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Improvement

Schizophrenia

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Schizophrenia is a disease with an increased familial incidence. It is characterized by delusions, hallucinations, socially inacceptable behavior and/or inadequate associations (so-called positive symptoms). Lack of motivation and of emotion also frequently occur (so-called negative symptoms). In some patients the positive symptoms predominate (type I), in others the negative ones (type II).

In schizophrenia there is reduced blood flow and glucose uptake especially in the prefrontal cortex and, in type II patients, also a decrease in the number of neurons (reduction in the amount of gray matter). In addition, abnormal migration of neurons during brain development is of pathophysiological significance (^ A2).

Atrophy of the spiny dendrites of pyramidal cells has been found in the prefrontal cortex and the cingulate gyrus. The spiny dendrites contain glutamatergic synapses; their gluta-matergic transmission is thus disturbed (^A1). In addition, in the affected areas the formation of GABA and/or the number of GABAergic neurons seems to be reduced, so that inhibition of pyramidal cells is reduced.

Special pathophysiological signficance is ascribed to dopamine: excessive availability of dopamine or dopamine agonists can produce symptoms of schizophrenia, and inhibitors of D2 dopamine receptors have been successfully used in the treatment of schizophrenia (see below). On the other hand, a reduction in D2 receptors has been found in the prefrontal cortex (^ A1), and a reduction of D, and D2 receptors correlates with negative symptoms of schizophrenia, such as lack of emotions. It is possible that the reduction in dopamine receptors is the result of an increased dopamine release and in itself has no pathogenetic effect.

Dopamine serves as a transmitter in several pathways (^ B):

♦ Dopaminergic pathways to the limbic (me-solimbic) system; and

♦ to the cortex (mesocortical system) are probably essential in the development of schizophrenia.

♦ In the tubuloinfundibular system dopamine controls the release of hypophyseal hormones

(especially inhibition of prolactin release; ^ p. 260 ff.).

♦ It controls motor activity in the nigrostriatal system (^p. 312ff.).

Release and action of dopamine are increased by several substances that promote the development of schizophrenia (^A3, left). Thus, the dopaminergic treatment of Parkinson's disease can lead to symptoms of schizophrenia, which in turn can limit the treatment ofParkinson's disease:

♦ L-dopa leads to an increased formation and release of dopamine.

♦ Monoamine oxidase inhibitors (MAO inhibitors) inhibit the breakdown of dopamine and thus increase its availability for release in the synaptic cleft.

Cocaine stimulates dopamine release in the synaptic cleft, too.

♦ Amphetamine inhibits dopamine uptake in presynaptic nerve endings and thus at the same time raises the transmitter concentration in the synaptic cleft.

Conversely, antidopaminergic substances can improve schizophrenia (^A3, right):

♦ Some substances (e.g., phenothiazines, hal-operidol) displace dopamine from receptors and thus have an antidopaminergic action.

♦ Inhibition of the uptake of dopamine in the synaptic vesicle, for example, by reserpine, ultimately impairs the release of the transmitter in the synaptic cleft. However, reserpine is at present not used therapeutically.

The long-term use of dopamine antagonists in a patient with schizophrenia can lead to "tardive dyskinesia" as a result of their action on the striatum (^p. 314). This complication can limit the treatment of schizophrenia.

It is possible that serotonin also plays a role in producing schizophrenic symptoms. Excessive serotonin action can cause hallucinations, and many antipsychotic drugs block 5-HT2A receptors (^ A1).

Negative symptoms:

lack of motivation, lack of emotion

Negative symptoms:

lack of motivation, lack of emotion

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Dependence, Addiction

Dependence or rather addiction is an acquired compulsion that dictates the behavior of those who are dependent or addicted. In drug dependence there is a great craving for the particular drug. For the dependent person, obtaining and supply of the drug become priorities overall other kinds of behavior. Among the most important of such drugs are nicotine, alcohol, opiates, and cocaine. There are, however, also many other drugs (especially sleeping pills [hypnotics] and analgesics) that can lead to dependence.

It is not only the supply of the particular drug that is important in the development of addiction, as only some of those who take a drug become dependent. Of great significance for the development of addictive behavior is a genetic disposition (^ A). It has been shown that in those dependent on alcohol or cocaine, certain polymorphisms of the gene for the do-pamine transporter (DAT-1) are especially common. Genetic defects of acohol dehydro-genase (ADH) or acetaldehyde dehydrogenase (ALDH) impair the breakdown of alcohol and thus increase its toxic effect. These enzyme defects therefore protect against alcohol dependence. The attempt has been made to achieve pharmacological inhibition of ALDH (with de-sulfiram) in order to force an increase in acet-aldehyde and thus stop addictive behavior through the toxic effect of acetaldehyde (nausea, vomiting, hypotension). Because of the high risk and relatively limited success this approach has now been abandoned.

Another important factor in dependence is the social context (^ A). Thus, a change in social environment can make it easier to give up drugs. Most of the soldiers, for example, who took drugs during the Vietnam War were not addicted after their return to the USA.

Frequently addicts develop a tolerance to the substance and the initial effect gradually weakens if drug intake continues (^ A,B). If intake is suddenly discontinued, there is a reversal of effect (^ B). Chronic intake weakens the effect of the drug and increases the reversal effect on discontinuance. If the addict wants to attain the same effect, the dosage has to be increased. When the drug is discontinued, withdrawal symptoms develop that get worse the longer the drug addiction had lasted. Withdrawal symptoms lead to physical dependence in the addict. Psychological dependence is the result of the need for the positive effects of the drug and/or the fear of the neurobiological or psychological withdrawal symptoms (^ A). The desire for the positive effects remains after the withdrawal symptoms have abated. Stress, among other factors, favors relapse.

Mesolimbic and mesocortical dopaminergic pathways (^ A; see also p. 352) apparently play an important role in the development of dependence or addiction. By activating these pathways, for example, with alcohol or opiates, the addict tries to produce a feeling of wellbeing or euphoria or, conversely, to prevent dysphoria. It is possible that on withdrawing the substance the activity of the do-paminergic system is reduced or the target cells are less sensitive. Withdrawal symptoms can be attenuated by activating endorphiner-gic, GABAergic, dopaminergic, or serotoniner-gic receptors.

The cellular mechanisms of tolerance have been in part elucidated for opiates. Stimulation ofthe receptors leads to phosphorylation via G protein receptor kinases and thus to the inacti-vation of the receptor (^ C). The receptors are also internalized. The effectiveness of receptor stimulation can also be reduced by influencing cellular signal transmission. The opiate receptor acts partly via inhibition of adenylylcyclase (AC), a decrease of cyclic adenosine monophosphate (cAMP) and reduced activation of protein kinase A (^ D). Taking opiates thus at first diminishes cAMP formation (^E2). Chronic intake, however, raises the expression of adenylylcyclase by influencing cAMP-responsive element-binding protein ([CREB] ^ p. 6 ff.). As a result, even in the presence of opiates, cAMP is still formed (^E3). Subsequent withdrawal of opiates will, for example, via a massive increase in cAMP (^ E4), lead to withdrawal symptoms.

Stress

Genetic disposition

ADH)

Social context

Drug intake

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