Chronic Methamphetamine Administration Research Articles

Attenuation of methamphetamine-induced neurotoxicity in copper/zinc superoxide dismutase transgenic mice.

Administration of methamphetamine (METH) to rats and nonhuman primates causes loss of terminals in the nigrostriatal dopaminergic system. The mechanism by which METH causes its neurotoxicity is not known. To evaluate further the role of oxyradicals in METH-induced neurotoxicity, we have tested its effects in CuZn superoxide dismutase (SOD) transgenic (Tg) mice, which express the human CuZnSOD gene. In non-Tg mice, acute METH administration causes significant decreases in levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striata and cortices of non-Tg mice. In contrast, there were no significant decreases in cortical or striatal DA in the SOD-Tg mice. The effects of METH on DOPAC were also attenuated in both structures of these SOD-Tg mice. Chronic METH administration caused decreases in levels of striatal DA and DOPAC in the non-Tg mice, whereas the SOD-Tg mice were not affected. These results suggest that METH-induced dopaminergic toxicity in mice may be secondary to increased production of reactive oxygen species such as the superoxide radical.

Autoradiographic localization of CCK-8 binding sites in the rat brain: Effects of chronic methamphetamine administration of these sites

The effects of chronic methamphetamine (MAP) administration (at a dose of 4 mg/kg for 14 days) on [ 3H]pCCK-8 binding sites in the rat brain were investigated by an in vitro quantitative receptor autoradiographic technique. The number of [ 3H]pCCK-8 binding sites was significantly reduced in layers III and IV of the medial frontal, anterior, and posterior cingulate cortices, in layers II–IV of the retrosplenial cortex, in layers III–VI of the dorsal insular cortex, and in the reticular nucleus of the thalamus, compared to these numbers in a control group of rats that received physiologic saline. Further, chronic methamphetamine administration led to a significant increase in the number of these binding sites in layer I of the entorhinal cortex. These findings indicate the CCK peptides in the limbic lobe may be closely related to the development of the behavioral changes associated with methamphetamine sensitization. In addition, these results provide supporting evidence for the involvement of the limbic system in the pathophysiology of schizophrenia.

Lack of effect of haloperidol or methamphetamine treatment on the mRNA levels of two dopamine D2 receptor isoforms in rat brain.

In order to investigate whether changes of the two mRNAs encoding the D2 receptor isoforms were induced by chronic haloperidol or methamphetamine treatment in rats, we measured the brain mRNA levels using in situ hybridization histochemistry (ISHH). We used two oligonucleotide probes, an "insert" probe to hybridize with the longer D2 receptor, D2(444), mRNA, and a "spanning" probe to hybridize with the shorter D2 receptor, D2(415), mRNA. Both D2 mRNAs were detected by ISHH in the caudate putamen, nucleus accumbens, substantia nigra, pars compacta and ventral tegmental area. The distributions and the amounts of the mRNAs for the two D2 isoforms did not change after chronic administration of haloperidol (1 mg/kg/day for 14 days, ip) or methamphetamine (4 mg/kg/day for 14 days, ip). These results suggest that the changes of D2 receptor density induced by chronic neuroleptic and psychostimulant treatment are not due primarily to receptor expression.

Two types of neuroplasticities in the kindling phenomenon: effects of chronic MK-801 and methamphetamine

Using the low-frequency kindling technique, we studied the effects of chronic MK-801 and chronic methamphetamine (MAP) administration on hippocampal kindling seizure development. In experiment 1, MK- (0.05, 0.1 mg/kg i.p.) was administered 2 h before each electrical stimulation until kindling developed into stage-3 seizure. In experiment 2, we started daily electrical stimulations two weeks after the last injection of chronic MAP administration (6 mg/kg/day, 14 days). The number of stimulating pulses required for the triggering of epileptic afterdischarge (pulse-number threshold, PNT) was used as an indicator of the seizure threshold. PNT, afterdischarge duration (ADD) and behavioral seizure stage (BSS) of each induced seizure in the initial stage of kindling; the kindling rates for stage 3 and stage 5 seizures; seizure parameters at the completion of kindling of the drug-treated groups were recorded and compared to the values of each saline-treated control group. Our result showed that MK-801 administration prior to each electrical stimulation selectively and significantly increased PNT in the initial stage of kindling without affecting other seizure parameters. Chronic pretreatment of MAP caused a selective and significant decrease of PNT of the first two stimulations in the kindling process. Taken together with the previous studies, these results suggest that long-term potentiation plays an important role in the development of the excitability of seizure focus but not of the induced seizure's propagation in the hippocampal kindling phenomenon. Clinically MK-801 seems to be a more efficacious drug in preventing the induction of seizures than in suppressing the acquired seizures.

Effects of chronic methamphetamine or phencyclidine administration on CCK gene expression in the rat brain

Effects of chronic methamphetamine or phencyclidine administration on CCK gene expression in the rat brain

逆耐性現象・キンドリング現象と精神医学

Abuse of psychostimulants such as methamphetamine by humans leads to psychotic symptoms which are virtually indistinguishable from those of paranoid schizophrenia. A similar progressive augmentation was observed in locomotion and stereotyped behavior of animals receiving chronic administration of methamphetamine. Thus, such behavioral sensitization or reverse tolerance phenomenon has been well established as an animal model of susceptibility to exacerbation of methamphetamine-induced paranoid psychosis and schizophrenia. On the other hand, kindling refers to a phenomenon whereby a progressively increasing epileptiform discharge emerges after repeated electrical stimulation in a limbic area and finally culminates in a generalized seizure. Kindling has been best characterized as a model of human temporal lobe epilepsy. This review summarizes the studies on reverse tolerance and kindling phenomenon so far conducted in our department. Acute exacerbation following a re-challenge of methamphetamine in the methamphetamine-treated animals is associated with enhancement of dopamine release in the striatum. The pharmacological and electrophysioloical studies of kindling revealed cumulative evidence that excitatory amino acids play an important role in the induction mechanism of kindling, but that the seizure triggering mechanism may be related to collapse of inhibitory gamma-aminobutyric acid function. Further studies are necessary to understand these two important phenomena for psychiatry.

Cholecystokinin binding sites in the rat forebrain: effects of acute and chronic methamphetamine administration.

Using the in vitro quantitative receptor autoradiographical technique, changes in the binding parameters of [propionyl-3H] propionylated CCK-8 [( 3H]pCCK-8) binding sites in the rat forebrain were investigated following acute and chronic administration of methamphetamine (MAP). The (Kd)app values of [3H]pCCK-8 binding sites in the frontal medial cortex and anterior cingulate cortex were significantly reduced after a single injection of 4mg/kg MAP. On the other hand, chronic treatment (14 days) with MAP at this dose significantly decreased the Bmax value of [3H]pCCK-8 binding sites in the anterior cingulate cortex accompanied by supersensitivity of locomotor effects to MAP. These findings suggest that dopamine (DA) neurons in these two regions are functionally related to intrinsic CCK-containing cortical neurons, and that CCK subsensitivity, perhaps due to an alteration in DA transmission, is involved in MAP sensitization. These findings may be relevant to the DA hypothesis of schizophrenia.

Long-term effects of chronic methamphetamine administration in rhesus monkeys

Biochemical and neuropathological effects of exposure to a high dose regimen of methamphetamine were evaluated in rhesus monkeys approximately 4 years after the last drug injection. Concentrations of dopamine and serotonin in caudate were below control levels as were concentrations of serotonin in several other brain regions. These changes were more severe in a monkey that was exposed twice to the drug regimen. A decrease in caudate synaptosomal uptake of both neurotransmitters as well as neuropathological changes were evident in that monkey. Although it is possible that partial recovery occurred, these results strongly suggest that methamphetamine-induced neurotoxicity may be permanent.

Enhancement of dopamine actions on rat nucleus accumbens neurones in vitro after methamphetamine pre‐treatment.

1. Intracellular recordings were made from the nucleus accumbens neurons in brain slices from rats previously treated with saline or methamphetamine. 2. In neurones from both methamphetamine- and saline (control)-treated rats, dopamine (0.1 mM) produced three types of responses: a biphasic response consisting of an initial hyperpolarization followed by a depolarization, a monophasic hyperpolarization and a simple depolarization. 3. Haloperidol (1 microM) reversibly suppressed both responses to dopamine; (-)-sulpiride (1 microM) selectively abolished the depolarization and prolonged the hyperpolarization. Forskolin (10 microM) and dibutyryl adenosine 3',5'-cyclic monophosphate (1 mM) mimicked the hyperpolarization. Both of the latter two substances were more effective in neurones from methamphetamine-treated rats than in neurones from control rats. 4. In slices from methamphetamine-treated rats, the dose-response curve for the dopamine hyperpolarization was shifted to the left of that seen in neurones from control rats by a factor of approximately 100. The dose-response curve for the dopamine depolarization was shifted to the right about 10-fold in neurones from rats treated with methamphetamine. 5. In slices from control rats, dopamine (less than or equal to 0.1 mM) and methamphetamine (less than or equal to 1 microM) had no effect on the EPSPs evoked by focal electrical stimulation of the periaccumbens regions: dopamine (greater than or equal to 10 nM) and methamphetamine (1 microM) markedly depressed the EPSPs in slices from methamphetamine-treated rats. Depolarizations evoked by application of exogenous glutamate were unaffected by dopamine (less than 5 microM). 6. In slices from methamphetamine-treated rats, dopamine (greater than or equal to 10 nM), forskolin (greater than or equal to 1 microM) and dibutyryl adenosine 3',5'-cyclic monophosphate (1 mM) depressed Ca2+-dependent spikes as well as the EPSPs. Haloperidol (1 microM) completely reversed the depressions of the EPSPs and Ca2+-dependent spikes by dopamine, while (-)-sulpiride (1 microM) was only partially effective. 7. These results indicate that chronic methamphetamine administration leads to enhancement of the actions of dopamine at D1 receptors located on glutamate and/or aspartate nerve terminals and of the dopamine hyperpolarization of principal neurones, which is also mediated by D1 receptors.

Rhythms in behaviors, body temperature and plasma corticosterone in SCN lesioned rats given methamphetamine

In aperiodic rats with lesions in the suprachiasmatic nuclei (SCN), rhythms with a circadian period in spontaneous locomotion, wheel-running, feeding, drinking, body temperature and plasma corticosterone were restored by chronic administration of methamphetamine. These rhythms were not entrained by a light-dark cycle. Wheel-running, feeding and drinking rhythms in individual rats were in phase in terms of ultradian bout as well as circadian fluctuation. Rhythms of the intraperitoneal temperature appeared accompanying the spontaneous locomotor rhythm. The phase relation between the two rhythms was similar to that of SCN dependent rhythms. Plasma corticosterone also fluctuated in a circadian fashion. The corticosterone peak preceded the activity onset of locomotor rhythm by a few hours, which was similar to the phase relation observed in the SCN intact animals. It is concluded that the oscillatory mechanism underlying the spontaneous locomotor rhythm in SCN lesioned and methamphetamine treated rats drives also other physiological rhythms. The phase-relations among them were similar to those of rhythms driven by the circadian pacemaker in the SCN.

The chronic administration of dopamine antagonists and methamphetamine changed the [ 3H]-cholecystokinin-8 binding sites in the rat frontal cortex

The specific cholecystokinin (CCK) binding in the slide-mounted tissue sections of the rat frontal cortex was measured with [ 3H]-CCK-8. The binding was saturable, reversible, high in affinity, and inhibited by caerulein. The chronic administration of dopamine (DA) antagonists and methamphetamine (MAP) showed a tendency to increase the [ 3H]-CCK-8 binding sites (Bmax) in the frontal cortex. Long-term treatments with DA antagonists led to the depletion of CCK-8 and may have caused an observed proliferation of CCK-8 receptors in the frontal cortex.

Dopaminergic agents affected neuronal transmission of cholecystokinin in the rat brain

In order to study the interaction between cholecystokinin (CCK) and dopamine (DA), we prepared an anti-CCK-8 antibody with low cross reactivity, and observed effects of administered various dopaminergic agents on CCK-immunoreactivity (CCK-IR) in discrete brain regions of rats. CCK-8 IR (boiling water extraction) and CCK-33 IR (acetic acid extraction) were also measured in the same sample. A single administration of haloperidol decreased the CCK-8 IR in the corpus striatum and that of racemic sulpiride significantly decreased the CCK-8 IR in the frontal cortex and the limbic system. In contrast, a single administration of apomorphine or methamphetamine increased the CCK-8 IR in the same regions. These findings suggest that an acute response of the CCK system to administered dopaminergic agents may be due to a change in the rate of release of CCK-8, but not to a change in its synthesis in areas in which DA neurons originating in the midbrain innervate. After chronic administration of racemic sulpiride or methamphetamine, CCK-8 IR in various brain regions exhibited a tendency close to that of control.

Tyrosine hydroxylase immunochemistry and quantitative light microscopic studies of the mesolimbic dopamine system in rat brain: Effects of chronic methamphetamine administration

Long-term treatment of rats with methamphetamine (20 mg/kg, IP, every 12 hours for 10 days) resulted in a large decrease in tyrosine hydroxylase staining axons and terminal boutons in the nucleus accumbens and frontal cortex, as well as the ventral tegmental area of the midbrain, when examined 60 days following termination of the drug treatment regimen. Quantitative analysis showed a 71 and 78% decrease in tyrosine hydroxylase staining processes in the nucleus accumbens and frontal cortex, respectively, and a 90% decrease in tyrosine hydroxylase positive material in the ventral tegmental area. Thus, tyrosine hydroxylase enzyme in both the cell bodies of the midbrain ventral tegmental area as well as in the nerve terminals in post-synaptic target regions of the forebrain is depleted by chronic methamphetamine administration.

Chronic methamphetamine and its withdrawal modify behavioral and neuroendocrine circadian rhythms

Chronic methamphetamine (MA) administration via the drinking water not only induced hyperactivity, but phase delayed the rat rest-activity cycle under entrained conditions. The minimum and/or maximum of the rhythms in eating, drinking, body weight, core body temperature and plasma/urine corticosterone were delayed. The different phase shifts of peak and trough values can also be a result of modulation in the wave form of the rhythms. The fall, but not the rise, of nocturnal pineal melatonin secretion occurred 4 hours earlier in MA-treated rats than in controls: this pattern was still present 1 week after withdrawal, but no longer after 4 weeks withdrawal. Neither chronic MA nor its withdrawal had any effect on plasma thyrotropin. These patterns after chronic MA intake fall into two groups: those rhythms whose peak and/or trough are delayed and those that are not. We thus interpret chronic MA application as modulating the eating rhythm (though not directly through rhythmic MA levels in the CNS), and that this in turn changes all food-dependent rhythms. In contrast, the circadian rhythms of melatonin and thyrotropin remain independent.

Effect of chronic administration of methamphetamine on the responsiveness of substantia nigra zona reticulata neurons to GABA or a GABA agonist in rats.

The effects of chronic administration of methamphetamine on the responsiveness of neurons of the substantia nigra zona reticulata (SNR) to gamma-aminobutyric acid (GABA) or to a GABA receptor agonist were examined. Neuronal activity was recorded from the SNR of rats that had been pretreated twice daily, for 6 consecutive days, with saline or with 5 mg/kg methamphetamine. Intravenous administration of the GABA receptor agonist, muscimol, caused a dose-dependent decrease in the unit activity of the SNR neurons and the SNR neurons became less sensitive to the depressant effects of the drug after chronic treatment with methamphetamine. Iontophoretic application, with increasing currents, of GABA produced a progressive inhibition of unit activity in control animals, an effect that was significantly reduced in rats pretreated with methamphetamine. These results support the hypothesis that long-term administration of methamphetamine increases the activity of the striatonigral GABA system and thereby reduces the sensitivity of postsynaptic GABA receptors in the SNR.

Behavioral and neurochemical changes in pups prenatally exposed to methamphetamine

Behavioral and neurochemical changes were examined in pups after repeated prenatal treatment with methamphetamine (MAP). MAP-pretreated pups showed decreased total motor activity with increased vertical activity. The reactivity to sound stimuli in MAP-pups differed from that in controls, suggesting impaired reactivity to the surroundings. No difference was found in development of the circadian rhythm of motor activity between MAP- and control pups. No behavioral sensitization to MAP was found in MAP-pups, regardless of the repeated prenatal exposure to MAP. This finding suggests that there is a certain developmental stage of the brain that is critical for long-term sensitization to dopamine agonists due to chronic MAP administration. Coincident with this, no change was found in the striatal catecholamine concentrations in MAP-pups. Radioreceptor assaying of various neurotransmitter receptors showed a significant decrease in the Bmax of 3H-spiperone binding in the frontal cortex of MAP-pups. These findings suggest that prenatal treatment with MAP produces impaired reactivity to the surroundings, in which the hyperserotonergic state of the frontal cortex may play an important role.

Effects of chronic methamphetamine on the nigral-striatal dopamine system in rat brain: Tyrosine hydroxylase immunochemistry and quantitative light microscopic studies

Chronic administration of methamphetamine (20 mg/kg, IP, every 12 hours for 10 days) produced a large decrease in tyrosine hydroxylase staining axons and terminal boutons in the caudate nucleus in rats when examined 60 days following the final methamphetamine injection. This effect was quantitated using the Leitz Data Acquisition and Display System (DADS) revealing that there was a 74% decrease in tyrosine hydroxylase positive processes in the caudate nucleus. Furthermore, this treatment also produced a large decrease in the number of tyrosine hydroxylase positive staining neuronal perikarya in the pars compacta of the substantia nigra. This effect was also quantitative using the Leitz-(DADS) system, revealing a decrease of 89% in tyrosine hydroxylase positive material. These data demonstrate that chronic administration of methamphetamine produces a long-term loss of tyrosine hydroxylase enzyme in both the cell bodies of the substantia nigra and the nerve terminals in the caudate nucleus. Whether this effect is due to the degeneration of the neurons or some metabolic effect remains to be determined.

Similarities in feeding behavior of chronic methamphetamine treated and withdrawn rats to VMH lesioned rats

During chronic methamphetamine (M) administration and after drug withdrawal, total daily food intake, water consumption and body weight increase was measured. Additionally, food intake in the early light phase provided an index of normal circadian rhythmicity. A parallel development of tolerance to the anorexic effect of M and increased feeding in the early light phase occured. A further abnormal behavior of both chronic M-treated and withdrawn rats was the lack of preference reversal when given free access to concentrated vs. diluted glucose solutions. Both disturbed circadian feeding rhythmicity and inhibition of the glucose preference reversal are found in rats with ventromedial hypothalamic (VMH) lesions. Reduced food intake and diminished body weight increase is a characteristic of lateral hypothalamic lesions. By analogy, chronic M-treatment could be considered to induce a functional state similar to lesions of the medial and lateral hypothalamus, each with a different time course.

Reduction in brain serotonin synthesis rate following chronic methamphetamine administration in rats

Chronic administration of methamphetamine (20 mg/kg i.p., every 12 h for 6 days) produced significant decreases in brain 5-hydroxytryptophan accumulation following decarboxylase inhibition and 5-hydroxyindoleaceic acid accumulation following probenecid treatment in rats. Administration of fluoxetine prior to each methamphetamine injection prevented these neurochemical changes. Acute methamphetamine treatment produced no changes in these neurochemical measures. These data demonstrate that chronic, but not acute, methamphetamine treatment reduces brain serotonin synthesis rate.

Effects of chronic methamphetamine administration on tryptophan hydroxylase activity, [ 3H]serotonin synaptosomal uptake, and serotonin metabolism in rat brain following systemic tryptophan loading

Chronic administration of methamphetamine (20 mg/kg, i.p., every 12 hr for 6 days) produced significant decreases in the V max of brainstem (−32.8%) and forebrain (−31.5%) tryptophan hydroxylase when measured 12 hr after the final injection. Serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and [ 3H]5-HT synaptosomal uptake were decreased by a similar magnitude following chronic drug treatment. Administration of fluoxetine prior to each methamphetamine injection prevented these neurochemical changes. Neither acute nor chronic methamphetamine treatment produced any significant changes in the K m of tryptophan hydroxylase for either substrate or cofactor. Systemic tryptophan loading (50 mg/kg, i.p.) one hour prior to sacrifice in chronic methamphetamine treated rats restored brain 5-HT and 5-HIAA levels to normal. These data suggest that chronic methamphetamine treatment decreases central serotonergic neurotransmission by reducing the activity of the rate-limiting enzyme in 5-HT biosynthesis, possibly by disrupting serotonergic nerve terminals.