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`Life Sciences, Vol. Al, pp. 605-610
`Printed in the U.S.A.
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`Pergamon Journals
`
`3'—5‘ CYCLlC—GUANOSINE MONOPHOSPHATE INCREASE IN RAT BRAIN HIPPDCAMPUS AFTER
`GAMMA—HYDROXYEUTYRATE ADMINISTRATION. PREVENTION BY VALPROATE AND NALOXONE.
`
`Philippe Vayer, Serge Gobaille, Paul Mandel and Michel Maitre
`
`Centre de Neurochimie du CNRS and INSERM U44, 5 rue Blaise Pascal,
`67084 STRASBOURG Cedex.
`
`(Received in final form May 21, 1987)
`Summary
`
`(CGMP) was observed in the
`increase (123%) of cyclic GMP
`An
`hippocampus
`of
`the rat killed by microwave
`irradiation 45 min
`after administration of 500 mg/kg y—hydroxybutyrate (GHB) IP. This
`increase is time and dose
`dependent.
`No modification in cyclic
`nucleotide content was observed
`in striatum and in cerebellum.
`As
`the role of GHB has been implicated in neurotransmission,
`the fact
`that this compound increases cyclic GMP accumulation in hippocampus
`in vivo may represent a mechanism by which the actions of GHB are
`mediated at
`the cellular level. Valproate (400 mg/kg) or naloxone
`(10 mg/kg) pretreatment completely abolish the cGMP
`increase due
`to GHB.
`A GABAergic and/or opiate phenomenon may be involved
`in
`the mechanism of GHB induced increase of CGMP.
`
`(CAMP) or
`An increase of adenosine 3'—5' cyclic—adenosine—monophosphate
`of 3‘—5‘ cyclic—guanosine—monophosphate (cGMP) or both have been observed after
`administration of several convulsant drugs and agents in experimental animals
`(1,2). Moreover,
`agents that
`lead to behavioral excitation tend to increase
`CGMP levels whereas those that depress motor activity decrease its levels (2).
`Interestingly,
`y—hydroxybutyrate (GHB) which occurs naturally in the brains of
`several mammalian species (3)
`including man (4),
`induces when administered to
`animals a state of behavioral sedation often called sleep or anaesthesia (5).
`In addition,
`GHB
`induces
`hypersynchronism in
`the electroencephalographic
`pattern in rat,
`rabbit and man (6,7,8).
`These effects have been described as
`epileptoid E.E.G.
`seizures which can be antagonized by anti-petit mal drugs.
`Besides these effects,
`GHB is a good candidate for a role in neurotransmission
`or neuromodulation (9). The cyclic nucleotides,
`involved in the cellular action
`of numerous neurotransmitters,
`can also mediate the neuroregulatory effects of
`GHB in mammalian brain.
`The aim of this paper is to investigate the effect of
`exogenous GHB on the level of cyclic nucleotides in three regions of
`the rat
`brain :
`hippocampus, which is considered as the burst generator for several
`acute epilepsy models (10,11),
`cerebellum, where cyclic nucleotides have been
`extensively studied (12,13,14),
`and striatum where GHB
`interacts with the
`dopaminergic system (8-15).
`
`Materials and Methods
`
`The
`Male adult Wistar rats weighing about 300 g were used in all studies.
`test
`animals were
`injected IP with GHB (sodium salt) and/or with the other
`substances
`(sodium valproate,
`or naloxone hydrochloride).
`The
`rats were
`sacrified after appropriate times by exposing the head to focused microwave
`irradiation (7.5 kW,
`1.6 sec.
`exposure) which prevents post—mortem changes in
`cyclic nucleotide levels (16).
`The dissected brain regions were kept
`in liquid
`0024-3205/87 $3.00 + .00
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`l987 Pergamon Journals Ltd.
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`Copyright
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`Page 3 of 8
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`

`
`"—”’3’
`
`._;
`
`The
`25 min.
`removed by centrifugation at 20,000 g for
`Protein was
`acid.
`supernatants were neutralized with 3M K 00
`and cyclic nucleotide contents were
`determined with
`the
`cAMP kit
`and %h
`CGMP R.I.A.
`kit
`from Amersham
`(Radiochemical Center). Protein contents of the different pellets were measured
`by the Lowry method (17) after solubilization in ZN Na0H.
`Results
`
`
`Cyclic nucleotides as a function of time after GHB administration
`
`Cyclic nucleotide levels were measured every 10 min during 120 min after
`injection at
`time zero of 500 mg/kg GHB.
`No significant changes were found for
`CGMP and CAMP in the cerebellum or in the striatum.
`(CGMP:
`cerebellum (3.02 1
`0.48 pmole/mg protein),
`striatum (0.25 f 0.06 pmole/mg protein);
`CAMP:
`cerebellum (6.29 i 0.53 pmole/mg protein),
`striatum (3.14 1 0.56 pmole/mg
`protein).
`In the hippocampus,
`the level of cGMP (0.28 i 0.05 pmole/mg protein)
`increases with time. The rise of cGMP was first noted 20 min after injection of
`GHB, with a maximum at 30-50 min (0.63 i 0.04 pmole/mg protein). After 110 min,
`the basal level of cGMP is restored (Fig.
`1). For CAMP, no significant changes
`were found (3.57 i 0.96 pmole/mg protein).
`
`Effect of various concentrations of GHB on CGMP levels in hippocampus
`
`200 mg/kg to 700 mg/kg GHB were administered IP to rats which were killed
`after 45 min by microwave irradiation.
`CGMP
`levels were determined
`in the
`dissected hippocampus.
`Fig.
`2 shows that
`the maximum increase in CGMP occurs
`for 400 — 500 mg/kg. Higher doses induced less accumulation of cGMP.
`
`Effect of valproate on the CGMP increase induced by GHB in hippocampus
`
`The animals were injected either with valproate (400 mg/kg IP) or with GHB
`(400 mg/kg IP) or pretreated with valproate (400 mg/kg IP)
`15 min before GHB
`injection (400 mg/kg IP).
`In all cases,
`45 min after the last injection,
`the
`animals were killed as
`described above
`and
`CGMP was determined
`in
`the
`hippocampus.
`Fig. 3 shows that valproate does not modify cGMP content, but GHB
`increases cGMP in hippocampus by about
`140% compared to controls injected with
`saline. However, pretreatment with valproate completly abolishes the GHB effect
`on CGMP
`levels (Fig.
`3). Under
`these conditions,
`no modifications of
`cGMP
`levels are observed compared to controls injected with saline or with valproate
`alone.
`
`,
`
`)
`
`\
`
`;
`
`5
`'
`
`
`
`Effect of naloxone on the cGMP increase induced by GHB ,
`
`the same protocol as described for the experiment
`For these experiments,
`with valproate was
`adopted,
`but
`this
`latter
`compound was
`replaced by
`administration of naloxone (10 mg/kg IP).
`As
`indicated by SNEAD et al.
`(19)
`naloxone completely blocked behavioral changes
`induced by administration of
`GHB.
`In particular,
`no catalepsy was observed in animals
`receiving both
`naloxone and GHB.
`Pretreatment with naloxone blocks the GHB effect
`on CGMP
`levels (Fig. 4).
`
`Discussion
`
`This work demonstrates the increase of cGMP accumulation induced by GHB in
`rat brain hippocampus.
`The control values of CGMP are identical
`to those
`previously
`described
`for
`hippocampus
`of
`rats
`sacrificed
`by microwave
`irradiation (18). No changes were found in the other regions studied either for
`cGMP or for CAMP levels.
`GHB caused a time and dose dependent accumulation of
`
`5
`
`F
`
`Page 4 of 8
`
`Page 4 of 8
`
`

`
`Vol. 41, No. 5, 1987
`
`GHB lncreases CGMP in Rat Brain Hippocampus
`
`607
`
`protein)
`
`CGMP(pmules/mg
`
`0
`
`20
`
`40
`
`60
`
`B0
`
`100
`
`120
`
`140
`
`time (min)
`
`FIG.
`
`1
`
`time after GHB administration (500
`cG.\iP levels in hippocampus as a function of
`mg/kg IP).
`Each point
`represents the mean of
`3 different determinations i
`S.E.M.. The CGMP levels between 2.0 and 100 min are significantly different from
`the control with p < 0.05 (Student's t test).
`
`l E
`
`E
`
`E
`
`I
`——
`__
`
`E
`
`0.5
`
`V
`
`04 ,_
`
`L H
`
`‘E:E
`3
`U)E\
`-—o
`g
`g
`EE}U
`
`3 n
`
`I
`
`.02|_
`
`0
`
`L
`O
`
`L____|
`100
`E00
`
`I
`300
`
`I
`400
`
`I
`500
`
`L
`E00
`
`I
`700
`
`E00
`
`GHB (mg/kg)
`
`FIG.
`
`2
`
`Effect of various GHB doses on CGMP levels in hlppocampus. The rats were killed
`45 min after GHB
`injection IP_ Each point
`represents the mean of
`3 different
`determinations
`: S.E.M.
`The
`CGMP
`levels
`between 400
`and
`600 mg/kg
`are
`Significantly different from the control with p < 0.05 (Student's t test).
`
`Page 5 of 8
`
`Page 5 of 8
`
`

`
`I
`
`I
`
`
`
`7
`
`I
`
`O U}
`
`U U]
`
`O b
`
`o In
`
`0OLh
`
`0
`
`
`
`
`
`CGMP(pmnles/mgprotein
`
`FIG.
`
`3
`
`Effect of valproate on CGMP increase induced by GHB in hippocampus.
`Animals
`injected (A) with valproate
`0 mg/kg
`or
`(B) pretreated with
`valproate (400 mg/kg)
`15 min before
`injectio
`00 mg/kg IP) or
`(C) with
`saline or
`(D)
`injected w'
`GHB (400 mg/kg 1P).
`Each value is the mean of 6
`different determinations _
`.E.M.
`(*) p < 0.05 vs saline control (Student's t test).
`
`
`
`FIG. 4
`
`e on CGMP increase in
`Effect of nalo
`(A) with naloxone
`Animals
`injec
`naloxone (10 mg/kg) 15 mi
`fore GHB inj
`ing
`0F (D)
`'§Cted
`'
`GHB
`mg/kg IP).
`determinat
`s i .
`(*) p < 0.
`vs saline control (Student's t test).
`
`I
`
`d by GHB in hippocampus.
`'
`mg/kg IP)
`or
`(B) pretreated
`ion (400
`kg) or (c) with 5.1.’
`h value '
`the mean of 6 different
`
`Page 6 of 8
`
`Page 6 of 8
`
`

`
`Vol. 41, No. 5, 1987
`
`GHB Increases CCMT in Rat Brain Hippocampus
`
`609
`
`this effect is maximum 30-50 minutes after injection for a
`cGMP in hippocampus;
`dose of 400 mg/kg which induce a strong sedation with loss of righting reflex.
`Behavioral modification was
`accompanied by an
`EEG pattern similar
`to those
`occuring during petit mal epilepsy (8). These phenomena are consistent with the
`reported hypothesis of an involvement of hippocampus in several acute epilepsy
`models
`(10-11). Moreover,
`CGMP has been implicated in seizure genesis and/or
`propagation (1).
`Some evidence indicates that
`the CGMP synthesis preceding the
`onset of epileptoid episodes most
`likely results from massive depolarization
`elicited by excitatory firing from cholinergic and glutamatergic neurons which
`are largely represented in hippocampus.
`(20). Consistently, a modification of
`brain acetylcholine after GHB administration has been reported (8). However,
`there is no apparent correlation between the onset
`and degree of behavioral
`change with the onset
`and magnitude of
`the rise in CGMP
`in hippocampus
`in
`response
`to GHB
`treatment.
`EEG paroxysms occur within 2
`to 3 minutes of
`administration (19)
`and catalepsy with loss of
`righting reflex is
`strongly
`established a
`few minutes
`after
`IP
`administration
`of
`700 mg/kg
`GHB.
`Nevertheless,
`the fact that
`the naturally occurring substance,
`GHB,
`increases
`CGMP accumulation in rat hippocampus in vivo,
`raises the possibility that this
`response may represent a mechanism by which the actions of GHB in brain are
`mediated at the neuronal level.
`in fact, several demonstrated properties of GHB
`in brain are in favor of a neurotransmitter or a neuromodulator role for this
`substance (9).
`in this respect,
`it should be noted that hippocampus
`is the
`richest human and rat brain region with regard to density of GHB high affinity
`binding sites (21-22).
`Thus an increase of
`the CGMP
`level might
`represent a
`transduction signal for GHB receptor stimulation.
`In contrast,
`cerebellum is
`practically devoid of GHB binding sites and striatum contains low densities of
`these receptors (21,22).
`The anticonvulsant drug valproate, which inhibits the
`epileptoid pattern of the EEG in animals injected with GHB, completely prevents
`CGMP accumulation in hippocampus induced by GHB administration. This result is
`not surprising in view of the fact
`that
`in general, many anticonvulsant drugs
`antagonize the increase of CGMP levels associated with experimental seizures
`(23). However,
`it is generally accepted that it is doubtful that the alteration
`of CGMP
`is a mechanism by which anticonvulsants exert
`their effects
`(24).
`Valproate
`is
`known
`to
`inhibit depolarization induced
`increases
`in cyclic
`nucleotide levels (24-25).
`These effects may be important
`in seizure control
`induced by GHB because elevated cyclic nucleotide levels have been implicated
`in the maintainance of sustained seizure discharge (1).
`
`to act via a reinforcement of GABAergic transmission
`Valproate is thought
`(26-27). However,
`this anticonvulsant drug also increases GHB levels possibly
`by inhibition of
`its catabolism (28,29).
`The GABA pool
`formed
`from GHB
`breakdown, which might be
`involved in the negative feedback’
`regulation of a
`GABAergic synapse,
`is thus reduced. Under
`these conditions,
`an increase in
`GABAergic brain activity which has been shown to decrease CGMP accumulation is
`conceivable (2).
`In contrast,
`GHB administration increases
`the GABA pool
`derived from GHB and thus
`exerts
`a
`feed back
`inhibition on certain GABA
`synapses,
`reducing inhibitory input
`in brain,
`leading to CGMP accumulation and
`epileptic phenomena. However,
`it is evident that further studies are required
`to support this hypothesis.
`
`Naloxone also antagonizes the GHB induced increase in CGMP in hippocampus.
`This opiate antagonist has been shown to block the petit mal epilepsy model
`provided by GHB treated animals
`(19). Cerebral metabolic depression is also
`inhibited by pretreatment with naloxone (30).
`In the present studies the amount
`of naloxone injected (10 mg/kg)
`is too low to envisage a possible action on
`GABAergic
`receptors
`(31).
`In
`addition,
`naloxone
`has
`no
`effects
`on
`pentylenetetrazol induced seizures,
`amygdaloid kindling or human seizures (32-
`33). Opioid receptor agonists elicit a dose—dependent and transient elevation
`of CGMP content
`in neuroblastoma cells
`(34).
`Thus,
`as
`EEG and behavioral
`
`Page 7 of 8
`
`Page 7 of 8
`
`

`
`.,-...,......
`
`..
`
`......
`
`...,........... W...
`
`.,-...--...
`
`4
`
`...-_.-
`
`._
`
`......
`
`.-,,,
`
`.......,,.....-.....,
`
`......
`
`endorphins may be involved in the neurophysiological and neuropharmacological
`effects of GHB, particularly in the hippocampus.
`
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`
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