Dopamine activity

Figure 7.8 Dopamine and motor function. When nigrostriatal dopamine activity is normal so is motor function. Any reduction in this DA activity, as in Parkinson s disease, results in reduced motor activity, i.e. akinesia. By contrast, too much DA activity, as in Huntington s Chorea, produces abnormal motor function, i.e. dyskinesia. The latter may be controlled by neuroleptic drugs (DA antagonists) but they can swing the balance in DA activity sufficiently to produce akinesia (Parkinsonism). DA agonists (and levodopa) may overcome akinesia but can induce DA overactivity and dyskinesia (peak dose effect) (see Chapter 15)...

QUESTION Could these changes in the autoreeeptors account for the cravings for cocaine or amphetamine If you are shutting down dopamine activity, that may lead to the desire to return to cocaine. 

Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 1999 2 358-363. 

Cornil C. A., Balthazart J., Motte P., Massotte L., Seutin V. (2002). Dopamine activates noradrenergic receptors in the preoptic area. J. Neurosci. 22(21), 9320-30. 

Another crucial problem for any neurochemical model is cause and effect. Neuroleptics have a high affinity for dopamine receptors, particularly the D2-subtype. There is also a highly significant positive correlation (r > +0.9) between this receptor binding and their clinical potency (Seeman, 1980). But, this does not necessarily implicate elevated dopamine levels as the cause of schizophrenia. Moreover, blockade of dopamine receptors happens very rapidly, whereas clinical benefits are only seen after chronic treatment. Rose (1973) has criticised the reductionist statement that an abnormal biochemistry causes schizophrenia because it relates cause and effect at different organisational levels (namely, the molecular and behavioural). But, while it can be legitimate to discuss cause and effect at the same level that chlorpromazine blocks dopamine receptors (one molecule altering the response of another), it is not valid to infer that increased dopamine activity causes schizophrenia. Put another way ... 

Indirect mechanisms Nicotine has indirect effects on monoamine systems. A considerable amount of research has examined the relationships between nicotine and dopamine activity in the brain, in light of dopamine s role in reinforcement and nicotine s addictive properties. Nicotine increases dopamine turnover in the striatum and cerebral cortex (Clarke and Reuben 1996 Tani et al. 1997 Nanri et al. 1998). It also increases burst activity in dopamine neurons of the ventral tegmental area (VTA), a primary source of dopamine to the forebrain (Nisell et al. 1995 Fisher et al. 1998). Such a firing pattern in the VTA is associated with processes of reinforcement, learning, and cognitive activity. Nicotine actions on dopaminergic neurons occur at both somatodendritic sites and synaptic terminals. Further, both systemic nicotine and direct administration into the VTA increase dopamine release in the nucleus ac-... 

Overall, p agonists increase transmission in the mesolimbic dopamine system (Devine et al. 1993 Johnson and North 1992). They inhibit GABAergic neurons in the ventral tegmental area, disinhibiting dopamine activity. In contrast, k agonists inhibit dopamine release in the same system. As with other drugs of abuse, an influence on the mesolimbic dopamine is believed to mediate the positive reinforcing effects of opioids. 

Cholinergic antagonists increase dopamine activity in the striatum, as measured in humans with PET (Dewey et al. 1993). The pedunculo-... 

Clarke PB. (1990). Mesolimbic dopamine activation—the key to nicotine reinforcement Ciba Found Symp. 152 153-62 discussion 162-68. 

It is not clear that the different variants of schizophrenia have a common etiology. It may well be that there are important differences in the underlying causes. However, one thing seems clear schizophrenia is associated with an excess of dopamine activity. Here is the supporting evidence. 

Parkinsonism, or Parkinson s disease, is named for James Parkinson who first described the disease back in 1817. It is nsnally a disease of the elderly characterized by a spectrnm of movement disorders involnntary movements, rigidity, slowness, and loss of balance. It may progress to mental impairment, including depression. This is basically the same spectrum of movement disorders sometimes seen in schizophrenia patients taking dopamine antagonists. This snggests that parkinsonism may reflect, in some manner, a deficit in dopamine activity. 

Here is one last word about L-dopa. It delivers dopamine to the entire brain, not just the nigrostriatal pathway. We know from our previous discussion that excess dopamine activity is associated with schizophrenia. It should not surprise you then that a rather common side effect of L-dopa is some of the symptoms of schizophrenia, including hallucinations. 

Dopamine agonists are employed to treat parkinsonism, a disease in which there is a deficit of dopamine activity in the nigrostriatal pathway. 

These paired processes, known as initiation and adaptation, do not represent a new concept. We ve long known that taking a drug one time can have very different effects from taking it repeatedly. Perhaps the most familiar examples are the drugs of abuse. For example, the acute effect of cocaine is to produce an intense but brief euphoria. Cocaine produces this effect by enhancing neurotransmission in dopamine-activated reward circuits in the brain. These initiating effects happen very quickly in response to the action of cocaine in the synapse. 

Third is the presence of other psychiatric or medical disorders. This can help gnide antidepressant selection in several ways. In some cases, an antidepressant may be preferred becanse it can treat both disorders. For example, the extensive evidence that flnoxetine is an effective treatment for bnlimia nervosa makes it preferable for patients with depression and bnlimia. Similarly, the depressed Parkinson s disease patient whose nenrological illness results from a lack of dopamine in a particular area of the brain may have both her depression and her Parkinson s disease improved by bnpropion, which increases brain dopamine activity. In other cases, an antidepressant shonld be avoided if it worsens the other illness or interacts adversely with a medication needed to treat the other illness. For example, TCAs and MAOIs can complicate glncose control in diabetics and shonld not rontinely be used by depressed diabetics. (See Table 3.11.)... 

Typical Antipsychotics. Since their introduction in the 1950s, antipsychotics have played a prominent role in the treatment of bipolar mania. When we recognized that dopamine activity is critical in the brain s reward centers, the notion arose that dopamine hyperactivity may contribute to the euphoria of bipolar mania. Therefore, it was natural to assume that the dopamine-blocking antipsychotics would be effective antimanic medications. 

Dopamine Pathways. Before we describe the typical antipsychotics in any detail, we should digress briefly to talk about the role of dopamine in the brain and how these medications affect it. First, there are four key pathways of dopamine activity in the brain, and each pathway has a particular significance ... 

The second theory is that some atypicals work by balancing dopamine blockade with serotonin receptor blockade. We know that one of the roles of serotonin is to attenuate (or lessen) dopamine activity. Blocking serotonin action therefore may release just enough dopamine activity in the nigrostriatal pathway to avoid EPS without interfering with the antipsychotic effects in the mesolimbic area. 

Yet another MAOI is selegiline (Eldepryl). Unlike the other MAOls, selegiline is seldom used to treat depression. At low doses, selegiline only inhibits the M AO-B enzyme. Therefore, it increases dopamine activity but does not have any pronounced effect on norepinephrine or serotonin. For this reason, it has been less useful as an antidepressant however, its primary use has been to treat Parkinson s disease. Of course, this selectivity for dopamine suggests that it may be helpful for ADHD as well. 

Bupropion (Wellbutrin, Zyban). Bupropion is a newer atypical antidepressant that was initially suggested to increase both norepinephrine and dopamine activity in the brain, though controversy surrounds this hypothesis. Although bupropion has not been studied extensively in ADHD, early evidence does indeed indicate that it may be effective for both inattention and hyperactivity/impulsivity. Its effectiveness for ADHD does not appear to rival the stimulant medications, though a recent controlled study for adult ADHD showed that bupropiou outperformed placebo. 

Norepinephrine-Blocking Medications. Medications that enhance dopamine activity and to a lesser extent those that enhance norepinephrine activity are believed to be the most successful treatments for ADHD. It may seem counterintuitive to try a medication that reduces norepinephrine turnover. The other ADHD medications... 

Despite these alternatives, there are a few patients who cannot tolerate stimulants or who may be susceptible to abusing them. In such cases, the alternatives are limited. The best treatments for poor attention (in lieu of the stimulants) are antidepressants that boost norepinephrine and/or dopamine activity in the brain. Currently, this includes the TCAs, MAOls, and possibly venlafaxine or duloxetine. 

Injury to certain areas within the brain s frontal lobes may produce a syndrome that resembles depression but without depressed mood or a sad affect. Instead, this apathetic syndrome is marked by a lack of motivation, little emotional response, profound psychomotor slowing, and disengagement from social interaction. Antidepressants, stimulants, and medicines that specihcally boost dopamine activity have been tried when treating apathy after TBI (see Table 12.1). 

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