Pharmacokinetics In Baclofen Overdose

Anderson, P.; Nohér, H; Swahn, Carl‐Gunnar

doi:10.3109/00099308409035078

Cited by 40 publications

(24 citation statements)

References 10 publications

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“…We chose to administer baclofen t.i.d. due to its relatively short half-life, which has been estimated to range from 4.58 (Anderson et al, 1984) to 6.8 hours (Wuis et al, 1989). …”

Section: Methodsmentioning

confidence: 99%

Differential development of tolerance to the functional and behavioral effects of repeated baclofen treatment in rats

Beveridge¹,

Smith²,

Porrino³

2013

Pharmacology Biochemistry and Behavior

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Baclofen, a gamma-aminobutyric acid (GABA)B receptor agonist, has been used clinically to treat muscle spasticity, rigidity and pain. More recently, interest in the use of baclofen as an addiction medicine has grown, with promising preclinical cocaine and amphetamine data and demonstrated clinical benefit from alcohol and nicotine studies. Few preclinical investigations, however, have utilized chronic dosing of baclofen, which is important given that tolerance can occur to many of its effects. Thus the question of whether chronic treatment of baclofen maintains the efficacy of acute doses is imperative. The neural substrates that underlie the effects of baclofen, particularly those after chronic treatment, are also not known. In the present study, therefore, rats were treated with either a) vehicle, b) acute baclofen (5 mg/kg) or c) chronic baclofen (5 mg/kg, t.i.d. for 5 days). The effects of acute and chronic baclofen administration, compared to vehicle, were assessed using locomotor activity and changes in brain glucose metabolism (a measure of functional brain activity). Acute baclofen significantly reduced locomotor activity (horizontal and total distance traveled), while chronic baclofen failed to affect locomotor activity. Acute baclofen resulted in significantly lower rates of local cerebral glucose utilization throughout many areas of the brain, including the prefrontal cortex, caudate putamen, septum and hippocampus. The majority of these functional effects, with the exception of the caudate putamen and septum, were absent in animals chronically treated with baclofen. Despite the tolerance to the locomotor and functional effects of baclofen following repeated treatment, these persistent effects on functional activity in the caudate putamen and septum may provide insights into the way in which baclofen alters the reinforcing effects of abused substances such as cocaine, alcohol, and methamphetamine both in humans and animal models.

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“…We chose to administer baclofen t.i.d. due to its relatively short half-life, which has been estimated to range from 4.58 (Anderson et al, 1984) to 6.8 hours (Wuis et al, 1989). …”

Section: Methodsmentioning

confidence: 99%

Differential development of tolerance to the functional and behavioral effects of repeated baclofen treatment in rats

Beveridge¹,

Smith²,

Porrino³

2013

Pharmacology Biochemistry and Behavior

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“…It is rapidly and completely absorbed from the gastrointestinal tract with peak serum concentrations achieved in 2 h 2 . About 15% of baclofen is metabolized by the liver and its mean plasma elimination half‐life is 3.5 h 1 …”

Section: Introductionmentioning

confidence: 99%

“…Baclofen is a synthetic derivative of the naturally occurring inhibitory neurotransmitter γ -aminobutyric acid (GABA). 1 It is a lipophilic drug that readily penetrates the blood-brain barrier and although its precise mechanism of action has yet to be elucidated, it appears that baclofen acts principally on the GABA B receptor at the spinal level in therapeutic doses. Baclofen has been widely used in multiple sclerosis, and other spinal lesions that cause skeletal hypertonus and spasticity.…”

Section: Introductionmentioning

confidence: 99%

Baclofen overdose: Defining the spectrum of toxicity

Leung

Whyte

Isbister

2006

Emerg Medicine Australasia

121

103

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“…The drug exhibits a short half-life, ranging between 4.5 h (Anderson et al, 1984) and 6.8 h (Wuis et al, 1989), such that it is typically prescribed three or four times daily to treat these conditions. Baclofen therapies are also being investigated for their potential to counterbalance over-stimulation of the dopamine (DA) system caused by alcohol, cocaine, and other addictive drugs; as presynaptic GABA B receptors located on mesolimbic neuron terminals in the nucleus accumbens (NAc) can effectively inhibit the release of DA (Brebner et al, 2005; Halbout et al, 2011; Xi and Stein, 1998).…”

Section: Introductionmentioning

confidence: 99%

Chronic baclofen desensitizes GABAB-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain

et al. 2015

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The GABAB receptor is a therapeutic target for CNS and neuropathic disorders; however, few preclinical studies have explored effects of chronic stimulation. This study evaluated acute and chronic baclofen treatments on GABAB-activated G-proteins and signaling protein phosphorylation as indicators of GABAB signaling capacity. Brain sections from rats acutely administered baclofen (5 mg/kg, i.p.) showed no significant differences from controls in GABAB-stimulated GTPγS binding in any brain region, but displayed significantly greater phosphorylation/activation of focal adhesion kinase (pFAKTyr397) in mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus) and elevated phosphorylated/activated glycogen synthase kinase 3-β (pGSK3βTyr216) in the prefrontal cortex, cerebral cortex, caudate putamen, nucleus accumbens, thalamus, septum, and globus pallidus. In rats administered chronic baclofen (5 mg/kg, t.i.d. for five days), GABAB-stimulated GTPγS binding was significantly diminished in the prefrontal cortex, septum, amygdala, and parabrachial nucleus compared to controls. This effect was specific to GABAB receptors: there was no effect of chronic baclofen treatment on adenosine A1-stimulated GTPγS binding in any region. Chronically-treated rats also exhibited increases in pFAKTyr397 and pGSK3βTyr216 compared to controls, and displayed wide-spread elevations in phosphorylated dopamine- and cAMP-regulated phosphoprotein-32 (pDARPP-32Thr34) compared to acutely-treated or control rats. We postulate that those neuroadaptive effects of GABAB stimulation mediated by G-proteins and their sequelae correlate with tolerance to several of baclofen's effects, whereas sustained signaling via kinase cascades points to cross-talk between GABAB receptors and alternative mechanisms that are resistant to desensitization. Both desensitized and sustained signaling pathways should be considered in the development of pharmacotherapies targeting the GABA system.

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Pharmacokinetics In Baclofen Overdose

Cited by 40 publications

References 10 publications

Differential development of tolerance to the functional and behavioral effects of repeated baclofen treatment in rats

Differential development of tolerance to the functional and behavioral effects of repeated baclofen treatment in rats

Baclofen overdose: Defining the spectrum of toxicity

Chronic baclofen desensitizes GABAB-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain

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