Effects of caffeine on the nigrostriatal dopaminergic system and on locomotor activity

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The nigrostriatal dopaminergic system originates in neurons located in the substantia nigra, mainly in the pars compacta and to a lesser extent in the pars reticulata. These neurons project via the median forebrain bundle and the lateral hypothalamus to the globus pallidus and terminate in the caudate nucleus.13,14 This system is involved in the control of locomotion.

The stimulant effects of caffeine on LCMRglcs in the structures mediating locomotor activity have been shown previously at quite high doses of caffeine, i.e., after the acute injection of 10 mg/kg caffeine or the continuous perfusion of the methylxanthine at a rate of 0.30 mg/kg/min. These studies all reported increases over control values in the rates of energy metabolism in the dopaminergic substantia nigra, both the pars reticulata and compacta and in structures of the extrapyramidal motor system (caudate nucleus, globus pallidus, sensorimotor and cerebellar cortex) as well as in numerous thalamic motor and sensory relay nuclei.15-19

Our more recent data show that the caudate nucleus is very sensitive to the effects of caffeine since LCMRglc is already significantly activated in this structure after the administration of the lowest dose of caffeine, 1 mg/kg to adult male rats (Figure 3.1). The functional activity of this nucleus is further increased at 2.5 mg/kg, about 40% over control levels, and remains activated at the two higher doses of the methylxanthine. In the two other structures of the nigrostriatal dopaminergic system (the substantia nigra pars compacta and the globus pallidus), LCMRglc increases after the injection of 2.5 to 10 mg/kg of caffeine, while the sensorimotor cortex shows a significant increase in LCMRglcs only after 5 mg/kg of caffeine. The high sensitivity of the caudate nucleus to caffeine is confirmed by the fact that a direct ionto-phoretic administration of the methylxanthine can also modify the spontaneous electrical activity of neurons in the caudate nucleus of the rat. This

NIGROSTRIATAL DOPAMINERGIC SYSTEM

SNPC DMCAU G PAL SMCX

Figure 3.1 Effects of the acute administration of increasing doses of caffeine on LCMRglcs in selected regions of the nigrostriatal dopaminergic system. Data are presented as percent of variation from control values. The animals received an acute i.v. injection of 1 to 10 mg/kg caffeine at 15 min before the onset of the [14C]2-deoxyglucose procedure. For experimental details, see Nehlig et al.17 SNPC: substantia nigra pars compacta; DMCAU: dorsomedial caudate nucleus; GPAL: globus pallidus; SMCX: sensorimotor cortex. * p< 0.05; ** p< 0.01, statistically significant differences from controls (Dunnett's t-test for multiple comparisons).

SNPC DMCAU G PAL SMCX

Figure 3.1 Effects of the acute administration of increasing doses of caffeine on LCMRglcs in selected regions of the nigrostriatal dopaminergic system. Data are presented as percent of variation from control values. The animals received an acute i.v. injection of 1 to 10 mg/kg caffeine at 15 min before the onset of the [14C]2-deoxyglucose procedure. For experimental details, see Nehlig et al.17 SNPC: substantia nigra pars compacta; DMCAU: dorsomedial caudate nucleus; GPAL: globus pallidus; SMCX: sensorimotor cortex. * p< 0.05; ** p< 0.01, statistically significant differences from controls (Dunnett's t-test for multiple comparisons).

activation is further confirmed by the caffeine-induced dopamine release in the caudate nucleus recently shown by microdialysis.2021 Thus, the methylx-anthine is able to activate the nigrostriatal pathway by stimulating dopamine release from the nigrostriatal nerve endings.22

There is a good correlation between caffeine-induced functional activation of the structures belonging to the nigrostriatal pathway and the well-known stimulant effects of the methylxanthine on locomotor activity. Indeed, the activation of LCMRglcs occurring in the structures belonging to the nigrostriatal pathway at low doses of caffeine (Figure 3.1), as well as the increase in functional activity in most areas of the extrapyramidal motor system recorded at high doses of the methylxanthine,15-19 reflect the stimulant effects of caffeine on locomotor activity and general behavior (for a review, see References 1 and 2). This effect is dose-dependent, and the minimal dose of caffeine necessary to affect locomotion is 1.5 mg/kg, which correlates well with the increase in LCMRglc in the caudate nucleus after 1 mg/kg of the methylxanthine. The stimulant effect of caffeine on locomotion has been shown to increase with doses ranging from 10 to 20 mg/kg and decrease with doses higher than 40 mg/kg (for a review, see References 1 and 2). The effect of caffeine on the nigrostriatal dopaminergic pathway has also been shown indirectly since 10 to 50 mg/kg of the methylxanthine are able to antagonize the akinesia induced by catecholamine depletion in mice.23

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