Since the primary pathological consequences of PD are due to the degeneration of a specific set of neurons that specifically release the neurotransmitter DA, it was suggested that DA-replacement therapy may be effective in treating the disease.² DA itself is not a suitable candidate since it does not cross the blood–brain barrier. For this reason, the pharmacological treatment of PD is largely based on administration of the precursor of DA, 3,4-dihydroxy-L-phenylalanine (L-DOPA). This treatment remains the most effective way to reduce the major symptoms of the disease; however, with prolonged administration the development of debilitating involuntary movements, known as L-DOPA-induced dyskinesias (LIDs), occurs.

In this article, we will present some background information about the regulation of striatal neuron activity and how this is altered not only in the DA-depleted state, but also following chronic L-DOPA administration. Such information is important in guiding more effective treatment strategies for PD.

Dopamine Regulation of Striatal Output
Two distinct pathways connect the striatum to the basal ganglia 'output' structures (see Figure 1). The so-called type I medium-spiny neurons (MSNs) directly inhibit the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). Thus, in this 'direct pathway' striatal neurons disinhibit the thalamic neurons responsible for excitation of the pre-motor cortex.³ As such, activation of the direct pathway facilitates voluntary movements.

The other group of MSNs, known as type II neurons, inhibits the external segment of the globus pallidus (GPe), which suppresses the excitatory cells of the subthalamic nucleus (STN). STN neurons are glutamatergic and excitatory and project to the GPi/SNr. This circuitous route to the thalamus is known as the 'indirect pathway' and provides a mechanism to modulate the disinhibitory actions of the direct pathway on the thalamus. Thus, the direct and indirect pathways act in concert to regulate motor control handled by the basal ganglia. The direct pathway facilitates movement by decreasing the tonic inhibition of basal ganglia 'outputs' to the thalamus, while the indirect pathway suppresses movements by increasing the inhibitory pathway.

In addition to being anatomically divergent, the direct and indirect pathways are also neurochemically distinct. Specifically, MSNs of the direct pathway express high levels of DA (D)-1 receptors (type I neurons), whereas neurons that form the indirect pathway preferentially express the D2 receptors (type II neurons).^4,5 Thus, DA release in the striatum differentially regulates the output of the direct and indirect pathways. D2-receptor stimulation inhibits type II striatal neurons that comprise the indirect output pathway, whereas D1-receptor stimulation facilitates activity in type I (direct pathway) striatal neurons. As such, the actions of DA on the direct and indirect pathways are antagonistic, and given that the direct and indirect pathways excite and attenuate movement, respectively, the net effect of DA is a facilitation of motor output (see Figure 1).