[ Pobierz całość w formacie PDF ]
Schmidt/Smolka/Rommelspacher 42
hGH (AUC)
hGH (AUC)
Discussion
Due to the dopamine hypothesis of addiction activation of the mesocortico-
limbic system is known to be a fundamental principle of reinforcement by drugs
of abuse that elicits psychomotor and motivational responses [18 21]. Increased
mesolimbic dopamine-mediated transmission was shown to occur after acute
administration of drugs of abuse, while longer-lasting neuroadaptive changes have
been observed during chronic drug use. In the case of psychostimulants and
opioids they may result in an augmented increase of dopamine release in the
nucleus accumbens (sensitization), while for ethanol the results are inconsistent
[1]. In contrast, drug withdrawal is often followed by a decrease in dopamine func-
tion that was shown for psychostimulants, opioids, ethanol and nicotine [1, 22].
As most of these findings were obtained in animal studies, we were
interested in neurobiological changes of the dopamine function in various
subgroups of human addicts. Therefore, the growth hormone secretion pattern
following a dopamine challenge was chosen to assess the central dopamine
function. However, it is unclear to what extent a hypothalamically mediated,
dopaminergic response is indeed informative about the functions of the
mesolimbic-mesocortical system.
Dopamine responsivity in alcoholics was demonstrated to be reduced
during chronic intoxication and tended to normalize with abstinence. We know
from other studies that the dopamine function is more compromised with a
higher intake [8] and there is a better treatment outcome in patients with a less
compromised dopamine system [16, 17]. Our finding that secretion of human
growth hormone after stimulation with the dopamine agonist apomorphine was
significantly lower or blunted in nonsmoking alcoholics (during chronic
ethanol intoxication) compared with findings in smoking alcoholics could
mean that smoking leads to a restoration or normalization of ethanol-induced
dopamine dysfunctions. The mechanism by which this effect is produced is
not clear, but one explanation might imply the release of dopamine by the
interaction of nicotine with nicotinergic receptors [2, 20].
Interestingly, neuroendocrine data in nonalcoholic smokers pointed to a
reduced dopaminergic responsivity possibly due to changes in postsynaptic
receptor functions as a consequence of increased dopamine release during ad
libitum smoking conditions. This interpretation would fit the finding of
Salonkangas et al. [23] evidencing high levels of dopamine activity in the basal
ganglia of cigarette smokers. After overnight abstinence dopaminergic respon-
sivity in smokers was again shown to range within decreased levels. It might be
speculated whether decreases in brain function during nicotine withdrawal
might reflect a low dopamine release [22, 24] that was not compensated on a
postsynaptic level as measured within our neuroendocrine test design.
Dopaminergic Dysfunction 43
Growth hormone levels after dopaminergic stimulation tended to be
normal in opioid addicts. A normalization of neuroendocrine or other brain
function could be due to a longer lasting adaptation of postsynaptic dopamine
receptors or altered gene expression during chronic opiate intoxication [25].
After opiate withdrawal a dramatic decrease in dopamine function could be
observed even 7 days after the discontinuation of drug opiate that had been
even more pronounced when an opioid antagonist had been used for rapid
detoxication.
Taking these results together, there is ample evidence that dopamine
dysfunction is a common final pathway in various forms of the addictions. The
alterations, however, differ with regard to the type of drug abused and the state
of disease.
References
1 Spanagel R, Weiss F: The dopamine hypothesis of reward: Past and current status. Trends
Neurosci 1999;22:521 527.
2 Dani JA, Heinemann S: Molecular and cellular aspects of nicotine abuse. Neuron 1996;16:
905 908.
3 Schultz W: Dopamine neurons and their role in reward mechanisms. Curr Opin Neurobiol 1997;7:
191 197.
4 Koob GF, Le Moal M: Drug abuse: Hedonic homeostatic dysregulation. Science 1997;278:52 58.
5 Robinson TE, Berridge KG: The neural basis of drug craving: An incentive-sensitization theory of
addiction. Brain Res Brain Res Rev 1993;3:247 291.
6 Wise RA: Neurobiology of addiction. Curr Opin Neurobiol 1996;2:243 251.
7 Balldin J, Berggren U, Lindstedt G, Sundkler A: Further neuroendocrine evidence for reduced D2
dopamine receptor function in alcoholism. Drug Alcohol Depend 1993;32:159 162.
8 Schmidt LG, Dettling M, Graef KJ, Heinz A, Kuhn S, Podschus J, Rommelspacher H: Reduced
dopaminergic function in alcoholics is related to severe dependence. Biol Psychiatry
1996;39:193 198.
9 WHO: International Classification of Diseases, rev 10, chap 5 (F): Mental and behavioral
disorders. Clinical descriptions and diagnostic guidelines. Geneva, World Health Organization,
1991.
10 Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, Burke J, Farmer A, Jablenski A, Pickens R,
Regier DA, Sartorius N, Towler LH: The composite international diagnostic interview: An
epidemiological instrument suitable for use in conjunction with different diagnostic systems and
in different cultures. Arch Gen Psychiatry 1988;45:1069 1077.
11 Schmidt LG, Smolka M: Relapse prevention in alcoholics by cigarette smoking? Involvement of
nicotine-dopaminergic mechanisms. Alcohol 2001;24:111 115.
12 Schmidt LG, Kuhn S, Smolka M, Schmidt K, Rommelspacher H: Lisuride, a dopamine D2 receptor
agonist, and anticraving drug expectancy as modifiers of relapse in alcohol dependence.
Prog Neuropsychopharmacol Biol Psychiatry 2002;26:209 217.
13 Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM: Assessment of alcohol
withdrawal: The revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar).
Br J Addict 1989;84:1353 1357.
14 Smolka M, Schmidt LG: The influence of heroin dose and route of administration on the severity
of the opiate withdrawal syndrome. Addiction 1999;94:1191 1198. [ Pobierz całość w formacie PDF ]
zanotowane.pl doc.pisz.pl pdf.pisz.pl aikidobyd.xlx.pl
Schmidt/Smolka/Rommelspacher 42
hGH (AUC)
hGH (AUC)
Discussion
Due to the dopamine hypothesis of addiction activation of the mesocortico-
limbic system is known to be a fundamental principle of reinforcement by drugs
of abuse that elicits psychomotor and motivational responses [18 21]. Increased
mesolimbic dopamine-mediated transmission was shown to occur after acute
administration of drugs of abuse, while longer-lasting neuroadaptive changes have
been observed during chronic drug use. In the case of psychostimulants and
opioids they may result in an augmented increase of dopamine release in the
nucleus accumbens (sensitization), while for ethanol the results are inconsistent
[1]. In contrast, drug withdrawal is often followed by a decrease in dopamine func-
tion that was shown for psychostimulants, opioids, ethanol and nicotine [1, 22].
As most of these findings were obtained in animal studies, we were
interested in neurobiological changes of the dopamine function in various
subgroups of human addicts. Therefore, the growth hormone secretion pattern
following a dopamine challenge was chosen to assess the central dopamine
function. However, it is unclear to what extent a hypothalamically mediated,
dopaminergic response is indeed informative about the functions of the
mesolimbic-mesocortical system.
Dopamine responsivity in alcoholics was demonstrated to be reduced
during chronic intoxication and tended to normalize with abstinence. We know
from other studies that the dopamine function is more compromised with a
higher intake [8] and there is a better treatment outcome in patients with a less
compromised dopamine system [16, 17]. Our finding that secretion of human
growth hormone after stimulation with the dopamine agonist apomorphine was
significantly lower or blunted in nonsmoking alcoholics (during chronic
ethanol intoxication) compared with findings in smoking alcoholics could
mean that smoking leads to a restoration or normalization of ethanol-induced
dopamine dysfunctions. The mechanism by which this effect is produced is
not clear, but one explanation might imply the release of dopamine by the
interaction of nicotine with nicotinergic receptors [2, 20].
Interestingly, neuroendocrine data in nonalcoholic smokers pointed to a
reduced dopaminergic responsivity possibly due to changes in postsynaptic
receptor functions as a consequence of increased dopamine release during ad
libitum smoking conditions. This interpretation would fit the finding of
Salonkangas et al. [23] evidencing high levels of dopamine activity in the basal
ganglia of cigarette smokers. After overnight abstinence dopaminergic respon-
sivity in smokers was again shown to range within decreased levels. It might be
speculated whether decreases in brain function during nicotine withdrawal
might reflect a low dopamine release [22, 24] that was not compensated on a
postsynaptic level as measured within our neuroendocrine test design.
Dopaminergic Dysfunction 43
Growth hormone levels after dopaminergic stimulation tended to be
normal in opioid addicts. A normalization of neuroendocrine or other brain
function could be due to a longer lasting adaptation of postsynaptic dopamine
receptors or altered gene expression during chronic opiate intoxication [25].
After opiate withdrawal a dramatic decrease in dopamine function could be
observed even 7 days after the discontinuation of drug opiate that had been
even more pronounced when an opioid antagonist had been used for rapid
detoxication.
Taking these results together, there is ample evidence that dopamine
dysfunction is a common final pathway in various forms of the addictions. The
alterations, however, differ with regard to the type of drug abused and the state
of disease.
References
1 Spanagel R, Weiss F: The dopamine hypothesis of reward: Past and current status. Trends
Neurosci 1999;22:521 527.
2 Dani JA, Heinemann S: Molecular and cellular aspects of nicotine abuse. Neuron 1996;16:
905 908.
3 Schultz W: Dopamine neurons and their role in reward mechanisms. Curr Opin Neurobiol 1997;7:
191 197.
4 Koob GF, Le Moal M: Drug abuse: Hedonic homeostatic dysregulation. Science 1997;278:52 58.
5 Robinson TE, Berridge KG: The neural basis of drug craving: An incentive-sensitization theory of
addiction. Brain Res Brain Res Rev 1993;3:247 291.
6 Wise RA: Neurobiology of addiction. Curr Opin Neurobiol 1996;2:243 251.
7 Balldin J, Berggren U, Lindstedt G, Sundkler A: Further neuroendocrine evidence for reduced D2
dopamine receptor function in alcoholism. Drug Alcohol Depend 1993;32:159 162.
8 Schmidt LG, Dettling M, Graef KJ, Heinz A, Kuhn S, Podschus J, Rommelspacher H: Reduced
dopaminergic function in alcoholics is related to severe dependence. Biol Psychiatry
1996;39:193 198.
9 WHO: International Classification of Diseases, rev 10, chap 5 (F): Mental and behavioral
disorders. Clinical descriptions and diagnostic guidelines. Geneva, World Health Organization,
1991.
10 Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, Burke J, Farmer A, Jablenski A, Pickens R,
Regier DA, Sartorius N, Towler LH: The composite international diagnostic interview: An
epidemiological instrument suitable for use in conjunction with different diagnostic systems and
in different cultures. Arch Gen Psychiatry 1988;45:1069 1077.
11 Schmidt LG, Smolka M: Relapse prevention in alcoholics by cigarette smoking? Involvement of
nicotine-dopaminergic mechanisms. Alcohol 2001;24:111 115.
12 Schmidt LG, Kuhn S, Smolka M, Schmidt K, Rommelspacher H: Lisuride, a dopamine D2 receptor
agonist, and anticraving drug expectancy as modifiers of relapse in alcohol dependence.
Prog Neuropsychopharmacol Biol Psychiatry 2002;26:209 217.
13 Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM: Assessment of alcohol
withdrawal: The revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar).
Br J Addict 1989;84:1353 1357.
14 Smolka M, Schmidt LG: The influence of heroin dose and route of administration on the severity
of the opiate withdrawal syndrome. Addiction 1999;94:1191 1198. [ Pobierz całość w formacie PDF ]