PSYCHOTROPIC DRUGS, BEHAVIOUR AND
~IEDIATORY
PROCESSES
Regulation of gamma-aminobutyrie aeid metabolism in different brain stractures by cholinergie and adrenergic droga A. I. BALAKLEEVSKY, N. P. BOBROVA and N. V. SHEVTCHENKO JfMil:aJ
I~.
Unitm'sily of Miru•
Recently the coneept of a close fnnctional interactioDJI between different neurotransmitter systems in the hrain hae found increasing support [1-4], especially in baeal ganglia (BG), which bave high levels of gamma aminobutyric acid (GABA), dopamine (DA) and rapid metabolism of acetyl• choline (ACh) [2,4,5]. Various studies indicate that direct an4 indirect DA-receptor stimulants exert an inhibitory inS.uence on the metabolism and functional activity of cholinergic neuroDIJ in BG [4,6,7]. On the other band, other studiea bave showed that cholinergic droga are able to influence the function of DA-neuron& [8, 9]. However, the information about the role of GABA-ergic system in neurotransmitter interactions is still rather scanty [10, 11]. Therefore we studied the functional state of GABA system in BG and other brain structures after injection& of some dopaminergic and cholinergic drngs in order to provide new information on functional interactions between DA-, ACh-, and GABA-systeme.
MATERIALS AND
~ETHODS
W e studied the main parameton that regulate the level of GABA and glutamate {12, 13], the activity of glutamic acid decarboxylase (GAD, 14) and GABA-aminotransferase (GABA-T, 15). The GABA mitabolism wae studied in whole mouse brain and in some structureA of rat brain as BG, cerebral cortex, brain stem and cerebellum.. The dntgs were injected intra.. peritonea.Uy (i. p.) or in the lateral ventricle of rat hrain (i. c. v.) at dosell influencing the activity of DA- and ACh- !Jystems and altering motor activity• .bft. lot. Svper. SftftiU (19"18) l&, 133-la&
134
TRANSMITTER~
IN
TliE
A.CTION
0}"
P!IYCHOTHOPIC
DRUG~
RESULTS
Preliminary experiments demonstrated that injections of GABA i. p. (in large doses) or i. e. -.;, stimolate GABA-'1' in most hrain structures and inhibit GAD in BG. Therefore, it was suggested that the activation of GABA-ergic receptors secondary to an increast"d release of GABA in tht• synaptic cleft may induce a compensatory l!timulation of GABA-T located postsynaptically. Another index of an increase of GABA-ergic activity Ì!< a rapid decrease of GABA level a:< a result of it:< incrtlased release and utilizatiou. The centrai muscarinic drug, oxotremorine (0.5 mg/kg, i. p.) cause~ an increasc of GABA metabolism in BG (Table l) and brain stem. This i~ manifested in decreased GABA level and GAD activity (in BG) 15 min after injection and also in continuous activation of GABA-T. Tbese altera· tions provide evidence for an increased release (and metabolism) of GABA from presynaptic sites. There were no significant modifications in other areas. Another muscarinic drug, arecoline (10 mg/kg, i. p.) causes rapid depletiou of GABA in rat BG and brain stem. There is also depletion of GABA in mouse brain (Fig. 1). In the other band, the muscarinic antagonist amizyk (benactyzine) (lO mg/kg, i. p.) causes an increase of GABA levels. Combina· tion of amizyle (30 min) and arecoline (15 min) abolishes their oppositc
TABLE l
The infiuenct"- of oxotremorine (0.5 m.g/kg i. p.) on the GABA system in the basal ganglia of rat brain (n = 6) l.>
Contro\
nnn
9U
n•in
l
GABA, mg'\,
X-!:: /X p
lll!l" ~·~
x=p l x
GAD, IJ.M GABA/p; of tissu~
x±_ l x
GABA-T, f.i.M glutamatefg oftissue
X± /X
GlutamatO,:;
72.9 '
-1-
0.6
o:ooi
19.5 ::r- 0.6
+
34.2
::!::
1.6
17.8 ± l.l
20.3
31.5
±
1.1
39.6 :f- 2.9 < 0.05
46.9 2.1 " 0.001
< 0.05
31.3.:: 2.(>
± 1.0
22.4
p
p
i
27.0
') o.s
"'o.oc. ~:
2.5
> 0.05
BAL\&Lt:EV!EY, BOBBOVA, !BEVTCIIENEO
Amlzyle {10mg,kg)
Arecollne (10mgkg)
30min
15mln
' Amizyle
arecollne
", ·'· 20
•
•
·'· 10
•
Q Fig. l. -
GASA
fa
• glutama\8
i3
GABA T
CJ
GAO
lf p
.o.os
lnftuenee of amizyle {bell8ctyzine) (10 mg/kg), lll"eooline (lO mgjkg) and iu simultaneOUll admiuistration on the GABA system in monse brain expreeed as% of control velues.
in8uence on G-ABA level& and metabolism. The inhibitor of ACh syntheais, hemicholinium-3, elearly in8uencea G-ABA metaboli&m in BG and whole brain since it increases GABA levels and reduces GABA metabolism already 5 min (6 !J-gfkg, i. c, v.) after administration. Powerful DA-ergic stimulants such as apomorphine (10 mgjkg, i. p.), L-DOPA (100 mgfkg, i. p.), fusaric acid (75 mgfkg, i. p., twice in 6 houn), or blockers such as haloperidol (2 mgfkg, i. p.), 6-hydroxydopam.ine (250 l.tgjkg, i. c. v. in 2 weeb), do not possess any signi&cant inftuence on GABA system in BG and other brain structures. However, the neuroleptic clozapine (2-5 mgfkg, i. p.) causes an increase of GABA level and inhibition of GABA-T in rat BG, brain stem, cerebral cortex (Fig. 2) and in mouse brain. Its action appears to be similar to tbat of the inhibitor of GABA-T, aminooxyacetie acid. In vicro clozapine also decreases the activities of GABA-T and GAD. Nonetheless clozapine increases the rate of disappearance from brain (me~ tabolism) of 14 C-GABA injected i. c. v. A postulated DA-receptor agonist as CB-154. (5 mgjkg, i. p.) inc:reases tbe GABA level and GAD activity in BG and cerebral cortex but not in other structu:res ofrat brain. Amantadine (lO mgfkg, i, p.) causes a marked decrease of ali parameten of GABA system. It, evidently, inhibits the functional activity of GABA system. .lnto. Iol. su,...-. S0111iU (111781 1., !:!3-138
136
TBANSHITTERS
IN
THE
ACTION
OF
PSYCHOTROPIC
DRUGS
Cerebrat cofle'
Q
GABA
E)
glutarnBte
m
GABA T
m
it
aAo
Fig. 2. -ln8.uenu of clozapine (5 mg/kg) on the GABA
~y&tem
p
005
in 110me atructures of rat
bndn (" % of controllevel). DISCUSSION
These data seem to indicate tbat m.uscarinic drugs (oxotremorine, arecoline) activate the metaholism and probahly the functional activity of GABA system in BG. On the other hand, hem.icholinium-3 and the muscarinic antagonist amizyle has an opposite induenee on GABA system. The last one removes the aetion of muL'Icarinic drugs. Some DA-ergic drugs which activate (L-DOPA, apomorphine, fusaric acid) or inhihit (haloperidol, 6-hydroxydopam.ine) DA transmission do not show a great infiuence on the G-ABA metabolism in whole brain and in brain regions. However, the activation of DA structures by amantadine decreases the release and metabolism of GABA. On the other band, the DA receptor antagonist clozapine increases GABA levels and GABA release. Consequently, stimulation of DA structures often (but not always) causes inhibition of GABA etructures, Ali the&e data together with earlier data of our laboratory (2, 3] and of the literature [1,4,11,16] allow to propose the following scbeme of neurotransmitter interactions in the BG. DA neurons localized in suhstantia nigra bave an inhibitory inftuence on cholinergic neurons in corpus striatum which through ~uscarinic receptors bave an activating inBuence on striata! GABA neurone; in turn, GABA neurons from corpus striatum can influenee the activity of DA neurons in suhstantia nigra both directly or indirecdy through intrinsic eholinergie neurons. .Aru•. 111.
Sllp~.
SmoUà (1978) lol, 133-138
BALAJU.EEVSKY, BO.BROVA, SUVTCHENKO
131
Sununary. - The influence of cholinergic and dopaminergic drugs has been studied on the metabolism of GABA by measuring the levels of GABA and glutamate and the activity of glutamic acid decarboxylase and GABAaminotransferase in mouse and rat brain and in some rat brain regions. Muscarinic agonista (oxotremorine, arecoline) induce a rapid decrease of GABA level and an increase of ite destruction, indicative of an inereased activity of GABA synapses in basal ganglia and brain stem. Minor changes in GABA metabolism are observed in cerebral cortex and cerebellum. On the other band, hemicholinium-3 and the muscarinic antagonist amizyle reduce the activity of GABA structures. Ami:zyle also abolishes the inftuence of mnacarinic druge on GABA nìetabolism. Most dopaminergic drug11 (apomorphine, L-DOPA, CB-154, fusaric acid, 6-hydroxydop8Dline, haloperidol) fail to influence GABA metabolism in whole brain and in basal ganglia. However, amantadine decreal'les GABA metabolism and clozapine inhibitll ita destruction and increases its level (like aminooxyacetic acid). These data indicate that cholinergic neurons bave a stimulant influence on the functional activity of GABA neurons.
REFERENCES Disinhibition as an orgauiaing princìplc in tbe ncrvou11 ~ystcm. Tbc rolc of tbc GABA sy&tcm. Application to neurologic psychlatric diaordcn. In: GABA in Nm.>0us SysUm Funaion. E. Robertt, T. N. Cbaec, D. B. Tower (Edt.) Raveo Pre.s, New York, pp. 515--539.
l. RoBBRTS, E. 1916.
2. BA.LAKLEBVSKY, A. I. U72. About neurohormonal etructure of brain basa! ganglia and regulation ofthcir activity. In: The Brain M«. E. & FR-1.'\~l.L, S.19:-,u. GAB.-\ in hrain: i t" f(,rnmtion from glutanwt