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The Parkinson's-Reversing Breakthrough

Medication for Parkinsons

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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)

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)

stimulation. Reinforcement is the manner in which one event (stimulus) strengthens the likelihood of its repetition, i.e. repeated lever pressing for a pleasurable reward. In this instance, of course, reinforcement is rewarding but it need not be. Reward and reinforcement are considered by some to be the basis of motivation.

In 1954, Olds and Milner first described the effects of intracranial self-stimulation (ICSS). Rats with electrodes implanted in certain brain regions appeared to find the stimulation mediated through them to be rewarding (pleasurable) and so would seek out whatever part of their surroundings they associated with it. In addition, such self-stimulation reinforced the animal's inclination to indulge in other activity such as pressing a lever for a food reward. Since it was thought that the brain pathways and NTs mediating ICSS could also be responsible for more natural pleasurable rewards such as food, drink and sex their identification generated much interest.

The brain area most commonly, but not uniquely, associated with ICSS is the medial forebrain bundle (MFB). This includes the axons of noradrenergic as well as dopaminergic neurons but it appears to be the ventral tegmentum area and the A10 DA neurons innervating the nucleus accumbens (and prefrontal cortex) which is most active, as evidenced by 2-deoxyglucose autoradiography during self-stimulation. In fact effective, i.e. rewarding, self-stimulation through electrodes in the VTA is accompanied by DA release in the nucleus accumbens (Fiorino et al. 1993). The threshold current (or frequency) of stimulation for the initiation of ICSS is lowered by amphetamine and raised by DA antagonists while the rate of lever pressing in response to a particular level of ICSS is potentiated or reduced by the same respective procedures. Animals also learn to press a lever to initiate the administration (injection) of certain drugs in preference to obtaining food or water and will continue this to a point of intoxication. Dopamine uptake blockers and D2 (or mixed) agonists are all strongly sought in self-administration trials and it became generally accepted that DA was paramount in mediating the reinforcing effects not only of ICSS but also of drug abuse and sex.

As a result of these observations it has been suggested that DA released in the nucleus accumbens is important in motivation by linking reward (especially when it is food) with the motor activity required to achieve it (Mogenson, Jones and Yim 1980). It is difficult, however, to distinguish a pure behavioural role for DA in actually initiating the sense of reward and motivation from its undisputed part in facilitating the motor response necessary to obtain the reward, e.g. a lever press in rats.

Salamone, Cousins and Snyder (1997) in fact suggest that the function of DA in the nucleus accumbens should not be described by terms such as motivation, reinforcement and reward. Rather it should be considered to mediate the higher-order motor and sensory processes that are important for the activation of aspects of motivation and responsiveness to conditioned stimuli.

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