The effects of acute and chronic morphine administration on GABA receptor binding

The effect of acute and chronic morphine administration and naloxone-precipitated withdrawal on the binding of [3H]GABA to its receptor sites in rat brain membranes was investigated. Acute morphine (25 mg/kg) administration produced a decrease in the GABA binding in cerebellum, cortex and striatum. This decrease appears to be due to a selective decrease in the number of high-affinity GABA receptor binding sites. In contrast, rats chronically treated with morphine by pellet implantation did not exhibit any changes in GABA receptor binding, except for an increase in pons medulla. However, in rats which were physically dependent, as indicated by naloxone-precipitated withdrawal, GABA binding was decreased significantly in cerebellum and striatum, relative to chronic morphine treatment or placebo pellet controls. This decrease was due to a decrease in the number of low affinity GABA receptor binding sites. Both chronic morphine and naloxone-precipitated withdrawal treatments produced an increase in GABA binding in the pons medulla. These results suggest that morphine may produce some of its effects by modulating GABAergic systems and that high and low affinity GABA receptor sites may play a differential role during various morphine treatments.     

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

Summary The effects of chronic administration of methamphetamine on the responsiveness of neurons of the substantia nigra zona reticulata (SNR) to gammaaminobutyric 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.     

Increased mesolimbic dopamine binding following chronic haloperidol treatment

It is well documented that chronic neuroleptic treatment creates a dopamine receptor supersensitivity in the striatum. The present study examined the effect of chronic neuroleptic treatment on mesolimbic dopamine receptor binding. Rats received either 0.5mg/kg of haloperidol, 50mg/kg of sodium phenobarbital, or 0.9% saline daily for 21 days. One week following the last injection, the rats were sacrificed and the septi were removed for the ³H-dopamine binding assay. Haloperidol treatment resulted in a 52% increase in ³H-dopamine binding in the septum, whereas phenobarbital treatment caused no significant change.     

Differential effects of chronic treatment with chlorpromazine versus cocaine on behavioral responsiveness to nigral GABA receptor stimulation

We examined whether any locus postsynaptic to the GABAergic striatonigral projection might be involved in the enhancement of behavioral response to dopaminergic stimulants induced by chronic treatment with either neuroleptic drugs or stimulants. Rats exposed chronically to either chlorpromazine or cocaine were tested for behavioral responses to bilateral intranigral microinfusions of muscimol (2.5 ng bilaterally). Chronic chlorpromazine-treated rats responded with more intense stereotypy to nigral muscimol than controls, but chronic cocaine-treated rats were less responsive than controls to intranigral muscimol. It therefore appears that changes in the responsiveness of neural outputs from, or distal to, substantia nigra may contribute to the enhanced behavioral effects of dopaminergic stimulants caused by chronic exposure to dopaminergic antagonists, but that the critical neural changes responsible for cocaine sensitization probably do not occur at, or distal to, the nigral outflow from the basal ganglia. At least at the nigral level, different neural mechanisms evidently mediate the increased stereotypy response to dopaminergic stimulation induced by chronic administration of either neuroleptic or stimulant drugs.     

Baclofen and muscimol: Behavioural and neurochemical sequelae of unilateral intranigral administration and effects on 3H-GABA receptor binding

Summary Log dose-response curves for induction of contralateral rotational behaviour in the rat by unilateral intranigral injections of the GABA agonist muscimol and the GABA analogue baclofen have been compared. Baclofen, 5–1000 ng, produced a maximal rotational response that was only 40% of that produced by 0.25–100 ng muscimol, and log dose-response curves failed to show parallelism. The behavioural effects of both drugs were only weakly antagonised by haloperidol and were not antagonised by 6-hydroxydopamine lesions of ipsilateral dopamine (DA) neurons, indicating that these responses were independent of DAergic mechanisms. The effects of baclofen were weakly antagonised by picrotoxin. Intranigral muscimol and baclofen substantially elevated striatal DA concentrations. While muscimol also substantially elevated striatal dihydroxyphenylacetic acid (DOPAC) but not homovanillic acid (HVA), baclofen did not significantly effect either DOPAC or HVA. Baclofen, GABA and muscimol displaced specific ³H-GABA binding in vitro with IC₅₀'s of 40 m 400 nM and 40 nM respectively. These results indicate that muscimol and baclofen do not act via a unitary GABAergic mechanism, but suggest that baclofen may be a partial GABA agonist, at least at nigral GABA receptors.     

Circling behavior induced by intranigral injections of GABA and muscimol in rats

Circling behavior induced by unilateral intranigral injections of GABA or muscimol was studied in rats. Both GABA (10–400 g) and muscimol (1–100 ng) evoked the same kind of contralateral circling behavior dose-dependently when injected into the substantia nigra. Muscimol was much more potent than GABA and its effect lasted longer. Neither GABA nor muscimol induced any ipsilateral circling. Pretreatment with bicuculline (3 mg/kg IP) significantly attenuated the intensity of circling behavior induced by intranigral injections of GABA or muscimol. Pretreatment with haloperidol (0.5 and 1.0 mg/kg SC) also significantly antagonized the circling behavior induced by GABA and muscimol. Pretreatment with atropine (10 mg/kg IP) significantly increased the intensity of circling behavior induced by intranigral injections of muscimol and tended to increase the intensity of circling behavior induced by intranigral injections of GABA. Pretreatment with strychnine (0.25 mg/kg IP) did not modify circling behavior induced by GABA, but did to some extent increase that induced by muscimol. These results indicate that the contralateral circling behavior induced by intranigral injections of GABA and muscimol seems to be dependent both on the activation of the dopaminergic nigrostriatal system and on the nondopaminergic nigral output system.     

Rotational behavior induced in rats by intranigral application of GABA-related drugs and GABA antagonists

GABA and GABA-related drugs such as muscimol, gamma-hydroxybutyric acid and baclofen injected unilaterally into the substantia nigra of rats elicited contraversive turning. Unilateral injections of picrotoxin and bicuculline produced either ipsi- or contraversive turning depending on the volume of vehicle. I.p. applied haloperidol did not abolish the muscimol-induced turning. This and the direction of rotational behavior suggests that the turning behavior elicited by GABA-related drugs is not mediated by the nigrostriatal dopaminergic tract.     

Effects of single and long-term haloperidol administration on open field behavior of rats

The effects of single and long-term haloperidol administration on rat open field behavior was studied. Withdrawal from long-term haloperidol treatment induced a significant increase in all parameters of activity recorded, expcept rearing. There was a direct relationship between the impairment of motor function induced by the single haloperidol administration and the increment of general activity observed after withdrawal from repeated drug administration. The results were considered to be a consequence of the supersensitivity of central dopaminergic receptors probably, of the mesostriatal pathway, that occurred in order to maintain the animal's homeostasis.     

Oral behaviour induced by intranigral muscimol is unaffected by haloperidol but abolished by large lesions of superior colliculus

It has been suggested that the GABAergic striatonigral projection may form part of the efferent pathway responsible for the expression of dopamine-related oral behaviour. Consistent with this suggestion are reports that bilateral injection of the GABA agonist muscimol can produce stereotyped gnawing and biting. We report here two experiments on this effect: (1) A dose of the dopamine receptor blocker haloperidol (0.4 mg/kg), which effectively antagonised oral stereotypy induced by systemically administered apomorphine or intranigral carbachol, had no effect on either the latency or the intensity of the gnawing produced by intranigral muscimol (1 mM); (2) large lesions involving the superior colliculus which effectively suppressed the oral stereotypy induced by 8mg/kg apomorphine completely abolished the gnawing induced by intranigral injection of muscimol. Collicular lesions suppressed both the gnawing which occurred spontaneously and that elicited by a perioral probe. These findings are consistent with the view that the substantia nigra is a relay station between the caudate nucleus and the superior colliculus in an efferent pathway mediating dopamine-related oral behaviour. In addition, they raise the possibility that such behaviour is produced by the sensitisation of a collicular-mediated perioral reflex.     

Presynaptic modulation of the release of GABA by GABAA receptors in pars compacta and by GABAB receptors in pars reticulata of the rat substantia nigra

The effect of GABA agonists and antagonists on K⁺-stimulated [³H]GABA release was studied to assess how presynaptic GABA receptors modulate GABA release. The release was affected in a quite different manner in the pars compacta and in the pars reticulata. Muscimol markedly inhibited the release from the pars compacta but had no effect on the release from the pars reticulata. Baclofen inhibited the release from the pars reticulata without affecting the release from the pars compacta. Bicuculline itself facilitated the release from the pars compacta but inhibited the release from the pars reticulata. Picrotoxin facilitated the release from the pars compacta and had no effect in the pars reticulata. The results suggest that the release of GABA from GABAergic terminals in the substantia nigra of the rat brain is modulated by GABA_A autoreceptors in the pars compacta and by GABA_B receptors in the pars reticulata.     

Oestrogen and progesterone change the binding characteristics of alpha-adrenergic and serotonin receptors on rabbit platelets

The binding characteristics of the alpha-adrenergic and serotonin receptors on intact rabbit platelets were identified using [3H]-dihydroergocryptine and [3H]-5-hydroxytryptamine respectively. In untreated female rabbits a single slpha-adrenoceptor and two serotonin receptors were identified with ligand affinities similar to those in human platelets. The effects of oestrogen and/or progesterone on the alpha-adrenergic and serotonin receptors of rabbit platelets were studied. Oestrogen alone increased the capacity of serotonin receptors but reduced that of the alpha-adrenoceptor. Oestrogen plus progesterone reduced the capacity of both receptors and reduced the affinity of the alpha-adrenoceptor. The possible mechanisms of the steroid-induced changes and the implications of these with regard to the effects of the oral contraceptive pill are discussed.     

Nigral actions of GABA agonists are enhanced by chronic fluphenazine and differentiated by concomitant flurazepam

Unilateral intranigral administration of baclofen (50–200 ng), muscimol (2.5–20 ng), or THIP (50–400 ng) in the rat led to contralateral circling behavior of a qualitatively similar nature. The potency of all three GABA-mimetics was enhanced in animals which had received the depot neuroleptic fluphenazine decanoate (10 mg/kg SC) 7 days prior to their intranigral administration. Significant differences between the nigral actions of the drugs could be demonstrated by their altered activity in the presence of a benzodiazepine. Flurazepam (500 ng) enhanced the intranigral potency of THIP, but reduced that of intranigral baclofen. Muscimol-induced circling behavior was unaffected by concomitant flurazepam. The data provide evidence for a functional supersensitivity of GABA-sensitive nondopaminergic projections from the substantia nigra in response to chronic neuroleptic treatment and reveal differences between the precise sites or modes of action of baclofen, muscimol, and THIP within this structure.     

Stimulation of GABA receptor binding by barbiturates

Barbiturates increase Na⁺-independent GABA binding to bovine cerebral cortex membranes. The relative activity of a series of compounds to enhance GABA binding correlates significantly with their anesthetic activity and with their ability to reverse bicuculline antagonism of GABA responses. There are regional differences in the maximal percent stimulation of GABA binding by pentobarbital; a low stimulation in cerebellum.     

Self-injurious behavior in rats produced by intranigral microinjection of GABA agonists

Bilateral injection of the GABA agonist muscimol (10–300 ng) into the caudal substantia nigra (pars reticulata) of rats produced dose-dependent stereotyped gnawing and self-biting. Limiting the opportunity to graw on inanimate objects shifted the dose-response curve for muscimol-induced self-injurious behavior (SIB) to the left and increased the maximum incidence of SIB. Microinjection of muscimol (30 ng) into the rostral and caudal regions of the substantia nigra were equally effective in producing SIB, though the incidence of SIB decreased sharply when muscimol was injected 1 mm rostral or caudal to the substantia nigra. Bilateral intranigral injection of THIP (100–1000 ng) and (±)baclofen (100–1000 ng) induced a low incidence of SIB. However, neither IP administration of picrotoxin (5 mg/kg) or simultaneous microinjection of (+)bicuculline methiodide (BMI; 300 or 1000 ng) along with muscimol (30 ng) blocked muscimol-induced SIB. In fact, (+)BMI increased the occurrence of self-biting and reduced the latency to onset of SIB. The involvement of GABAergic mechanisms in muscimol-induced SIB is discussed.     

Prolonged treatment with the GABA agonist THIP increases dopamine receptor binding more than it changes dopaminergic behaviour in mice

To investigate the influence of the GABA-agonist, THIP, (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol) on the striatal dopaminergic system in mice after repeated administration, THIP, cis(Z)-flupentixol, or haloperidol were given alone or in combinations for 12 days. The binding of ³H-spiroperidol was greatly increased, and that of ³H-cis(Z)-flupentixol was slightly increased after treatment with THIP alone. After repeated treatment with neuroleptics, only slight increases in the binding were seen. There was no additive effect when treatments with THIP and the neuroleptics were combined. Repeated administration of THIP did not induce changes in the ability of an acute dose of either haloperidol or cis(Z)-flupentixol to antagonize methylphenidate-induced stereotyped gnawing. The behavioural supersensitivity induced by chronic treatment with the two neuroleptics was not changed by concomitant treatment with THIP.     

Release of endogenous GABA from the substantia nigra is not controlled by GABA autoreceptors

Summary The characteristics of the release of GABA from slices of the rat substantia nigra, elicited by electrical stimulation at frequencies of 0.5–48 Hz and by elevated K⁺ concentrations ranging from 15–35 mmol/l, was studied. Comparisons were made with cortical slices where the data were not available from previous studies.No GABA release could be evoked from rat nigral slices by electrical stimulation between 0.5 and 4 Hz, in contrast to cortical slices, in which this pool is sensitive towards inhibition by (–)-baclofen. Also, comparatively less GABA release could be evoked from nigral than from cortical slices by K⁺ concentrations between 15 and 25 mmol/l. While (–)-baclofen at 10 mol/l inhibited release caused by 15 mol/l K⁺ in cortical, it did not in nigral slices. GABA release caused by higher frequencies (8–48 Hz) or 30 mmol/l K⁺ concentrations was Ca²⁺-dependent and in the former case also tetrodotoxin-sensitive. It had similar characteristics as in cortical slices and was insensitive towards (–)-baclofen, muscimol and bicuculline. Even more markedly than in the cortex, 30 mmol/l K⁺ released greater amounts of GABA than electrical stimulation at 24 Hz of a similar duration, suggesting the existence of one or several additional pool(s) of lesser excitability.Since the majority of gabaergic nerve endings in the nigra belong to striato- and pallidonigral projection neurons and those in the cortex probably exclusively to various types of interneurons, it seems that (a) one or several of the latter release GABA at low frequencies in a baclofen-sensitive manner and are absent or rare in the s. nigra, and (b) the striato- and pallidonigral projection neurons are not controlled by presynaptic autoreceptors of the GABA_A or GABA_B type, because neither GABA release elicited by electrical stimulation nor by 30 mmol/l K⁺ was affected by agents interfering with these types of receptors.Send offprint requests to P. C. Waldmeier at the above address     

Lack of Na+ -independent binding of [3H]GABA or [3H]Muscimol to subcellular particles of C6 glioma cells

Using several different experimental conditions, centrifugation assays revealed that no “specific” high-affinity Na⁺-independent binding of [³H]GABA (3–15 nM) or [³H]muscimol (6–92 nM) occurred to subcellular particles prepared from C₆ glioma cells. Therefore, like the membranes of glial cells grown in primary culture and like the modified oligodendroglial membranes of myelin, the transformed glial membranes of C₆ cells do not appear to possess GABA-receptors. These results provide further evidence that the depolarizing actions of GABA on glia that have been recorded in electrophysiological studies occur indirectly rather than by activation of glial GABA-receptors.     

Sensitivity to haloperidol of caudate neurones excited by nigral stimulation

A technique was developed combining multibarrelled glass microelectrode recordings with local superfusion of the caudate nucleus. Haloperidol had a prolonged reversible blocking action on caudate neurones excited orthodromically by substantia nigra stimulation. These cells were unaffected by microiontophoretic applications of dopamine.     

Biphasic effects of direct,but not indirect,GABA mimetics and antagonists on haloperidol-induced catalepsy

Summary At very low doses the GABA agonists SL 76002 and muscimol diminish haloperidol-induced catalepsy. At somewhat higher doses these compounds potentiate catalepsy. Biphasic effects on DA-receptor mediated functions have previously been noted with bicuculline and picrotoxinin. In contrast, manipulation of GABA levels by enzyme inhibition induced only a monophasic effect on dopamine-mediated behaviour. The potentiation of GABA levels by enzyme inhibition induced only a monophasic effect on dopamine-mediated behaviour. The potentiation of haloperidol-induced catalepsy by GABA mimetics is also observed with dipropylacetate, delta-aminovaleric acid and gamma-acetylenic GABA. This GABA-mimetic potentiation of catakepsy was blocked by the coadministration of bicuculline. These results confirm and extend the hypothesis that GABA-neurons influence DA neuron function. Furthermore they suggest that more than one group of GABA receptors influence directly and/or indirectly DA neuronal function, with different resultant effects.     

Effects of chronic nicotine and haloperidol administration on muscarinic receptor-mediated phosphoinositide turnover in rat brain slices

Muscarinic receptor-mediated phosphoinositide (PI) turnover in rat brain slices was assessed after chronic administration of nicotine (12 mg/kg/day) or haloperidol decanoate (1.5 mg/kg/day), either alone or in combination, for 6 weeks. Nicotine alone did not significantly alter carbachol-induced inositol monophosphate (IP₁) accumulation in the frontal cortex, but did result in a significant increase in the hippocampus, and in a decrease in the striatum. Haloperidol alone attenuated carbachol-stimulated IP₁ accumulation in all three brain regions. Chronic treatment with combined nicotine and haloperidol resulted in no significant change in carbachol-sensitive IP₁ accumulation in either the frontal cortex or hippocampus but did result in a decrease in the striatum. The results suggest significant cross-talk between cholinergic and dopaminergic systems in affecting PI metabolism.