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

摘要

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.