Basal Ganglia and Cerebellum

The basal ganglia and the cerebellum interact with the cortex through a series of feedback circuits. The basal ganglia, a group of midbrain nuclei, are involved mainly with the initiation and execution of a movement, whereas the cerebellum tends to modulate ongoing movement (Fig. 5). Again, pathology clearly describes the role played by these structures in motor coordination. The most relevant disorders are the dyskinesias, or abnormal movements. Basal ganglia degeneration results in movement disorders such as Parkinson's disease (selective destruction of dopamine-con-taining neurons) and Huntington's disease (selective destruction of GABA interneurons). Parkinson's disease is classically associated with the triad of resting tremors, muscle rigidity (cogwheel-like), and slowness of movement (bradykinesia, with a festinating gait). Huntington's dyskinesias tend to be the opposite of Parkinson's, with excessive initiation of unwanted movements. Cerebellar degeneration is associated with asynergy, the inability to achieve a properly timed and balanced activation of the muscles during movement. Asynergy causes a decomposition of movements, resulting in the move going too far or falling short (dysmetria—the error is overcom-pensated). The gait becomes uncertain in cerebellar damage, with the feet placed far apart and the steps overshooting (ataxia), and it is no longer possible to make movements in rapid succession (dysdiadochokinesia). There are corresponding disturbances of speech and vision. In cerebellar injuries, the tremors do not appear at rest, but rather occur during movement (intention tremors), and the muscle tone tends to be low, with weak muscles that become tired easily. These are the kind of disturbances often seen at the roadside in field sobriety exercises such as one-leg-stand, walk-and-turn, and the finger-to-nose test when a driver is under the influence of drugs such as marijuana.

CB1 receptors are highly expressed in the basal ganglia and the cerebellum. To understand the possible effect of THC binding to these receptors, some well-established neuronal connections between these structures are relevant to review prior to correlation with CB1 receptor distribution. The basal ganglia illustrates well the concept of disinhibition at the neuronal level. Two key pathways are described: the direct and the indirect pathways (Figs. 6 and 7).

The association cortex and substantia nigra send excitatory impulses to the caudate putamen. The excitation comes from the neurotransmitter released at these synapses, glutamate, which is the major excitatory amino acid transmitter in the human brain. This in turn activates a GABA interneuron, GABA being the major inhibitory neurotransmitter in the human brain. The release of GABA occurs in the globus pallidus (internal segment) and at the synapse of another GABA neuron. This latter neuron is called a tonic neuron. It is always active, releasing GABA in motor nuclei of the thalamus (ventral lateral and anterior), resulting in inhibition of the thalamic excitatory outflow to the premotor cortex. The stimulation of the GABA interneuron turns off (inhibits) the tonic GABA neuron, resulting in disinhibition of the excitatory thalamic outflow to the premotor cortex: as a result, movement is initiated. Electrophysiology has shown that electrical activity in the tonic GABA neuron ceases before execution of a complex movement and resumes once the movement is underway.

The indirect pathway is more complex than the direct pathway. The tonic GABA neuron from the internal segment of globus pallidus is also under excitatory control from a glutamate excitatory interneuron from the subthalamic nucleus. Under normal conditions, this glutamate interneuron is inhibited by a tonic GABA neuron that arises from the globus pallidus external segment. In the indirect pathway, excitatory inputs from the associative cortex turn on a GABA interneuron from the caudate-putamen. This prevents the tonic GABA neuron from the globus pallidus from firing and disinhibits the glutamate interneuron from the subthalamic nucleus. The firing of the glutamate interneuron results in stronger inhibitory tone from the tonic GABA neuron projecting to the thalamus and prevents movement from being initiated. An alternative with the opposite effects arises from dopamine-containing inhibitory neurons from substantia nigra impacting the same GABA interneuron as the cortical excitatory input. The indirect pathway antagonizes the direct pathway and therefore allows fine control of the excitatory outputs to motor and premotor cortices, allowing coordinated movements to occur.

Association

Cortex Premotor

Association

Cortex Premotor

Premotor Cortex

Fig. 6. Initiation of movement: the direct pathway. Neurons in dashed line are inhibitory, containing principally y-aminobutyric acid (GABA); neurons in solid line are excitatory, containing principally glutamate. A tonic neuron is a neuron that always fires. CB1 receptors are found on GABA interneurons and glutamate projection neurons, leading to complex motor effects.

Fig. 6. Initiation of movement: the direct pathway. Neurons in dashed line are inhibitory, containing principally y-aminobutyric acid (GABA); neurons in solid line are excitatory, containing principally glutamate. A tonic neuron is a neuron that always fires. CB1 receptors are found on GABA interneurons and glutamate projection neurons, leading to complex motor effects.

Cerebellar Drugs

Fig. 7. Initiation of movement: the indirect pathway. Neurons in dashed line are inhibitory, containing principally y-aminobutyric acid (GABA); neurons in solid line are excitatory, containing principally glutamate. A tonic neuron is a neuron that always fires. The indirect pathway opposes itself to the direct pathway, allowing coordination of movements. Notice the role of nigral dopamine in movement initiation.

Fig. 7. Initiation of movement: the indirect pathway. Neurons in dashed line are inhibitory, containing principally y-aminobutyric acid (GABA); neurons in solid line are excitatory, containing principally glutamate. A tonic neuron is a neuron that always fires. The indirect pathway opposes itself to the direct pathway, allowing coordination of movements. Notice the role of nigral dopamine in movement initiation.

Basal Ganglia Cerebellar Pathways
Fig. 8. Cerebellar pathways: CB1 receptors are found on virtually all principal glutamate or y-aminobutyric acid inputs to cerebellar Purkinje cells.

In the basal ganglia, CB1 receptors are found on GABA medium spiny projection neurons (interneurons), particularly at the axon terminal. CB1 receptors are also found on glutamate projection neurons, and whereas GABA interneurons are inhibitory, glutamate neurons are excitatory. The effect on movement initiation is therefore complex, depending on which system is inhibited by CB1 receptor stimulation. Basal motor activity is regulated in part by CB1 receptors, and a general inhibition of movement and tremors has been reported in animal experiments and human observations. Decreased glutamate release from the subthalamic neurons (indirect pathway) would result in this inhibition, as well as a decreased release of GABA from interneurons of the direct pathway or from the GABA tonic neurons of the globus pallidus projecting to the subthalamic nucleus (indirect pathway).

The wiring to and from the cerebellum is analogous to the ones in the basal ganglia (Fig. 8). The cerebellum receives three kinds of information: from the cortex, from vestibular nuclei in the brainstem, and from the spinal cord. The impulses come through excitatory climbing and mossy fibers. Climbing fibers are important because they adjust the flow of information that reaches the Purkinje cells and influence motor learning by inducing plastic changes in the synaptic activity of Purkinje neurons. The cerebellum has a unique output, the Purkinje neurons, which are GABA-containing neurons. They send information through inhibitory control of deep cerebellar relay nuclei, which in turn inform the thalamus and then the cortex, giving the cerebellum access to corticospinal projection neurons. This allows the cerebellum to organize the sequence of muscular contractions in complex ongoing movements and finely regulate them.

CBj receptors are found on virtually all the principal glutamate and GABA inputs to cerebellar Purkinje cells and, through inhibition of glutamate or GABA release, can exert complex motor effects.

Rodriguez de Fonseca et al. (33) have reviewed the literature related to motor effects of Cannabis on animals and humans. Studies of locomotor activities (LMA) in mice have showed dose-dependent effects of THC, with a decreased LMA at doses of 0.2 mg/kg and increased LMA at doses of 1-2 mg/kg and eventually catalepsy at doses in excess of 2.5 mg/kg. These changes could relate to differential sensitivities of neuron populations to CB1 stimulation, resulting in different levels of inhibition of excitatory glutamate or inhibitory GABA release. Human studies have corroborated these results: impaired balance (34) and problems with tracking and pursuit of a moving point of light (35). Importantly, often unpublished Drug Recognition Officer reports filled out by law-enforcement experts and collected in a number of forensic toxicology laboratories anecdotally support the impaired locomotor functions of humans under the influence of Cannabis. Some interesting new studies have used knockout mice models. A knockout mouse is an animal model in which a fertilized ovum from a pregnant female mouse (rat) has been genetically altered in a way to delete a specific gene and is then reimplanted to allow the pregnancy to continue. The offspring is then referred to as a knockout animal because in every nucleated cell a specific gene is missing. The lack of expression of the protein encoded by the missing gene results in symptoms that can be carefully correlated with the role of this protein in the wild animal. However, it is impossible to predict any effects from compensatory changes in expression of other genes as a result of the deletion. CB1 knockout mice have been developed (36) and have been extensively studied. But conflicting results have been reported: a decreased basal activity in these animals suggests that tonic activation of CB1 receptors actually promote movements. On the other hand, Ledent et al. (37) showed increased locomotor activity in a different strain of knockout mice (CD1 vs C57BL/6J). The availability of a selective antagonist of CB1 receptors, rimonabant (SR141716A), also contributed some information on the effects of THC on psychomotor movement, with an increased LMA noted in mice treated with the antagonist (38).

Continue reading here: Effects of Cannabinoids on the Limbic System

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