, olanzapine (a newer antipsychotic) and haloperidol (a commonly used antipsychotic medication used as a control condition), in treating amphetamine-induced psychosis. The results show that both olanzapine and haloperidol at clinically relevant doses were efficacious in resolving psychotic symptoms, with the olanzapine condition showing significantly greater safety and tolerability than the haloperidol control as measured by frequency and severity of extrapyramidal symptoms. Only one RCT of treatment for amphetamine psychosis has been published. Outcomes from this trial indicate that antipsychotic medications effectively reduce symptoms of amphetamine psychosis, the newer generation and more expensive antipsychotic medication, olanzapine, demonstrates significantly better tolerability than the more affordable and commonly used medication, haloperidol.There are other two studies that did not meet the inclusion criteria for this review. The results of these two studies show that agitation and some psychotic symptoms may be abated within an hour after antipsychotic injection.Whether this limited evidence can be applied for amphetamine psychotic patients is not yet known.The medications that should be further investigate are conventional antipsychotics, newer antipsychotics and benzodiazepines. However, naturalistic studies of amphetamine psychotic symptoms and the prevalence of relapse to psychosis in the presence of amphetamine, are also crucial for advising the development of study designs appropriate for further treatment studies of amphetamine psychosis.

REPORT OF THE WORK OF THE INTERNATIONAL FORUM "SURGERY AGAINST TERRORISM: SURGERY OF DAMAGES. ERRORS, DANGERS, COMPLICATIONS"

The effect of single delta;sleep inducing peptide (DSIP- 60 μg/kg body weight) administration on the parameters of rat brain metabolism under the conditions of chronic amphetamine (2.5 mg/kg body weight, 21 days) or Madopar-125 in a dose corresponding to 50 mg L;DOPA/kg body weight (30 days) was investigated. The neurotransmitter systems were evaluated based on the content of biogenic amines, their metabolites, and activity of neurotransmitter-catabolising enzymes: serotoninergic system was characterized by MAO A activity, serotonin (5’-OT) and 5’-hydroxyindolil acetic acid (5’-HIAA) content, and dopaminergic system by MAO B activity, dopamine (DA), noradrenalin (NA), and homovanilliс acid (HVA) content in the cortex and caudate nucleus of control and experimental rats. The changes in neurotransmitter metabolism parameters induced by DA-activating substances had certain specificity. Characteristics of the corrective effect of DSIP under the conditions of amphetamine or L;DOPA action were demonstrated depending on the type of a pharmacologic agent or brain structures. It is proposed that DSIP effect in vivo is based on the activation of serotonergic system and normalizes brain metabolism, which leads to adaptive behavior of animals. A possibility of using DSIP, by analogy with a drug Deltaran, for the treatment of depressions of various origin, cerebral ischemia, etc. is discussed.

Expression of c-fos mRNA in the basal ganglia associated with contingent tolerance to amphetamine-induced hypophagia

Tolerance to the hypophagic effect of psychostimulants is contingent on having access to food while intoxicated. Rats given chronic injections of such drugs with access to food learn to suppress stereotyped movements, which interfere with feeding. In contrast, controls given the drug after food access do not learn to suppress stereotypy and, therefore, do not become tolerant. To determine the role of the basal ganglia in this phenomenon, we used in situ hybridization to measure the expression of c-fos mRNA, a marker for neural activation, in the brains of tolerant and nontolerant rats. Rats given chronic amphetamine injections prior to food access learned to suppress stereotyped movements, whereas yoked controls given the drug after feeding did not. Following an acute injection of amphetamine, both of these groups had higher levels of c-fos mRNA than saline-treated controls throughout the striatum, in the nucleus accumbens core, the ventral pallidum and layers V–VI of the motor cortex. In contrast, tolerant rats, which had learned to suppress stereotypy, had higher levels of c-fos mRNA than both amphetamine- and saline-treated controls in the entopeduncular nucleus, globus pallidus, subthalamic nucleus, pedunculopontine nucleus, nucleus accumbens shell, olfactory tubercle, somatosensory cortex, and layers II–IV of motor cortex. These data suggest that the learned suppression of amphetamine-induced stereotypy involves the activation of dorsal striatal pathways previously implicated in response selection as well as the ventral striatum, long implicated in appetitive motivation and reinforcement.

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.

Influence of Chronic Exercise on the Amphetamine‐Induced Dopamine Release and Neurodegeneration in the Striatum of the Rat

The aim of this study was to verify the effect of chronic exercise on the striatal dopamine (DA) outflow induced by low and high single doses of amphetamine (AMPH), and verify the existence of an exercise protective role on neurodegeneration. Adult male Sprague-Dawley rats were randomly separated into six groups: chronic exercise, saline; chronic exercise, 5 mg kg(-1) AMPH; chronic exercise, 30 mg kg(-1) AMPH; without exercise, saline; without exercise, 5 mg kg(-1) AMPH; without exercise, 30 mg kg(-1) AMPH. Chronic exercise consisted of an 8-week running program on a treadmill, with increasing intensity. Animals were anesthetized, placed into a stereotaxic frame and an intracerebral guide cannula implanted into the caudate-putamen. When indicated, microdialysis was performed. Dialysate samples were collected during 30-min intervals for 6 h, before and after the intraperitonial administration of AMPH or saline solution. HPLC with electrochemical detection was used to quantify DA. Chronic exercise did not significantly change the extracellular DA basal values. Regarding the maximal DA levels in the dialysates, in the rats treated with 5 mg kg(-1) AMPH, there was no significant difference between groups with and without chronic exercise; on the contrary, in animals treated with 30 mg kg(-1) AMPH, the DA release was lower in the group with chronic exercise. Moreover, the maintenance of higher levels of DA along time in the training group suggests a diminished reuptake of DA. By using the Fluoro-Jade C staining technique, we did not find neuronal death in any of the groups. In conclusion, these results suggest that chronic exercise leads to a diminished release and reuptake of DA after administration of a high dose of AMPH, whereas neither chronic exercise nor AMPH seems to induce neurodegeneration.

ΔFosB Mediates Epigenetic Desensitization of the c-fosGene After Chronic Amphetamine Exposure

The molecular mechanisms underlying the transition from recreational drug use to chronic addiction remain poorly understood. One molecule implicated in this process is DeltaFosB, a transcription factor that accumulates in striatum after repeated drug exposure and mediates sensitized behavioral responses to psychostimulants and other drugs of abuse. The downstream transcriptional mechanisms by which DeltaFosB regulates drug-induced behaviors are incompletely understood. We reported previously the chromatin remodeling mechanisms by which DeltaFosB activates the expression of certain genes; however, the mechanisms underlying DeltaFosB-mediated gene repression remain unknown. Here, we identify c-fos, an immediate early gene rapidly induced in striatum after acute psychostimulant exposure, as a novel downstream target that is repressed chronically by DeltaFosB. We show that accumulation of DeltaFosB in striatum after chronic amphetamine treatment desensitizes c-fos mRNA induction to a subsequent drug dose. DeltaFosB desensitizes c-fos expression by recruiting histone deacetylase 1 (HDAC1) to the c-fos gene promoter, which, in turn, deacetylates surrounding histones and attenuates gene activity. Accordingly, local knock-out of HDAC1 in striatum abolishes amphetamine-induced desensitization of the c-fos gene. In concert, chronic amphetamine increases histone H3 methylation on the c-fos promoter, a chromatin modification also known to repress gene activity, as well as expression levels of the H3 histone methyltransferase, KMT1A (lysine methyltransferase 1A, formerly SUV39H1). This study reveals a novel epigenetic pathway through which DeltaFosB mediates distinct transcriptional programs that may ultimately alter behavioral plasticity to chronic amphetamine exposure.

Amphetamine treatment increases corticotropin-releasing factor receptors in the dorsal raphe nucleus

Psychostimulant use increases anxious behavior, likely through interactions between central corticotropin-releasing factor (CRF) and serotonergic systems. The current study examined whether chronic amphetamine treatment (2.5 mg/kg, 14 days) or withdrawal altered CRF receptor densities in the serotonergic dorsal raphe nucleus (dRN). Amphetamine treatment increased CRF 2 receptor densities in most subregions of the dRN, and CRF 2 receptors were still elevated following 6 weeks of withdrawal. No changes in CRF 1 receptor densities were observed following amphetamine treatment or during withdrawal. Selective increases in dRN CRF 2 receptors may be related to increased anxiety-like behaviors following psychostimulant use.

ASSOCIATION BETWEEN COMT, BDNF AND LATERAL VENTRICULAR VOLUME IN SCHIZOPHRENIA AND BIPOLAR DISORDER

Amphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia.

Melatonin inhibits amphetamine-induced nitric oxide synthase mRNA overexpression in microglial cell lines

Amphetamine (AMPH) derivatives are the most commonly abused drugs. Chronic or intermittent AMPH abuse may create temporary or permanent disturbances in the dopaminergic system of the brain that may predispose individuals to Parkinsonism. AMPH induces a massive release of dopamine from synaptic vesicles and then generates reactive oxygen species (ROS). Furthermore, nitric oxide (NO), produced in the central nervous system (CNS) mediated by the activation of microglia, appears to play a critical role in stress-induced brain damage. In the present study, we examined the involvement of NO in the neurotoxic effects of AMPH, to investigate the hypothesis that altered nitric oxide synthase (NOS) function was involved. AMPH at a concentration of 0.4-3.2mM has a cytotoxic effect on highly aggressively proliferating immortalized (HAPI) cells, a rat microglial cell line. The effect of AMPH on increasing inducible NOS (iNOS) mRNA in HAPI microglial cells is concentration-dependent. Pretreatment with either S-methylisothiourea (S-MT), a selective iNOS inhibitor, or melatonin, a major secretory product of pineal gland, counteracted the over expression of iNOS induced by AMPH in a concentration-dependent manner. The induction of iNOS by AMPH in microglial cells could be an important source of NO in CNS inflammatory disorders associated with the death of neurons and oligodendrocytes. Administration of exogenous melatonin will be beneficial, as it reduces iNOS mRNA expression, and may, therefore, be able to be used as a neuroprotective agent in toxicity induced by AMPH or other immunogens.

Persistent downregulation of hippocampal CREB mRNA parallels a Y‐maze deficit in adolescent rats following semi‐chronic amphetamine administration

We investigated possible differences in the impact of chronic amphetamine administration during adolescence and adulthood on aspects of behaviour and brain chemistry. Adult (n=32) and adolescent (n=32) male Sprague-Dawley rats were given either D-amphetamine sulphate (10 mg kg(-1) daily, i.p.) or saline (1 mL kg(-1), i.p.) for 10 days. Rats were subsequently tested for anxiety-like behaviour, learning and memory, and sensorimotor gating. Nine weeks later, rats received saline (1 mL kg(-1)) or acute amphetamine challenge (1.5 mg kg(-1)) and the expression levels of mRNA for tyrosine kinase B (TrkB) or cAMP response element-binding protein (CREB) were measured in the hippocampus. The adolescent amphetamine pretreated group revealed a deficit in exploration on the Y-maze during a 6 h retention test. The frequency of visits to the novel arm was 35% lower for the amphetamine group compared with controls. In parallel, a 43% decrease in hippocampal CREB mRNA, but not TrkB mRNA, was observed in periadolescent rats treated chronically with amphetamine 9 weeks earlier. None of the effects were detected in the adult treated cohort. Chronic amphetamine treatment during periadolescence resulted in altered behaviour on the Y-maze and persistent downregulation of hippocampal CREB mRNA expression. Given that this group had intact spatial learning and reference memory, it would appear that the deficits observed on the Y-maze reflect a dysfunction in response to novelty. Because no effects of amphetamine treatment were observed in the adult cohort, these data suggest idiosyncratic sensitivity of periadolescence to the long-term effects of psychostimulants.

Melatonin inhibits amphetamine-induced increase in α-synuclein and decrease in phosphorylated tyrosine hydroxylase in SK–N–SH cells

alpha-Synuclein is an abundant presynaptic protein implicated in neuronal plasticity and neurodegeneration disorders. Understanding alpha-synuclein function in dopaminergic cells could add to our knowledge of this key protein which is implicated in Parkinson's disease. Chronic or intermittent amphetamine (AMPH) abuse may create temporary or permanent disturbances in the dopaminergic system of the brain that may predispose individuals to Parkinsonism. Our previous studies showed that neurotoxicity induced by AMPH was mediated by enhanced oxidative stress and these effects were abolished by melatonin, a main secretory product of pineal gland. The present study was conducted to investigate the effect of AMPH on alpha-synuclein in regulating tyrosine hydroxylase (TH), a rate limiting enzyme for dopamine synthesis, in cultured human dopaminergic SK-N-SH cells. Of these, phosphorylation of Ser40 (pSer40) contributes significantly to TH activation and dopamine synthesis. Our data indicated that AMPH significantly increased the level of alpha-synuclein to 183% of the control value while reducing the levels of phosphorylated TH (TH-pSer40) enzyme and mitochondrial complex I to 78 and 52.9% of the control values, respectively and these effects were attenuated by melatonin. Further studies are needed to explore the mechanism by which alpha-synuclein contributes to TH-pSer40 dephosphorylation and the mechanism by which melatonin contributes to this interaction.

Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans

Chronic drug use has been associated with increased impulsivity and maladaptive behaviour, but the underlying mechanisms of this impairment remain unclear. We investigated the ability to adapt behaviour according to changes in reward contingencies, using a probabilistic reversal-learning task, in chronic drug users and controls. Five groups were compared: chronic amphetamine users (n = 30); chronic cocaine users (n = 27); chronic opiate users (n = 42); former drug users of psychostimulants and opiates (n = 26); and healthy non-drug-taking control volunteers (n = 25). Participants had to make a forced choice between two alternative stimuli on each trial to acquire a stimulus-reward association on the basis of degraded feedback and subsequently to reverse their responses when the reward contingencies changed. Chronic cocaine users demonstrated little behavioural change in response to the change in reward contingencies, as reflected by perseverative responding to the previously rewarded stimulus. Perseverative responding was observed in cocaine users regardless of whether they completed the reversal stage successfully. Task performance in chronic users of amphetamines and opiates, as well as in former drug users, was not measurably impaired. Our findings provide convincing evidence for response perseveration in cocaine users during probabilistic reversal-learning. Pharmacological differences between amphetamine and cocaine, in particular their respective effects on the 5-HT system, may account for the divergent task performance between the two psychostimulant user groups. The inability to reverse responses according to changes in reinforcement contingencies may underlie the maladaptive behaviour patterns observed in chronic cocaine users but not in chronic users of amphetamines or opiates.

Regulation of psychostimulant-induced signaling and gene expression in the striatum.

Amphetamine (AMPH) and cocaine are indirect dopamine agonists that activate multiple signaling cascades in the striatum. Each cascade has a different subcellular location and duration of action that depend on the strength of the drug stimulus. In addition to activating D1 dopamine-Gs-coupled-protein kinase A signaling, acute psychostimulant administration activates extracellular-regulated kinase transiently in striatal cells; conversely, inhibition of extracellular-regulated kinase phosphorylation decreases the ability of psychostimulants to elevate locomotor behavior and opioid peptide gene expression. Moreover, a drug challenge in rats with a drug history augments and prolongs striatal extracellular-regulated kinase phosphorylation, possibly contributing to behavioral sensitization. In contrast, AMPH activates phosphoinositide-3 kinase substrates, like protein kinase B/Akt, only in the nuclei of striatal cells but this transient increase induced by AMPH is followed by a delayed decrease in protein kinase B/Akt phosphorylation whether or not the rats have a drug history, suggesting that the phosphoinositide-3 kinase pathway is not essential for AMPH-induced behavioral sensitization. Chronic AMPH or cocaine also alters the regulation of inhibitory G protein-coupled receptors in the striatum, as evident by a prolonged decrease in the level of regulator of G protein signaling 4 after non-contingent or contingent (self-administered) drug exposure. This decrease is exacerbated in behaviorally sensitized rats and reversed by re-exposure to a cocaine-paired environment. A decrease in regulator of G protein signaling 4 levels may weaken its interactions with metabotropic glutamate receptor 5, Galphaq, and phospholipase C beta that may enhance drug-induced signaling. Alteration of these protein-protein interactions suggests that the striatum responds to psychostimulants with a complex molecular repertoire that both modulates psychomotor effects and leads to long-term neuroadaptations.

Multiple aneurysms in the female breast: a case report

Arterial aneurysms are defined as localized abnormal dilatations in an arterial wall. We report the first case of multiple true aneurysms in the female breast in a patient with a history of chronic amphetamine abuse who presented with a probable subarachnoid haemorrhage (SAH).

Regulator of G-Protein Signaling 4 Interacts with Metabotropic Glutamate Receptor Subtype 5 in Rat Striatum: Relevance to Amphetamine Behavioral Sensitization

Regulator of G-protein signaling (RGS) 4 negatively modulates signaling of several Galpha(q)-coupled receptors, including metabotropic glutamate receptor (mGluR) subtype 5 in neuronal and non-neuronal cell lines. In the brain, both RGS4 and mGluR5 receptors are enriched in the striatum, and their functions have been linked to psychostimulant-induced behavior and synaptic plasticity. However, it is not known whether RGS4 and mGluR5 interactions occur in rat striatum and whether chronic amphetamine (AMPH) treatment produces changes in RGS4 levels that are correlated with mGluR5 receptor activity. Using coimmunoprecipitation, the present study demonstrated that endogenous RGS4 binds mGluR5 receptors as well as key mGluR5-associated proteins, Galpha(q/11), and phospholipase C-beta1 (PLCbeta1) in preparations from rat striatum. In the next experiment, rats were treated with AMPH (5 mg/kg i.p. daily) for 5 days followed by 3 weeks of abstinence. At this time point, animals pretreated with AMPH displayed sensitized behavioral responses to AMPH challenge and decreased RGS4 protein in dorsal striatum and nucleus accumbens. Behavioral sensitization to AMPH was also accompanied by an increase in Galpha(q/11) and PLCbeta1 in dorsal striatum. In contrast, total levels of mGluR5 receptors in the striatum were not altered by any AMPH treatment. In conclusion, the present study demonstrates that RGS4 protein is an integral part of the mGluR5 protein complex in the striatum. This study further suggests that AMPH-induced changes in mGluR5-associated protein levels (RGS4, Galpha(q/11), and PLCbeta1) may be related to altered coupling of striatal mGluR5 receptors in animals sensitized to AMPH.

Protein Kinase C Inhibition by Tamoxifen Antagonizes Manic-Like Behavior in Rats: Implications for the Development of Novel Therapeutics for Bipolar Disorder

Rationale: In the context of bipolar disorder (BPD) research it was demonstrated that administration of the structurally dissimilar mood stabilizers lithium and valproate produced a striking reduction in protein kinase C (PKC) in rat brain. In a small clinical study, tamoxifen (a PKC inhibitor) had antimanic efficacy. However, both lithium and valproate exert many biochemical changes and attribution of therapeutic relevance to any molecular findings needs to be based on linking them to behavioral effects. Objectives: The present study was designed to explore such relationship by studying the effects of PKC inhibition in amphetamine-induced behavioral animal models of mania and changes in GAP-43. Methods: The effects of two daily tamoxifen (1 mg/kg) i.p. injections on acute or chronic (7 injections) amphetamine (0.5 mg/kg) -induced behaviors and GAP-43 phosphorylation were tested. Results: The study demonstrates that tamoxifen significantly reduced amphetamine-induced hyperactivity in a large open field without affecting spontaneous activity levels and normalized amphetamine-induced increase in visits to the center of an open field (representing risk-taking behavior). Tamoxifen also attenuated amphetamine-induced phosphorylation of GAP-43, a result that is consistent with the behavioral findings. Conclusions: These results support the possibility that PKC signaling may play an important role in the pathophysiology and treatment of BPD. These findings may have direct clinical implications as they offer a new avenue for attempts to develop more specific drugs for the disorder.

Calcium channel antagonists suppress cross-tolerance to the anxiogenic effects of d-amphetamine and nicotine in the mouse elevated plus maze test

The purpose of the current experiments was to examine the anxiety-related effects of repeated amphetamine and nicotine administration using the mouse elevated plus maze (EPM). d-amphetamine was administered daily for 8 days (2 mg/kg, i.p.). On the 9th day, mice were challenged with amphetamine (2 mg/kg, i.p.) or nicotine (0.1 mg/kg, s.c.), and were tested 30 min after this last injection. Additionally, a distinct group of mice was pretreated with nicotine (0.1 mg/kg, s.c., 6 days). These mice were subjected to nicotine (0.1 mg/kg, s.c.) or amphetamine (2 mg/kg, i.p.) challenge on the seventh day to see if full crossover effects developed after the pretreatment of both psychostimulant drugs. Moreover, the L-type voltage-dependent calcium channel antagonists nimodipine (5 and 10 mg/kg, i.p.), flunarizine (5 and 10 mg/kg, i.p.), verapamil (5 and 10 mg/kg, i.p.) and diltiazem (5 and 10 mg/kg, i.p.) were injected prior to each injection of chronic d-amphetamine or nicotine. We observed cross-tolerance to the anxiogenic effects of d-amphetamine and nicotine that was blunted by a pretreatment with calcium channel blockers. Overall our findings imply that similar neural calcium-dependent mechanisms are involved in the anxiety-related responses to chronic amphetamine and nicotine injections. As anxiety seems to be an important factor for the development of psychostimulant dependence, the L-type VDCC antagonists can offer an interesting approach for the pharmacotherapy of addiction, including amphetamine and/or nicotine dependence.

Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers

Recent studies suggest that calcium influx via L-type calcium channels is necessary for psychostimulant-induced behavioral sensitization. In addition, chronic amphetamine upregulates subtype Cav1.2-containing L-type calcium channels. In the present studies, we assessed the effect of calcium channel blockers (CCBs) on cocaine-induced behavioral sensitization and determined whether the functional activity of L-type calcium channels is altered after repeated cocaine administration. Rats were administered daily intraperitoneal injections of either flunarizine (40 mg/kg), diltiazem (40 mg/kg) or cocaine (20 mg/kg) and the combination of the CCBs and cocaine for 30 days. Motor activities were monitored on Day 1, and every 6th day during the 30-day treatment period. Daily cocaine administration produced increased locomotor activity. Maximal augmentation of behavioral response to repeated cocaine administration was observed on Day 18. Flunarizine pretreatment abolished the augmented behavioral response to repeated cocaine administration while diltiazem was less effective. Measurement of tissue monoamine levels on Day 18 revealed cocaine-induced increases in DA and 5-HT in the nucleus accumbens. By contrast to behavioral response, diltiazem was more effective in attenuating increases in monoamine levels than flunarizine. Cocaine administration for 18 days produced increases in calcium uptake in synaptosomes prepared from the nucleus accumbens and frontal cortex. Increases in calcium uptake were abolished by flunarizine and diltiazem pretreatment. Taken together, the augmented cocaine-induced behavioral response on Day 18 may be due to increased calcium uptake in the nucleus accumbens leading to increased dopamine (DA) and serotonin (5-HT) release. Flunarizine and diltiazem attenuated the behavioral response by decreasing calcium uptake and decreasing neurochemical release.

Chronic amphetamine treatment reduces NGF and BDNF in the rat brain

Amphetamines (methamphetamine and d-amphetamine) are dopaminergic and noradrenergic agonists and are highly addictive drugs with neurotoxic effect on the brain. In human subjects, it has also been observed that amphetamine causes psychosis resembling positive symptoms of schizophrenia. Neurotrophins are molecules involved in neuronal survival and plasticity and protect neurons against (BDNF) are the most abundant neurotrophins in the central nervous system (CNS) and are important survival factors for cholinergic and dopaminergic neurons. Interestingly, it has been proposed that deficits in the production or utilization of neurotrophins participate in the pathogenesis of schizophrenia. In this study in order to investigate the mechanism of amphetamine-induced neurotoxicity and further elucidate the role of neurotrophins in the pathogenesis of schizophrenia we administered intraperitoneally d-amphetamine for 8 days to rats and measured the levels of neurotrophins NGF and BDNF in selected brain regions by ELISA. Amphetamine reduced NGF levels in the hippocampus, occipital cortex and hypothalamus and of BDNF in the occipital cortex and hypothalamus. Thus the present data indicate that chronic amphetamine can reduce the levels of NGF and BDNF in selected brain regions. This reduction may account for some of the effects of amphetamine in the CNS neurons and provides evidences for the role of neurotrophins in schizophrenia.

General Anesthesia and Chronic Amphetamine Use: Should the Drug Be Stopped Preoperatively?

Prescription amphetamines are being used more often for several medical conditions. Anesthesia concerns focus on the cardiovascular stability of patients who may be catecholamine-depleted and thus have a blunted response to intraoperative hypotension. Previously we reported one case of a patient receiving chronic amphetamine therapy who had a stable intraoperative course. We now report eight additional patients taking chronic prescription amphetamines who underwent a safe general anesthesia and outcome. Predominantly prescribed for narcolepsy and attention deficit hyperactivity disorder, amphetamine drugs had been given to these 8 patients for 2 to 10 yr. Ages ranged from 22 to 77 yr and genders were equally divided. All required general anesthesia for their surgical procedures and 6 of the 8 patients were tracheally intubated. Anesthesia operating room times ranged from 30 min to 4.25 h. The authors conclude that amphetamine use need not be stopped before surgery and anesthesia.