Effects of baclofen on nigral dopaminergic cell activity following acute and chronic haloperidol treatment

doi:10.1016/0361-9230(80)90087-8

Brain Research Bulletin

Volume 5, Supplement 2, 1980, Pages 537-543

https://doi.org/10.1016/0361-9230(80)90087-8 Get rights and content

Abstract

Baclofen, a GABA derivative, has proven useful in the treatment of spasticity when given in low doses. Despite numerous studies its mechanism of action remains unclear. For example, baclofen has been found to inhibit dopaminergic cell activity but only at dosages over 50 times the antispasticity dose. Using extracellular single unit recording techniques, we have examined the effects of baclofen on the activity of rat nigral dopaminergic neurons and its interaction with haloperidol. Both acute and chronic haloperidol treatment significantly enhance the inhibitory effects of IV baclofen on these cells. Acute haloperidol pretreatment potentiates the inhibitory effects of single low doses of baclofen without significantly altering the dose response curve for baclofen, whereas chronic haloperidol treatment apparently potentiates both effects. Furthermore, low doses ofbaclofen reverse the depolarization inactivation of nigral DA cells caused by chronic haloperidol treatment. These results are discussed in relation to the action of baclofen on nigral inputs and its possible efficacy in the relief of some neuroleptic-induced side effects.

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Cited by (22)

Long-Term Reduction in Ventral Tegmental Area Dopamine Neuron Population Activity Following Repeated Stimulant or Ethanol Treatment
2007, Biological Psychiatry
Citation Excerpt :
The second side was used to establish the impact of pharmacological challenge. Apomorphine (20 μg/kg, i.v.; Sigma) (Shen and Chiodo 1993) or in a few animals baclofen (.1 mg/kg, i.v.; Sigma) (Grace and Bunney 1980) was administered and the cells-per-track procedure was conducted 20 minutes later. Apomorphine or baclofen administration was utilized to confirm the possibility that low population activity in VTA DA neurons was caused by depolarization inactivation.
Drugs of abuse exert profound effects on the mesolimbic/mesocortical dopaminergic (DA) systems. Few studies have investigated the long-term adaptations in ventral tegmental area (VTA) DA neuron activity after repeated exposure to drugs of abuse. We investigated changes in the electrical activity of VTA DA neurons after cessation from treatment with several stimulants and ethanol.
Adult rats were treated with stimulants (amphetamine: 2 mg/kg per day, 5 days/week, 2 weeks; cocaine: 15 mg/kg per day, 5 days/week, 2 weeks; nicotine: .5 mg/kg per day, 5 days; ethanol: 10 g/kg per day, 3 weeks) and the single-unit activity of VTA DA neurons was studied in vivo 3 to 6 weeks later.
Stimulant and ethanol treatment decreased basal VTA DA neuron population activity but not firing rate or firing pattern. This effect was reversed by acute apomorphine, suggesting that the underlying mechanism for reduced population activity was depolarization inactivation. Anesthesia did not confound this result, as similar effects were observed in amphetamine-treated rats recorded in a conscious preparation.
Reduced basal VTA DA neuron population activity presumably due to depolarization inactivation is a common and long-term neuroadaptation to repeated treatment with stimulants and ethanol. This change in VTA DA neuron activity could underlie the persistent nature of addiction-associated behaviors.
GABA<inf>B</inf> receptor stimulation accentuates the locomotor effects of morphine in mice bred for extreme sensitivity to the stimulant effects of ethanol
2006, Pharmacology Biochemistry and Behavior
Mice selectively bred for divergent sensitivity to the locomotor stimulant effects of ethanol (FAST and SLOW) also differ in their locomotor response to morphine. The GABA_B receptor has been implicated in the mediation of locomotor stimulation to both ethanol and morphine, and a reduction in ethanol-induced stimulation has been found with the GABA_B receptor agonist baclofen in FAST mice. We hypothesized that GABA_B receptor activation would also attenuate the locomotor stimulant responses to morphine in these mice. In order to test this hypothesis, baclofen was administered to FAST-1 and FAST-2 mice 15 min prior to morphine, and activity was recorded for 30 min. Baclofen attenuated stimulation to 32 mg/kg morphine in FAST-1 mice, but only at a dose that also reduced saline activity. There was no stimulant response to 32 mg/kg morphine in FAST-2 mice, or to 16 mg/kg or 48 mg/kg morphine in FAST-1 mice, but the combination of baclofen with these morphine doses accentuated locomotor activity. Therefore, it appears that GABA_B receptor activation is not a common mechanism for the locomotor stimulant responses to ethanol and morphine in FAST mice; however, these data suggest that GABA_B receptor activation may instead enhance some of the behavioral effects of morphine.
Facilitatory effect of unilateral lesion of the ventral tegmental area on locomotor response to stimulation of the contralateral ventral tegmental area: Involvement of GABAergic transmission
1999, Brain Research
It was found previously that in the rat, unilateral electrolytic lesion of the ventral tegmental area (VTA) facilitated feeding induced by electrical stimulation of the homologous VTA tissue in the contralateral hemisphere. In the present work, VTA stimulation-induced locomotor response was tested in male Wistar rats using a latency to move/stimulation frequency curve shift paradigm in order to check for functional generality of the “contralateral facilitation effect” and also with the aim of elaborating an easy and reliable behavioral model to study this phenomenon. In a further step, the hypothesis was tested that enhancement of function of the intact VTA results from elimination of tonic GABAergic influence derived normally from the lesioned VTA. GABA_A (bicuculline, doses 0, 0.5 and 5.0 ng) and GABA_B (phaclofen, doses 0, 500 and 1000 ng) receptors antagonists, and for comparison, a GABA_A receptor agonist (muscimol, doses 0, 12.5, 25.0 and 50.0 ng), were injected unilaterally to VTA and their effect on locomotor response elicited by electrical stimulation of the contralateral VTA was tested in a latency/frequency paradigm. It was found that similar to feeding, locomotor response evoked by unilateral electrical stimulation of the VTA was facilitated after contralateral VTA lesion which manifested as a decrease of the locomotion threshold and a leftward shift of the function relating latency to move to stimulation frequency. The effect was immediate, long-lasting and specific to the VTA destruction; lesions outside the VTA area caused gradual impairment of the locomotor response to stimulation. The facilitatory effect of the electrolytic lesion could be replicated by bicuculline, which significantly facilitated stimulation-induced behavior. Phaclofen exerted slight facilitating influence only at a low dose. No effect of muscimol on the locomotion threshold was found. We conclude that “the contralateral facilitation effect” at the level of VTA reflects the interhemispheric regulation of activity of the dopaminergic (DA) cells in which GABA_A-mediated interhemispheric communication plays a significant role.
Effects of the enantiomers of (±)-HA-966 on dopamine neurons: an electrophysiological study of a chiral molecule
1995, European Journal of Pharmacology
The present study was conducted to evaluate the effects of the resolved enantiomers of (±)-1-hydroxy-3-aminopyrrolidone-2 ((±)-HA-966) on the electrophysiological properties of dopamine-containing neurons in the substantia nigra of the chloral hydrate anesthetized rat. Both (+)- and (−)-HA-966 produced a dose-dependent reduction in firing rate that eventually resulted in total cessation of spontaneous neuronal activity (ID₅₀ = 5.7 and 57.8 mg/kg i.v., respectively). The inhibitory effects of both drugs were accompanied by a marked increase in the regularity of neuronal firing and a concomitant suppression of bursting activity. Although approximately 10-fold less potent than the (−) enantiomer, the inhibitory effects of (+)-HA-966 were completely antagonized by the centrally active, GABA_B receptor antagonist, CGP-35348 (300 mg/kg i.v.). These data suggest that the complementary electrophysiological effects of the enantiomers of (±)-HA-966 on nigral dopamine neurons are mediated through a common mechanism of action possibly involving a novel interaction with GABA_B receptors.
The role of mesoaccumbens-pallidal circuitry in novelty-induced behavioral activation
1995, Neuroscience
When exposed to an environment for the first time, rats express greater behavioral activation than rats which were previously habituated to that environment. The circuit containing the ventral tegmental area, nucleus accumbens and ventral pallidum is required for the expression of locomotor activity elicited by amphetamine-like psychostimulants. It was hypothesized that this circuit is necessary for the expression of novelty-induced motor activity. Dopamine is a neurotransmitter in the projection from the ventral tegmental area to the nucleus accumbens, while GABA is contained in the projections from the nucleus accumbens to the ventral pallidum and from the ventral pallidum back to the ventral tegmental area. Prior to exposing rats to a novel or habituated environment, they received a microinjection of either saline vehicle or one of the following drugs: fluphenazine (dopamine antagonist) into the nucleus accumbens, muscimol (GABA_A agonist) into the ventral pallidum, or baclofen (GABA_B agonist) into the ventral tegmental area. Each of these pretreatments prevented novelty-induced motor activation without suppressing the activity of habituated animals. In contrast, when these microinjections were made into adjacent motor nuclei of the basal ganglia, including fluphenazine into the striatum, muscimol into the globus pallidus and baclofen into the substantia nigra, they were ineffective in blocking novelty-induced motor activity.
These data indicate that the integrity of the circuit that contains the ventral tegmental area, nucleus accumbens and ventral pallidum is required for the manifestation of novelty-induced motor activity.
Behavioral aspects of GABAergic-dopaminergic interactions in the central nervous system
1989, European Journal of Pharmacology
GABAergic-dopaminergic relationships in rats were analysed quantitatively by means of behavioral studies. Acute and long-term haloperidol administration induced significant leftward displacement of the control dose-response curves for picrotoxin but not those for strychnine or 3-mercaptopropionic acid (3-MPA). Apomorphine given acutely increased the sensitivity of the animal to strychnine but not to picrotoxin or 3-MPA. In animals that presented convulsion a stereotyped gnawing and/or licking behavior was observed immediately after the ictus activity as a consequence of the combined acute administration of haloperidol and picrotoxin. Long-term haloperidol treatment increased the gnawing and/or licking behavior immediately before and/or after the ictus activity induced by picrotoxin (1 and 72 h after haloperidol withdrawal) or 3-MPA (72 h after withdrawal). A possible effect of the drugs employed on the DA-nigroamygdaloid and/or the GABA-striatonigral fiber systems is discussed.

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Effects of baclofen on nigral dopaminergic cell activity following acute and chronic haloperidol treatment

Abstract

J. Neurol. Sci.

Brain Res.

Neuropharmacology

Eur. J. Pharmac.

Brain Res.

Brain Res.

Eur. J. Pharmac.

Acute and chronic haloperidol treatment: Comparison of effects on nigral dopaminergic cell activity

Life. Sci.