Dopamine increases/decreases synaptic vesicle recycling and in schizophrenia the proteins/mRNA is decreased. We isolated cDNA clone, similar to amphiphysin 1 (vesicle protein) mRNA from the neocortex of rats injected repeatedly with methamphetamine using polymerase chain reaction (PCR) differential display. This clone is highly homologous to the 3′ region of the human amphiphysin gene. PCR extension study using a primer specific for the rat amphiphysin 1 gene and a primer located within the clone revealed that it is the 3′ UTR region of the rat amphiphysin 1 gene. Furthermore, in situ hybridization revealed that amphiphysin 1 mRNA is expressed in the cerebrum, medial thalamus, hippocampus and cerebellum. In the cerebellum, amphiphysin mRNA expression was confined to upper granule cell layer. Repeated methamphetamine administration increased amphiphysin I mRNA expression in both anterior part of the cerebrum, and the cerebellum. However, the repeated administration did not alter mRNA expression of the other vesicle proteins, synaptotagmin I, synapsin I, synaptojanin and dynamin I, we conclude that the repeated administration selectively increased amphiphysin 1 mRNA expression. Thus, amphiphysin 1 does not work as synaptic recycling, but it is suggested, as a part of pathogenesis of brain tissue injury (under Ca 2+ and Mg 2+ devoid environment) in repeated methamphetamine-injected states, the gene regulate actin-asssembly, learning, cell stress signaling and cell polarity.

In the cerebellum, there are numerous cholecystokinin (CCK-8)-containing fibers. Since systemic CCK-8 injection-induced anxiety (psychological stress) activates the locus coeruleus cells that send mossy fiber inputs to the cerebellum, we examined whether systemic CCK-8 injections activate the rat and mouse cerebellum. First, injections of CCK-8 were found to induce c-fos mRNA expression in a vague patchy pattern that is different from single methamphetamine-induced Zebrin band-like c-fos mRNA expression, suggesting that the CCK-8 activating mossy fibers induce gene expression differently from the dopamine-containing mossy fibers in the ventral tegmental area. Second, since CCK-8 facilitates neural activity of dopamine in the midbrain, we examined whether repeated methamphetamine administration that induced behavioral sensitization had similar effects on the cerebellar CCK system. Repeated administration of methamphetamine suppressed the CCK-8-induced c-fos mRNA expression in the rat cerebellum. Third, capsaicin injections (physical stress) into a hind limb of the rat increased junD mRNA expression with no effect on c-fos mRNA expression, and repeated methamphetamine injections had no effect on the capsaicin-induced expression of junD mRNA. Fourth, either single injection of methamphetamine or CCK-8 to mice increased c-fos mRNA expression in the locus coeruleus, and so noradrenalin, but not dopamine, might interact with CCK-8-activating system. However, we considered the possibility unlikely. Thus, we conclude that repeated methamphetamine administration though dopamine selectively inhibits the c-fos mRNA expression after CCK-8 injection in the cerebellum.

The cerebellum has a parasagittal modular structure, in which Zebrin (Aldolase) positive and negative bands expressed in Purkinje cell layers alternate, and is involved in amphetamine psychosis. Administration of SKF38393, a D1 receptor agonist, reversed the behavioral sensitization of methamphetamine. In the vermis, there were the binding sites of SKF38393. In methamphetamine-sensitized rats the expression of the Aldolase mRNA positive bands move laterally in the rat vermis. We provide here the evidence that the D1 agonist injections also reversed the expression pattern of both the Aldolase mRNA in Purkinje cells and Ube (ubiquitin activating enzyme) 1x mRNA in Golgi interneurons of the sensitized rats. Thus the reverse changes in gene expression pattern in the vermis may be involved in the mechanisms of the behavioral plasticity and suggests the new treatment of drug abuse.

Repeated intermittent administration of methamphetamine (MAP) produces an enduring hypersensitivity to the motor stimulant effect of MAP, termed behavioral sensitization. Dopamine plays a critical role in the development and expression of behavioral sensitization. Here, we investigated whether a dopamine D1 receptor agonist could reverse behavioral sensitization to MAP. Administration of MAP (1.0 mg/kg, i.p.) to rats once every 3 days for a total of 5 times (days 1–13) induced the enhancement of locomotor activity after MAP challenge (0.5 mg/kg, i.p.) on day 20, verifying the development of behavioral sensitization. The MAP-sensitized rats then received a dopamine D1 agonist, R-(+)-SKF38393 (3.0 mg/kg, i.p.), once a day for 7 consecutive days (days 21–27). Behavioral analysis on days 30 and 41 revealed that the enhanced locomotor activity was reversed by repeated R-(+)-SKF38393 administration. Moreover, repeated R-(+)-SKF38393 administration reversed the increased dopamine release in the striatum after MAP challenge on day 41. Thus, repeated administration of the dopamine D1 receptor agonist induces the reversal of established behavioral sensitization to MAP and of increased dopamine release in the striatum, lasting for at least 2 weeks. Dopamine D1 receptor agonists may be useful therapeutic agents for the treatment of psychostimulant addiction.

In the cerebellum the mossy and climbing projections, which excite Purkinje cells, display a parasagittal and striped organization. These projections also excite Zebrin (aldolase C: Aldoc) parasagittally. To evaluate the possibility that external stimuli can change the organization of the bands of Aldoc mRNA, we compared the effects of repeated methamphetamine administration on the Aldoc mRNA stripes in the four transverse (anterior, central, posterior and nodular) regions of the vermis with the effects on the glutamate transporter EAAT4 (SCL1A 6) mRNA stripes. In the posterior region the injections four times daily increased the fragmentation of the Aldoc mRNA stripes. The presence of a large amount of fragmentation (forty/cerebellum slice), was accompanied with large lateral dislocations of the Aldoc mRNA stripes. In the central and nodular regions, where the size of the stripe areas decreased significantly the stripes were dislocated laterally. The dislocations of the Aldoc mRNA bands did not occur after a single methamphetamine injection and thus repeated injections were necessary to change the distributions of the lateral bands. In contrast, the distributions of the SCL1A 6 mRNA stripes did not change, even though there was mild fragmentation (six/slice) of the SLC1A 6 mRNA stripes in the anterior region and decreases in the numbers (twelve/slice) in the nodular region. We concluded that excess dopamine selectively changes the location of the Aldoc mRNA compartments in the vermis while the SLC1A 6 mRNA stripes could be changed by other inputs and thus the specific transmitter system might change the specific compartment of the cerebellum.

In an attempt to find whether vasopressin (VP) secretion is suppressed by learned emotional stress, we have given rats under a hypertonic condition simultaneously applied light and tone that had been paired previously with footshocks and have quantified immunoreactive VP (ir-VP) in the plasma. In a training session light (60 watt) and tone (2 kz) of 3-s duration which were paired with electric footshocks (50 Hz, 1-s duration) were given to rats 11 times at an interval of 30 s. Various lengths of time after the training, the rats were tested with light and tone, which were unpaired with footshocks and repeatedly applied every 15 s for 3 min in the box used for training. Hypertonic NaCl (0.5 M, 2 ml/ 100 g b. w.) was injected s. c. 30 min before testing to increase the basal level of plasma VP. After testing, plasma ir-VP was significantly less in the experimental group than in the 0-mA control group of rats that were trained without FS. The values for the experimental group were also significantly less than those of untested control rats that had been trained with FS but were not tested. Plasma osmolality and blood haemoglobin concentration were not significantly different between control and experimental groups. Plasma immunoreactive adrenocorticotrophic hormone (ir-ACTH) level was higher and motor activity as expressed by cumulative time period of body movement during testing was lower in the experimental group than in either of the control groups. The difference in plasma ir-VP between experimental and control groups was statistically significant two days but not seven days after training, whereas ACTH and motor activity in experimental groups were still significantly different from those in control groups seven days after training. The suppressive VP and augmentative ACTH responses to testing disappeared in the rats that had received light and tone repeatedly during the intervening period between training and testing. These data support the hypothesis that emotional stimuli suppress VP secretion.

5-HT and dopamine receptor antagonists have become widely used as atypical antipsychotics. Although 5-HT2A receptor antagonistic activity is thought to contribute to the atypical aspects of these agents, the precise mechanism remains unknown. M100907 (R(+)-alpha(2,3-dimethoxyphenyl)-1-[2(4-fluorophenyl)ethyl)]-4-piperidine –methanol), a selective 5-HT2A receptor antagonist, is reported to attenuate phencyclidine (PCP)-induced locomotion in rodents. For the purpose of identifying regions in which M100907 exerts its effect, we investigated the effects of M100907 on PCP-induced Fos expression in rat brain. PCP (5 mg/kg, subcutaneously, s.c.) induced Fos expression in the cingulate cortex area 3, the agranular insular cortex, the piriform cortex, the nucleus accumbens, the anterior paraventricular thalamic nucleus and the ventral lateral septal nucleus. Pretreatment with M100907 (0.5 mg/kg, s.c.) attenuated Fos expression induced by PCP in the nucleus accumbens core, the shell, the agranular insular cortex and the piriform cortex. M100907 did not induce Fos expression in any of the regions investigated including the dorsolateral caudate/putamen when given alone. These results indicate that 5-HT2A receptor antagonism attenuates Fos expression in a regionally specific manner in rat brain in the PCP model of psychosis.

The effects of repeated methamphetamine administration on c-fos mRNA and aldolase C (Zebrin) mRNA expression in the rat cerebellum were investigated. A single dose of methamphetamine induced c-fos mRNA expression in granule and Purkinje cells of both anterior and posterior lobes. In the posterior lobe, in particular, c-fos mRNA signals were distributed in a parasagittal organization, like Zebrin bands. Repeated methamphetamine injections reduced methamphetamine-induced c-fos mRNA signals in the anterior hemisphere and in part of the posterior vermis (lobule VII) and posterior hemisphere. Aldolase C mRNA signals in Purkinje cells decreased only in lobules where methamphetamine-induced c-fos signals were not reduced (lobules VI and IX). Therefore, differential decreases in c-fos mRNA and aldolase C mRNA expression after repeated methamphetamine administration depend upon the localization of Purkinje cells in the cerebellum. Since c-fos mRNA and aldolase C mRNA expressions are markers of excitability and the metabolic state of Purkinje cells, respectively, hypofunction of inhibitory Purkinje cells could be induced if methamphetamine is repeatedly injected. Since repeated methamphetamine administration in this experimental paradigm increased horizontal movement and the rearing activity of rats, the hemisphere of the cerebellum may be involved in development of methamphetamine-induced motor behavioral sensitization in addition to the striatum and the nucleus accumbens.

Monoclonal antibody mabQ113 has been used to study the distribution of Prukinke cell axon collaterals in the rat cerebellar cortex. MabQ113 recognizes a polypeptide antigen, zebrin I, that is confined to a subset of Purkinje cells. Antigenic Purkinje cells are arranged in parasagittal compartments running throughout the cortex. No other cerebellar cells are immunoreactive. Immunoreactive axon collaterals are confined principally to the infraganglionic plexus with only a few extending into the molecular layer. Three probable target cells for the axon collaterals have been identified: Golgi cells, Lugaro cells, and other Purkinje cells. About 90% of immunoreactive axon collaterals in the anterior lobe are located beneath the mabQ113+ Purkinje cell compartment in which they originate but some do invade the neighboring mabQ113-territory. In the anterior lobe vermis, the distribution of invading mabQ113+ collaterals is not symmetrical, such that the probability of an invading collateral from the P2+ compartment is greater at the medial boundary into P1-than at the lateral into P2-. The distribution of immunoreactive collaterals is consistent with their playing a role in synchronizing the firing of Purkinje cells within the same compartment.

1. Intravenous administration of cholecystokinin (CCK) results in a transient activation of oxytocin neurones in the rat, and hence to oxytocin secretion: this activation is followed by expression of c-fos mRNA and of Fos-like immunoreactivity (Fos-LI) in magnocellular oxytocin neurones. Fos-like immunoreactivity is also induced in the regions of the brainstem that are thought to relay information from the periphery to the hypothalamus. 2. Administration of the selective CCKA receptor antagonist MK-329, but not the CCKB receptor antagonist L-365,260, prior to CCK injection, prevented oxytocin release as measured by radioimmunoassay and oxytocin neuronal activation as measured by electrophysiology and by the lack of induction of c-fos mRNA. 3. MK-329 abolished the release of adrenocorticotrophic hormone (ACTH) following injection of CCK. 4. MK-329 prevented the expression of Fos-LI in the hypothalamic magnocellular nuclei and in the area postrema and dorsal vagal complex of the brainstem. 5. L-365,260 had no effect on the expression of Fos-LI in the brainstem, but attenuated that seen in the hypothalamic magnocellular nuclei. 6. We conclude that CCK acts on CCKA receptors, either in the area postrema or on peripheral endings of the vagus nerve, to cause the release of hypothalamic oxytocin and ACTH. Information may be carried to the hypothalamus in part by CCK acting at CCKB receptors.

Annals of the New York Academy of SciencesVolume 689, Issue 1 p. 133-145 Induction of c-fos in Magnocellular Neurosecretory Neurons A Link between Electrical Activity and Peptide Synthesis? G. Leng, G. Leng Department of Neurobiology and MRC Unit AFRC Babraham Institute Babraham, Cambridge CB2 4AT, United KingdomSearch for more papers by this authorS. M. Luckman, S. M. Luckman Department of Neurobiology and MRC Unit AFRC Babraham Institute Babraham, Cambridge CB2 4AT, United KingdomSearch for more papers by this authorR. E. J. Dyball, R. E. J. Dyball University Department of Anatomy Downing Street Cambridge, United Kingdom andSearch for more papers by this authorM. Hamamura, M. Hamamura Department of Physiology Jichi Medical School Minamikawachimachi, Tochigi 329-04, JapanSearch for more papers by this authorP. C. Emson, P. C. Emson Department of Neurobiology and MRC Unit AFRC Babraham Institute Babraham, Cambridge CB2 4AT, United KingdomSearch for more papers by this author G. Leng, G. Leng Department of Neurobiology and MRC Unit AFRC Babraham Institute Babraham, Cambridge CB2 4AT, United KingdomSearch for more papers by this authorS. M. Luckman, S. M. Luckman Department of Neurobiology and MRC Unit AFRC Babraham Institute Babraham, Cambridge CB2 4AT, United KingdomSearch for more papers by this authorR. E. J. Dyball, R. E. J. Dyball University Department of Anatomy Downing Street Cambridge, United Kingdom andSearch for more papers by this authorM. Hamamura, M. Hamamura Department of Physiology Jichi Medical School Minamikawachimachi, Tochigi 329-04, JapanSearch for more papers by this authorP. C. Emson, P. C. Emson Department of Neurobiology and MRC Unit AFRC Babraham Institute Babraham, Cambridge CB2 4AT, United KingdomSearch for more papers by this author First published: July 1993 https://doi.org/10.1111/j.1749-6632.1993.tb55543.xCitations: 7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume689, Issue1The Neurohypophysis: A Window on Brain FunctionJuly 1993Pages 133-145 RelatedInformation