Caffeine Effects on the Brain and Behavior: A Metabolic Approach

Chapter 6

Caffeine Effects on the Brain and Behavior: A Metabolic Approach Astrid Nehlig

Downloaded by MICHIGAN STATE UNIV on November 29, 2013 | http://pubs.acs.org Publication Date: January 15, 2000 | doi: 10.1021/bk-2000-0754.ch006

INSERM U 398, Faculty of Medicine, 11 Rue Humann, 67085 Strasbourg, France

Caffeine is a worldwide consumed stimulant with known effects on behavior and sleep while its addictive potential is debated. With [ C]2-deoxyglucose autoradiography which allows to correlate cerebral functional activity to the behavioral effects of a drug, we studied the effects of increasing doses of caffeine on cerebral glucose utilization in adult rats. At 1 mg/kg, caffeine activated the caudate nucleus involved in the control of locomotion, the raphe nuclei and locus coeruleus mediating mood and sleep. After 2.5 and 5 mg/kg caffeine, metabolic activation spread mainly to the other brain regions mediating locomotion. The functional activation of the shell of the nucleus accumbens, involved in addiction and reward was only induced by 10 mg/kg caffeine. Thus, conversely to amphetamine and cocaine which quite specifically activate the latter structure at low doses, the caffeine-induced activation of the nucleus accumbens shell occurred together with that most other brain regions. These data confirm the high sensitivity of locomotion, mood and sleep to low doses of caffeine and provide functional evidence of the lack of addictive potential of caffeine at the usual level of human consumption. 14

Caffeine is the most widely used psychoactive substance in the world. Caffeine is consumed in a variety of forms, i.e., drinking coffee, tea, mate, soft drinks; chewing cola nuts; consuming cocoa products; taking over-the-counter pain or slimming medication. The mean daily caffeine consumption for all adult consumers and from all sources reaches 2.4-4.0 mg/kg for a 60-70 kg subject in the North America and the U K and 7.0 mg/kg in Scandinavia (3,4). Among children under 18, the mean daily intake of caffeine is about 1.0 mg/kg in the United States and less than 2.5 mg/kg in Denmark (3). Mild positive subjective effects occur at low

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© 2000 American Chemical Society

In Caffeinated Beverages; Parliment, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

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to moderate doses of caffeine (50-300 mg, i.e., 1-3 cups of coffee) and are described as feelings of well-being, alertness, energy and ability to concentrate. At high doses (300-800 mg), rather negative feelings such as anxiety, nervousness, insomnia are reported (for review, see refs. 1 and 2). Most of the effects of caffeine on the central nervous system reflect its antagonism at the level of adenosine receptors (1,5,6). Here, I will review the effects of caffeine on cerebral glucose utilization in order to correlate the data with the well-known effects of caffeine on functions known to be sensitive to caffeine such as locomotor activity, mood and sleep and I will also consider the possible dependence to caffeine.

Caffeine and Cerebral Energy Metabolism The effects of caffeine on cerebral metabolic rates for glucose (LCMRglcs) described in this review have been explored by the quantitative autoradiographic [ C]2-deoxyglucose method (7) which allows the simultaneous visualization of functional activity in discrete areas of the brain of conscious animals. This technique permits the identification of neuronal pathways affected by a pharmacological agent and is very useful for relating behavioral effects to the central action of a drug. H

Effects of Caffeine on the Nigrostriatal Dopaminergic System and on Locomotor Activity 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. They project via the median forebrain bundle and lateral hypothalamus to the globus pallidus and terminate in the caudate nucleus (8,9). This system is involved in the control of locomotion. The caudate nucleus appears to be very sensitive to the effects of caffeine since LCMRglc is already significantly increased in this structure after the administration of the lowest dose of caffeine, 1 mg/kg to adult male rats (Figure 1). The functional activity of this nucleus is further increased at 2.5 mg/kg, about 40% over control levels and remains activated after 5 and 10 mg/kg caffeine. In the substantia nigra pars compacta and globus pallidus, LCMRglc increases after 2.5-10 mg/kg of caffeine while the sensorimotor cortex shows an increase in LCMRglcs only after 5 mg/kg of caffeine. In accordance with the present data, it has been shown that a direct iontophoretic administration of caffeine modifies the spontaneous electrical activity of neurons in the caudate nucleus (10), and that caffeine is able to induce dopamine release (11,12) and the expression of immediate early genes in the caudate nucleus of the rat (13,14). There is a good correlation between caffeine-induced functional activation of structures belonging to the nigrostriatal pathway and the well-known stimulant effects of caffeine on locomotor activity. This effect is dose-dependent; the minimal

American Chemical Society Library 1155 IBth St., N.W. In Caffeinated Beverages;DC Parliment, Washington, 20036T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.

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dose of caffeine necessary to affect locomotion is 1.5 mg/kg which correlates well with the increase in LCMRglc recorded in the caudate nucleus after 1 mg/kg caffeine. The stimulant effect of caffeine on locomotion increases with doses up to 20 mg/kg and decreases with doses higher than 40 mg/kg (1,2).

Figure 1: Effects of increasing doses of caffeine on LCMRglcs. Data are presented as percent of variation from control values. Rats received caffeine i.v. at 15 min before the onset of the [ C]2-deoxyglucose procedure (IS). Abbreviations: SNPC: substantia nigra pars compacta, DMCAU: dorsomedial caudate nucleus, GPAL: globus pallidus, SMCX: sensorimotor cortex. * ρ < 0.05, ** ρ < 0.01, statistically significant differences from controls (Dunnett's t-test for multiple comparisons). J4

Effects of Caffeine on the Noradrenergic and Serotoninergic Cell Groupings and on the Sleep-Wake Cycle The serotoninergic cell groupings, the medial and dorsal raphe nuclei as well as the noradrenergic cell grouping, the locus coeruleus are very sensitive to caffeine. These structures are involved in the control of sleep, mood and well-being (18). In the 3 structures, LCMRglcs are already activated after 1 mg/kg and remain increased at the higher doses of caffeine used, 2.5-10 mg/kg (Figure 2). These data


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correlate well with the known sensitivity of sleep and mood to caffeine (18,19). Indeed, in the rat, caffeine stimulates spontaneous electrical activity in neurons of the reticular formation; this effect appears at low doses, 1-2.5 mg/kg i.v. and its extent and duration increase with the dose (20,21). Caffeine (0.1-0.5 mg/kg) lowers also electrical activity in the thalamus which appears as an important site for the arousal induced by caffeine (22,23). Moreover, caffeine reduces serotonin availability at postsynaptic receptor sites (24) which elicits a reduction in the sedative effect of the amine on activity and influences sleep mechanisms and motor function (25,26).

Noradrenergic and serotoninergic cell groupings

• 1 mg/kg • 2,5 mg/kg ED 5 mg/kg Β10 mg/kg

M RAP

DRAP

LC

Figure 2: Effects of increasing doses of caffeine on LCMRglcs. Data represent percent of variation from control values. Rats received caffeine /.v. at 15 min before the onset of the [ C]2-deoxyglucose procedure (13). Abbreviations: MRAP: medial raphe, DRAP: dorsal raphe, LC: locus coeruleus. * ρ < 0.05, ** ρ < 0.01, statistically significant differences from controls (Dunnett's t-test for multiple comparisons). I4

Effects of Caffeine on the Mesolimbic Dopaminergic System and Addictive Effects The possible dependence on caffeine has been questioned for over a decade (27-31). The mesolimbic dopaminergic system which plays a critical role in drug


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dependence (32) originates in the ventral tegmental area, projects to the nucleus accumbens and terminates in the medial prefrontal cortex. The nucleus accumbens that plays a central role in the mechanism of drug dependence is divided into a core and a shell part. The medioventral shell is related to the limbic "extended amygdala" assumed to play a role in emotional, motivational and reward functions, whereas the laterodorsal core regulates somatomotor functions (33). The specificity of cocaine, amphetamine, morphine, alcohol and nicotine is to selectively activate dopamine release in the shell of the nucleus accumbens (34,35), a property that has been related to the strong addictive properties of these drugs (32,36). Conversely caffeine at doses ranging from 0.5-5 mg/kg does not trigger any release of dopamine in the shell of the nucleus accumbens (37).

Mesolimbic dopaminergic system ο

• 1 mg/kg • 2,5 mg/kg El 5 mg/kg 1810 mg/kg

VTA

ACSH

ACCO

PFCX

Figure 3: Effects of increasing doses of caffeine on LCMRglcs. Data are presented as percent of variation from control values. Rats received caffeine i.v. at 15 min before the onset of the f CJ2-deoxyglucose procedure (13). Abbreviations: VTA: ventral tegmental area, ACSH, nucleus accumbens, shell, ACCO: nucleus accumbens, core, PFCX: medial prefrontal cortex. * ρ < 0.05, ** ρ < 0.01, statistically significant differences from controls (Dunnett's t-test for multiple comparisons). J4

Our data show that the increase in LCMRglcs recorded in the structures of the mesolimbic dopaminergic system are of lower amplitude than those recorded in



51 the other brain regions studied (Figure 3). Moreover the significant activation of functional activity appears only at quite high doses, 5 mg/kg for the area of origin, the ventral tegmental area and 10 mg/kg for the two subdivisions of the nucleus accumbens and the medial prefrontal cortex. These data show that at the doses daily consumed by most people (2-2.5 mg/kg), caffeine does not activate the brain circuitiy of dependence and reward. Moreover, the activation of functional activity in the shell of the nucleus accumbens occurs only at high doses of caffeine (10 mg/kg, i.e., about 4-5 times the average daily human consumption) at which the methylxanthine activates also the core of the nucleus and induces widespread non specific metabolic increases in a majority of brain regions (1,15-17). These widespread effects of high doses of caffeine on brain functional activity are likely to reflect the numerous adverse side effects of the ingestion of large amounts of caffeine. Conversely the effects of amphetamine, cocaine and nicotine on the neural substrates underlying addiction are rather specific and occur at doses that do not usually lead to the activation of many other brain regions (35,38,39). The difference in the functional consequences of the psychostimulants, cocaine and amphetamine compared to caffeine could relate to their respective mechanism of action. Amphetamine and cocaine induce a release or inhibit the uptake of dopamine (40) which will bind to both D l and D2 dopamine receptors in the striatum. At low doses caffeine acts preferentially at the level of adenosine A2a receptors (41) that are mainly found in the striatum where they colocalize with dopamine D2 receptors (42). When the circulating levels of caffeine increase, the methylxanthine binds also to adenosine A l receptors (41) which are among other regions located in the striatum where they colocalize with D l dopamine receptors (42). In the present study, it appears that caffeine mimics the effects of amphetamine and cocaine only at rather high doses (10 mg/kg) when the binding to A l adenosine receptors is likely to occur.

Conclusion The areas controlling locomotor activity and the sleep-wake cycle appear to be highly sensitive to low concentrations of caffeine while the structures involved in addiction and reward are only activated after high doses of caffeine. These doses activate also numerous brain regions and are likely to induce also the adverse effects occurring after the ingestion of large doses of caffeine (4,43). Our data are rather in accordance with the reported observation that the effects of caffeine are used consciously or unconsciously to manage the mood state and to alleviate the adverse effects of caffeine deprivation (44,45). Moreover, human caffeine consumption is fractioned over the day while the doses given in the present study were injected as an i.v. bolus. Thus, the present data are rather in favor of caffeine acting as a positive reinforcer at doses reflecting the general human consumption and do not support the participation of the brain circuitry of addiction and reward in the dependence on caffeine reported even at very low doses (1 cup/day) in a recent human study (31).


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Acknowledgements This work was suppported by a grant from the Institut National de la Santé et de la Recherche Médicale (INSERM U 272 and 398) and the Institute for Scientific Information on Coffee (LS.I.C) Paris, France.


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Caffeine Effects on the Brain and Behavior: A Metabolic Approach

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