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

Abstract

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.

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

“…Studies have reported a reduction in efficacy following chronic administration of baclofen and the need to increase the dose to maintain its antispasmodic effect (Heetla et al, 2009; Nielsen et al, 2002). These clinical findings are consistent with the observation that tolerance develops to baclofen's locomotor effects after 5 to 11 days of baclofen in rodents (Beveridge et al, 2013; Gianutsos and K. E. Moore, 1978; Levy and Proudfit, 1977). Interestingly, region-specific reductions in cerebral metabolism were observed in acutely treated rats compared with controls, but not in chronically treated animals (Beveridge et al, 2013).…”

“…These clinical findings are consistent with the observation that tolerance develops to baclofen's locomotor effects after 5 to 11 days of baclofen in rodents (Beveridge et al, 2013; Gianutsos and K. E. Moore, 1978; Levy and Proudfit, 1977). Interestingly, region-specific reductions in cerebral metabolism were observed in acutely treated rats compared with controls, but not in chronically treated animals (Beveridge et al, 2013). These findings emphasized that region-specific changes in neuronal activity must be investigated in order to properly evaluate baclofen's potential as a treatment for conditions that require use of the drug for extended periods.…”

Acute and chronic alcohol administration: Effects on performance of zebrafish in a latent learning task

“…Alcohol impairs learning and memory in humans and other mammalian organisms [19–21]. Thus, quantification of learning and memory may be an efficient method with which alcohol’s effects on brain function may be studied, and with which mutation or drug treatment induced attenuation of the impairing effects may be identified in forward genetic or drug screens.…”

Baclofène : traitement révolutionnaire ou polémique française ?

“…Dans une étude chez l'animal, en utilisant le modèle murin d'état de stress post-traumatique dont on connaît la comorbidité avec la consommation d'alcool, l'administration de baclofène per os réduirait la prise d'alcool [14], jouant un rôle spécifique dans la diminution de l'activité psychomotrice précédant la prise d'alcool ou craving [15]. L'administration de baclofène aurait égale-ment montré des résultats intéressant dans d'autres addictions : au niveau clinique, réduction du nombre de cigarettes par jour [16], au niveau préclinique avec un rôle possible dans traitement des addictions aux produits psychostimulants [12,17,18], avec une réponse réduite aux amphétamines [12] et à la cocaïne [17].…”

“…De nombreuses études ont en effet montré une réduction des effets du baclofène au fil du temps avec le développement d'un phénomène de tolérance et la nécessité d'augmenter les doses pour maintenir l'effet théra-peutique [19,20]. Beveridge et al [15] en 2013, dans leur étude chez le rat, trouvent en effet une diminution de cet effet avec l'usage chronique du baclofène, sans épuisement total toutefois au moins au plan fonctionnel puisque la consommation de glucose dans le striatum et le septum reste significativement plus basse, ce qui pourrait expliquer l'effet thérapeutique du baclofène au long cours.…”