Psychopharmaeologia (Berl.) 42, 243 — 248 (1975)
`(“E by Springer-Verlag 1975
`
`Modifications by Lithium of Behavioral Responses
`to Methamphetamine and Tetrabenazine
`
`TATSUO FURUKAWA
`
`Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka, Japan
`
`[TSUKO USHIZIMA and NOBUFUMI ONO
`
`Department of Pharmacology, School of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
`
`Received October 3, 1974; Final Version March 14, 1975
`
`Abstract. Different groups of mice were injected 5.c. daily
`with lithium chloride in three doses (0.52, 1.58 and 4.72rneqfkg)
`or with saline for a period of 3 weeks. Lithium administered
`acutely or chronically did not affect spontaneous locomotor
`activities. However, methamphetamine-induced hype1'-lD_co-
`motor activities were inhibited in the lithium groups as com-
`pared with those in the saline group, While the hyper-l0co-
`motor activities induced by tctrabenazine in the nialamidc—
`pretreated animals were reduced to some extent but not
`significantly by lithium. Tetrabenazine brought about an
`
`initial transient increase followed by a decrease of spontaneous
`locomotor activities in the lithium groups, whereas it induced
`only a decrease of the activities in the saline group. In addition,
`jumping and vertical jumping behaviors, which were not
`observed in the saline group, occurred 30-60 min after
`tetrabenazine in the lithium groups. These effects of lithium
`tended to increase with an increase of the doses administered
`and with a prolongation of its daily administration. The
`results demonstrate that lithium modifies behavioral responses
`to methamphetamine and tctrabenazinc.
`
`Key words: Lithium — Methamphetamine — Tetrabenaziue — Behavior — lutcraction.
`
`
`Although it has been proposed that lithium salts have
`valuable therapeutic and prophylactic effects in manic-
`depressive psychosis, their mode of action in affective
`illness remains obscure and knowledge about their
`pharmacological action is far from complete. The
`need to clarify behavioral eflicets oflithium has, during
`the past few years, stimulated considerable research
`using infrah uman animal subjects, which has produced
`certain consistent results. It has been reported that
`after repeated administrations of lithium no sedation
`was observed in mice (Carroll and Sharp, 19? 1), nor
`reduction of spontaneous motor activity in rats (Perez-
`Cruet et ai‘., l9?'1). Lithium reduced rearing frequency
`in rats, while there was no discernible effect upon
`horizontal locomotor activity (Johnson, 1972). Rats
`administered lithium were less active than those
`
`treated with saline (Syme and Syme, 1973), and
`lithium decreased the voluntary activity of rats without
`affecting their reactivity or muscle strength (Smith
`and Smith, 1973). No alteration in the rate of self-
`stirnulatory behavior was found (Ramsey et ai'., 1972).
`Lithium had an antagonistic eiiect on motor hyper-
`activity induced by the combined use of desmethyl—
`imiprarnine and benzoquinolizine (R0. 4-1284) (Ma-
`tussek and Linsmayer, 1968) and that elicited with
`
`combined use of dexamethasone and chlordiazcpoxide
`(Cox erai, 197])
`in rats. In mice,
`the behavioral
`activation caused by morphine was antagonized by
`lithium (Carroll and Sharp, 19Tr'1).
`Paralleling such studies have been suggestions
`about neurochcmical mechanisms underlying the affec-
`tive disorders. The catecholamine hypothesis proposes
`that some, if not all, depressions are associated with
`an absolute or relative decrease in catecholainines
`
`available at central adrencrgic receptors sites, while
`elation, conversely, may be associated with an excess
`of such amines (Shildkaut, 1965). Associated with this
`hypothesis has been the proposal
`that actions of
`lithium on brain rnonoatnine metabolism may be
`the mechanism by which it produces its effects (Kopin,
`1969).
`The aim of the present investigation was to study
`effects of lithium on behavioral responses induced
`by methamphetamine and tetrabenazine, which are
`alleged to act on metabolism of endogenous brain
`catecholarnincs.
`
`Materiofs and Methods
`
`The 240 animals serving as subjects in the experiment were
`healthy ddY male albino mice obtained from Kuroda Animal
`
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`244
`
`Psychopharmacologia (Berl.), Voi. 42, Fasc. 3 {19’i‘5)
`
`
`
`.3»?
`
`4‘/’
`-4"
`
`?
`
`BT23?
`
`DII]NEIII
`:-stI
`:-
`
`E
`o
`-1
`m
`LL
`
`062
`
`-Fig.1. Acute effects of lithium on spontaneous locomotor
`activity. —-— saline (N: 10};
`----- --
`lithium chloride
`22 rngfkg (0.52 meqjkg} (N = 10); —v ——— lithium chloride
`6'! mglkg (1.58 meqlkg) (N = 10); ----- -- lithium chloride
`200 mgfkg (432 mcqlkg) (N: 10)
`
`follow. All statistical tests of differences between experimental
`treatments were carried out using Student’s t test (P < 0.05).
`
`Results
`
`1. Eficcts of Lithium
`
`on Spontaneous Locomotor Activity
`
`Spontaneous locomotor activity, arnbulation, was
`measured at several
`time intervals after a single
`administration of lithium or saline. As Fig.1 shows,
`all treatments were followed by decreases in ambula-
`tion which were maximal at 3 hrs and lasted for more
`
`than 6 hrs. Decreases following administration of the
`various doses of lithium were not significantly dilferent
`from those of the saline group.
`During chronic treatment, i.e., daily administra-
`tions of lithium or saline for 3 weeks, body weight
`increased similarly in the lithium-treated animals and
`saline—trcated animals. Ambulation was measured at
`
`23.5 hrs after the 1st, 7th, 14th and 21st administra-
`tions of lithium or saline. Results of these tests are
`
`reported in Table 1. Again, no significant differences
`in ambulation were observed when the measures for
`
`the various treatments were compared.
`
`2. Effects of‘ Lithium on Methamphetamine-Induced
`Hyper-Locomotor Activity
`
`As shown in Fig.2, methamphetamine, 5 mg/kg, in-
`jected 1 hr after the 1st, 7th, 14th and 21st daily ad-
`ministrations of lithium or saline induced increases in
`ambulation which were maximal 30 min later and lasted
`
`over 3h1's. The methamphetamine-induced increases
`were significantly less in the lithium than in the saline
`groups. This effect tended to be more pronounced
`as the dose of lithium and the period of its daily
`administration increased.
`
`When methamphetamine was used at dose levels
`of 2 mgfkg similar results were obtained.
`
`Laboratory {I<umamoto, Japan). They were caged in groups
`of 10 For a week before as well as throughout the experiment,
`and were always placed with their cagemates after injection
`or between behavioral test trials. The body weights of mice
`were l5—l7 g at arrival and 18—2l g at the beginning of
`lithium injection. The food consisted of MF, Oriental Yeast
`Ltd. The animals were permitted food and water ad iibimm
`except during drug trials. All
`trials and brecdings were
`carried out at an environmental temperature 24 :'
`1 “C and
`moisture 50 1 l(}%.
`The mice were divided randomly into 4 groups of
`10 animals. Each received a daily injection of saline as
`control, or of lithium chloride in doses of 22 mglkg
`{U.52 meqfkg), 67 mgfkg (1.58 meqfkg), or 200 mgfkg}
`(4.72 meqlkg). They were given one subcutaneous injection
`each day for 21 days, administrations being between 9:40 AM
`and 10:20 AM. Difl'erer1t groups were used for each item of
`the experiment. Number of mice used for each experiment
`are shown in the explanatory description for each Table and
`Figure.
`Three measures of behavior were recorded. The first
`used the test situation in which to observe spontaneous motor
`activity. The open-field chamber was 60 cm in diameter and
`50 cm in height; the floor was divided into 19 blocks. A mouse
`was placed on the center of the floor and observed for 1 min.
`Two preliminary training trials were given at 30 min intervals
`in order to establish a relatively stable baseline prior to the
`test trials, which began 30 min later. The short period for
`each test trial was chosen so as to measure drug effects at
`short time intervals after administration. Locomotor activity,
`ambulation, was expressed in terms of the number of blocks
`traversed during 1 min.
`The observation of the second measure of behavior
`employed what has been referred to as a “passive avoidance"
`situation. Each mouse was placed at the center of an octago-
`nal platform made with non—transparcnt plastic, 35 cm high
`and 32cm in diameter. Whether or not it jumped off the
`platform during 1-min period was recorded. This observation
`was repeated three times at an interval of 10 min. Thejumping
`response was then calculated in terms of the percentage of
`animals in each group which jumped during the 3 trials.
`Preliminary observations had suggested a third be-
`havioral measure, vertical jumping. Each mouse was placed
`at the center of the floor of a cylinder-shaped open chamber
`constructed of transparent plastic, 7 cm in height and 20 cm
`in diameter. The behavior observed during each 1 min trial
`was whether or not a subject jumped vertically in such a way
`as to reach 1'' cm or more above the floor of the chamber.
`This observation was repeated three times at the intervals
`of 10 min. The vertical jumping response was then expressed
`in terms of the percentage of animals in each group which
`jumped vertically during the 3 trials.
`The drugs used were lithium chloride (Kishida Chemical),
`methamphetamine hydrochloride (Dainippon Pharmaceuti-
`cal} tetrabcnazine hydrochloride (F. Hollman-La Roche) and
`nialamide hydrochloride [Pfizer-Taito). Lithium chloride
`was dissolved as 1.12, 3.35 and 10% solution with distilled
`water, sterilized, and administered subcutaneously within a
`volume of 0.1 mllanimal, using 0.25 ml syringe. The other
`drugs were also dissolved with distilled water and injected
`subcutaneously within the volume of 0.1 mlf10 g. Meth-
`amphetamine, 5 mgfkg, was administered 1 hr and tetra-
`benazine, 5 mgfkg, 2 hrs after lithium.
`In the nialamide
`pretreated animals, nialamidc was injected,
`in a dose of
`10 mgfkg, 24 hrs before tctrabenazine.
`The various behaviors were measured at intervals after
`injections which are indicated in the figures and tables which
`
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`

`
`T. Furukawa er a!.: Lithium on Methamphetamine and Tetrabenazine
`
`245
`
`Table 1. Effects of lithium administered daily on spontaneous locomotor activity. All values Show the me£_Ln_ number of lnlocks
`traversed i standard errors in 10 mice. The activity was measured 23.5 hrs after 1st, 7th, 14th and 21st ll'l_]CCU{)l'lS of lithium
`or saline
`
`
`
`Control
`
`1st
`
`7th
`
`14th
`
`21st
`
`Saline
`LiCl
`
`34.0 _-l: 5.2
`29.0 i 4.3
`29.2 3; 4.2
`28.5 i 4.9
`28.3 i 3.4
`33.1 i 3.5
`32.6 i 4.0
`35.1 -L 3.2
`23.4 i 3.3
`29.5 i 3.5
`22 mgfkg
`67 mgfkg
`23.3 i 3.2
`25.0 i 3.7
`27.1 -_- 4.7
`31.8 'l_~ 5.9
`24.5 i 4.3
`
`200 mgfkg
`24.5 i 2.5
`24.5 i 1.9
`26.2 i 5.3
`23.4 i 4.2
`30.0 i 5.7
`
`Lici Isi
`
`Lici
`
`I41h
`
`A
`METHAMPHETAMINE
`
`.20
`
`
`
`C
`METHAMPHETAMINE
`
`n
`K
`3 90
`i 3E D:
`16 I‘-
`«= sn: o
`
`E 6
`2 ‘.5
`CiZ
`
`
`
`0
`
`I5
`
`so
`
`so
`
`I20
`TIME [MINUTES]
`
`I30
`
`0
`
`I5
`
`350-
`
`'50
`
`T55
`TIME (MINUTES)
`
`Téfi
`
`LICI Tfh
`
`Licl 2Ist
`
`B
`
`:20
`
`D
`METHAMPHETAMINE
`
`g ,1
`F
`
`9°
`
`D 3
`
`E
`
`'5 I-
`-1; 8 60
`'1 3
`:3 m
`2 '5
`g 30
`
`
`
`
`iéfi
`TlMEiMINUTES‘l
`
`60
`
`I 20
`TIME (MINUTE 51
`
`I30
`
`lil‘l'cets of lithium administered daily on the methamphetamine-induced l1yper—locomotor activity. A parinel shows
`Fig. 2A — D.
`1st administration of lithium, B pannel 7th, C pantie] 14th and D pannel 21st. Methamphetamine, 5 mglkg, was administered
`subcutaneously 1 hr after lithium. Each point shows mean value i S.E.M. * Mark denotes a significant change from saline
`r
`control according to I test (P < 0.05). O ———O saline (N: 10);
`I-——--O lithium chloride 2.2rng,»'kg (0.52 mcqfltg) (N: 10)"
`A—— -A lithium chloride 67 mgfltg (1.58 mcqfkg) N = 10}; 1-----A lithium chloride 200 mgfkg (4.72 meqfkg] {N = 10)
`
`3. Effects of Lithium
`
`on the Hyper-Locomotor Response
`to Tctrabenazine Administered after Nialamide
`
`in the lithium group, but dilferences between the
`lithium and saline groups were not statistically sig-
`nificant.
`
`5 mg/kg, administered 24 hrs after
`Tetrabcnazine,
`pretreatment with nialamide and 1 hr after the 1st,
`7th, 14th and 21st daily administrations of lithium or
`saline brought about similar hyper-locomotor activi-
`ties which were maximal 30 min later and lasted for
`Zhrs. Fig.3 summarizes the results. The maximal
`response to tetrabcnazine was reduced to some extent
`
`4. Efiects of Lithium
`
`on Behavioral Responses to Tetrabenazine
`
`In the saline groups, tetrabenazinc injected 1 hr after
`the 1st, 7th, 14th and 21st administrations of lithium
`or saline induced monotonic decreases in ambulation
`lasting for more than 3 hrs. It also elicited dcc1'eases
`
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`

`
`246
`
`
`MOTOR
`
`ACTIVITYNO.OFBLOCKTRAVERSED
`
`so |-iC|
`
`'4'“
`
`mm_iM,DE
`TETRABENRZINE
`
`CI0
`
`Llll
`
`42°
`
`
`0
`3°
`6°
`90
`I20
`‘
`‘
`‘
`‘
`T'“‘E‘"'_""”E9’
`_
`Fig.3. E[Tects of lithium administered daily on the hyper—
`loeomotor response to tetrabenazine administered after nial-
`.
`.
`.
`.
`.
`amide. Tetraberiazinc, 5 mgfkg, was administered subculane-
`ously 2 hrs after 14th injections of lithium, and nialamide
`(10 mgfkg) 24 hrs before tetrabeiiazine. Further explanations
`and number of mice used as Fig. 2
`
`Psyehopharmaeologia (Berl.), Vol. 42, Fase. 3 (1975)
`
`in an(i1b:1il:tion in the lithium groups, but this_was
`prece e
`ytemporaryinereases which were maximal
`at about 5 min and disappeared within 10 min after
`the injection. Recovery from the tcti'abenazine—induced
`decrement
`in ambulation tended to be more rapid
`with higher doses and with prolonged administration
`of lithium. Fig. 4 summarizes the results.
`The jumping (passive avoidance) and vertical
`jumping behaviors occurred in the lithium groups
`during the 30-60 min after injection of letrabenazine
`despite their depressed locomotor activity. These
`behaviors were not observed in the Saline group
`-
`-
`Jurn
`b h
`'
`ping e avlor was observed even at the Smaller
`doses of ]ithium= but Vertical jumping behavior was
`53311 Only 31 the 137331" 51035 ]eV3]5- Th’-353 TCSUIIS are
`summarized in Table 2.
`
` C
` A
`
`TETRBEIUI ZINE
`
`TETRIIBENAZLNE
`
`
`
`TlIlE'.’MlNU‘|'E5l
`
`mo
`
`_
`‘
`_
`_
`''°’" 60*’
`TIMEININUTESJ
`
`U0‘ 71h
`
`Lil:l 2151
`
`-to
`
`Q}-
`E E
`*1 I
`5 5'5
`5 §
`'5 E3 o
`
`eZ
`
`3
`Q
`3" §‘‘ -1
`g E-It 5
`E
`
`30
`
`_
`
`B
`TETRABENAZINE
`
`‘
`I
`v
`?
`
`0
`_,‘\
`I
`
`D
`TETRABENIZINE
`
`if2 o0Z
`
`TIME CMNLITES}
`
`1'||uE{|u|u;_|'|'Es)
`
`Fig. 4A —D. Eiieets of lithium administered daily on the tetrabeiianinednduced hyper—locornotor activity. Tetrabenazinc, 5 mgfkg,
`was administered subcutaneously 2 hrs after lithium. Further explanations and number of mice used as Fig. 2
`
`Table 2. Jumping and vertical jumping behaviors observed after tetrabenazine. Each value show the number of mouse in
`which the behavior can be positively observed among 10 mice. Tetrabenazine, 5 mgfkg, was administered subcutaneously
`2 hrs after 1st, 7th, 14th and 21st administrations of lithium or saline, and the behaviors were observed 1 hr after tetrabenazirie
`
`Behavior
`
`1st
`
`7th
`
`14th
`
`2131
`
`
`Jump.
`v. Jump.
`Jump.
`v. Jump.
`Jump.
`v. Jump.
`Jump.
`v. Jump.
`
`Saline
`LiCl
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`3
`0
`3
`0
`4
`‘I
`5
`22 mgfkg
`1
`2
`1
`2
`0
`2
`0
`2
`67 mgfkg
`
`200 rngfkg 4 7 0 5 4 8 2 5
`
`
`
`
`
`
`
`
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`
`T. Furukawa er ai'.: Lithium on Methamphetamine and Tetrabenazine
`
`247
`
`Discussion
`
`As the safety margin in dosage of lithium has been
`thought to be narrow, if administration of lithium
`becomes toxic, its observed elfects on behavior may
`be due to its non-specific rather than specific action.
`Two observations suggest that such toxicity was not
`involved in the present experiment. Firstly, body
`weight, determined throughout the experiment was
`not significantly different for saline and lithium groups.
`Secondly, lithium administered acutely or chronically
`in the dosages given, did not, in fact, affect spontaneous
`locomotor activity. It appears reasonable, therefore,
`to interpret behavioral effects observed in the present
`investigation in terms of specific actions and inter-
`actions of lithium.
`
`As regards the interaction of lithium with amphet-
`amine, related closely to methamphetamine in chemi-
`cal structure and pharmacological actions, Lal and
`Sourkes (19Tr'2) reported that lithium did not afiect
`amphetamine-induced stereotyped behavior,
`and
`Matussed and Linsmayer (1968) that lithium treat-
`ment of the rats for several days could not prevent
`an amphetamine excitation but prolonged the amphet-
`amine—indttced stereotyped behavior. In the present
`study, administration of lithium inhibited the meth-
`amphetamine—induced hyper-locomotor activity in
`mice in a relatively dose-dependent manner. It has
`been reported that
`lithium and amphetamine have
`opposite effects on the threshold of intracranial rein-
`forcement, lithium raising and amphetamine lowering
`the threshold (Cassens and Mills, 1973). Opposing
`actions may contribute to the counteractive effect of
`lithium on methamphetamine.
`From the viewpoint of brain amine metabolism,
`amphetamine releases amines, reduces amine uptake,
`and inhibits monoamine oxidase activity in large
`doses (Farnebo, 1971 ; Glowinski and Axclrod, 1965;
`Rutledge, 1970; Svensson, 1991) thereby increasing
`the availability of amines to receptor sites and in-
`ducing central excitalion. On the other hand, lithium:
`induces a depletion of brain amines when given to-
`gether with a tyrosine or a tryptoph-an hydroxylase
`inhibitor (C01'1'0dl£t‘(tt’., 1967, 1969); inhibits mono-
`amines release (Katz er at, 1968; Bindler er aI., 1971);
`acts to increase amines uptake (Colburn es mi, 1967;
`Korniskcy and Buckner, 1974); activates brain mono-
`amine oxidase activity (Kiseleva, 1972); and, alters
`amines eatabolism toward deamination (schildkraut
`er ai., 1969; Schanberg er ai'., 1967), thereby decreasing
`availability of amines to receptor sites. ln addition,
`lithium probably blocks brain receptors for amines
`since lithium inhibits brain adenyl cyclase activation
`(Forn and Valdecasas, 1971) and cyclic-AMP content
`increase (Berndt, 1973) stimulated by amines. There-
`
`lithium and methamphetamine are thought to
`fore,
`cause opposite changes in brain amines metabolism.
`in fact, it was proposed that
`lithium inhibited the
`methamphetamine-induced changes
`in brain nor-
`epinephrine metabolism (Nozu eral, 1973). Thus,
`the biochemical effects on amines metabolism ofier
`
`a plausible explanation for the antagonistic eltect of
`lithium on methamphetamine. However. although
`reserpine or tetrabenazine administered after mono-
`amine oxidase inhibitor was proposed to clicite
`hyperactivity because more endogenous amines were
`released as active form by inhibition of the enzyme
`activity, lithium reduced but did not affect significantly
`this hyperactivity.
`As concerns the interaction between lithium and
`
`tctrabenazine, it was reported that the tetrabena2ine-
`induced behavioral inhibition tended to be diminished
`in smaller doses of lithium whereas the inhibition
`
`tended to be potentiated in larger doses of lithium
`(Perkinson at at, 1969). In the present study, lithium
`affected behavioral responses to tetrabenazine in a
`complicated manner: after tetrabenazine in the lithium-
`trcated mice, an initial transient hyperactivity occured,
`duration of inhibitory effect was shortened in some
`degree, and jumping and vertical jumping behavior
`appeared.
`From the viewpoints of brain amine metabolism,
`reserpine, related closely to tetrabenazine, depletes
`amines, activates monoamine oxidase activity, releases
`amines as inactivated form, and inhibits amines uptake
`(Izumi et at,
`196.9‘,
`lversen, 1967; Glowinski and
`Axelrod, 1965),
`thereby causing less active amines
`available to the receptor sites and central sedation.
`Segawa and Nakano (1974) have reported that lithium
`lessens the depletion rate of brain 5-HT by reserpine,
`and have proposed that lithium decreases the release
`of 5-HT by changing the properties of synaptic
`vesicular membrane and interfering with the releasing
`mechanism of reserpine at synaptic vesicles. Although
`it can be presutned that this counteractive effect of
`lithium on the rauwolfia alkaloid-induced depletion
`rate of brain amines may be involved in the behavioral
`interaction of lithium with tetrabenazine, there are
`still difficultics in elucidating the complicated be-
`havioral interaction of both drugs.
`As the removal of morphine or administration
`of morphine antagonist
`in rats or mice physically
`dependent upon morphine cause a withdrawal syn-
`drome charaeterized by an uncontrollable urge to
`jump (Way .9: at, 1969; Francis and Schneider, 1971 ;
`Saelcns er a!., 1971), the jumping behavior has been
`thought
`to be specially related to morphine with-
`drawal syndrome. However, it is thus demonstrated
`that this behavior is not always related to morphine
`withdrawal
`syndrome since the behavior can be
`
`5of6
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`
`

`
`248
`
`observed after sodium 5-(1,3-dimethylbutyl)-5-ethyl
`barbiturate (Koppanyietaf., 1970) or at-naphthyl—
`oxyaeetic acid (Weissrnan, 1973), and after combined
`use of lithium and tctrabenazine, as in the present
`experiments.
`
`References
`
`Bemdt, S. F.: Effects of lithium on cyclic 3’,5'-AMP metab-
`olism in rat brain. Naunyn-Schmiedcbergs Arch. Phar-
`macol. 277, R4 (1973)
`Bindler, E. H., Wallacl1,M. B., Ger5hon,S.: Effect of lithium
`on the release of “C-norepinephrine by nerve stimulation
`from the perfused cat spleen. Arch.
`int. Pharmacodyn.
`190, 150——l54 (1971)
`Carroll, B. J., Sharp, P. T.: Rubidium and lithium: Opposite
`effect on amine-mediated excitement. Science 172, 1355-
`13570971)
`Casscns, G. P., Mills, A. W.: Lithium and amphetamine:
`Opposite effects on threshold of intracranial reinforce-
`ment. Psyebopharmacologia (Berl.) 30, 283-290 (1973)
`Colburn, R. W., Goodwin, F‘. K ., Bunney, W. E., Davis, J. M. :
`Effect of lithium on the uptake of’ noradrenaline by
`synaptosomes. Nature (Lond.) 215, 1395- 1397 (1967)
`Corrodi, H., Fuxe, K., Hokfelt,T., Schou, M.: The effect
`of lithium on cerebral monoamine neurons. Psycl1ophar-
`macologia (Bert) I1, 345 — 353 ( I967)
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`
`_
`
`Dr.T. Furukawa, Department of Pharmacology, School of Medicine
`Fttkuoka University, Fukuoka , Japan
`
`6of6
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`Alkermes, Ex. 1036
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`6 of 6
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`Alkermes, Ex. 1036