Original articleElevated motor threshold in drug-free, cocaine-dependent patients assessed with transcranial magnetic stimulation
Introduction
Cocaine has been shown to influence both excitatory (glutamate [GLU]) and inhibitory (γ-aminobutyric acid [GABA]) brain neurotransmitters. A relative balance of GABA and GLU neurotransmission is involved in the activation or inhibition of brain circuits (McCormick 1998). Witkin (1993) demonstrated that GLU antagonists can block the locomotor stimulant effects of cocaine. Earlier, Rockhold et al (1991) showed that GLU receptor antagonists can block cocaine induced convulsions and death. Similarly, a relationship between cocaine induced behavior and GABAergic activity has also been demonstrated. The functional status of straiatal GABA-A receptors appears to be inversely related to the magnitude of cocaine-induced behavior (Peris et al 1998). More recently, gamma-vinyl-GABA (GVG), an irreversible inhibitor of GABA transaminase, which increases brain GABA levels, blocked cocaine-induced locomotor activity, and lowered brain stimulation reward threshold (Kushner et al 1999).
To examine this balance of cortical excitation and inhibition we used transcranial magnetic stimulation (TMS). When a stimulus of enough strength is delivered (motor threshold or MT) to the motor cortex the cortico-spinal pathway is activated and the muscle (or muscles) represented by the stimulated region contract. The threshold strength of the magnetic pulse necessary to induce a motor response can then be used as an indication of the degree of cortical excitability of the region stimulated (Abbruzzese et al 1996). MT is thought to reflect ion channel conductivity and hence membrane excitability in pyramidal neurons (Ziemann et al 1996).
Several conditions and pharmacologic manipulations influence this threshold. Conditions causing slow conduction, such as multiple sclerosis, are associated with an elevated MT (Ho et al 1999). Some investigators found patients with Parkinson’s disease to have a lowered MT indicating a state of hyperexcitability or decreased cortical inhibition (Cantello et al 1991), whereas others did not (Priori et al 1994). Furthermore, psychiatric patients have been examined in two studies. Abarbanel et al (1996) provided evidence of a decreased MT in schizophrenic patients consistent with deficient inhibitory processes. This decrease was not present in depressed patients (Abarbanel et al 1996). Palmieri et al (1999) also demonstrated that long-term usage of diazepam in anxiety disorder patients significantly increased MT. In these subjects the MT can be further enhanced by the administration of an additional single dose of diazepam. This increase in MT by diazepam could not be demonstrated in normal control subjects (Ziemann et al 1996); however, Palmieri et al (1999) reported an elevated MT in subjects with a diazepam overdose and subjects with idiopathic recurrent stupor. The administration of flumazenil (a benzodiazepine antagonist) in these two conditions promptly returned normal cortical excitability.
Repeated administration of psychostimulants like cocaine has been shown to induce sensitization. Sensitization implies an increased response to the drug over time. The behavioral sensitization to cocaine might relate to its positive properties of arousal, motor activation, and intense euphoria Gawin and Ellenwood E 1988, Post et al 1987, as well as to increased dysphoria, manic symptoms, and paranoia over time Manschereck et al 1988, Sherer et al 1988. This sensitization process is dependent on the stimulation of glutamate receptors (Pierce et al 1996). The increased sensitivity to the behavioral effects of cocaine is paralleled by increased sensitivity to the proconvulsant effects of this drug (Post 1980).
No direct evidence for sensitization in humans has thus far been provided because of the unavailability of safe technology to examine cortical excitability of human subjects. TMS, thus, provides a unique and exciting opportunity to examine cortical excitability in awake humans in a noninvasive and safe method. This pilot project probes cortical excitability in cocaine-dependent subjects to provide functional evidence for motor sensitization (evidenced by a finding of lowered MT). The presence of altered MT in abstinent subjects may also be evidence of persistent cocaine-induced damage.
Section snippets
Subjects
The motor thresholds of 10 cocaine-dependent subjects (4 men and 6 women, mean age 36 ± 7 years) and 10 age- and gender-matched subjects (4 men and 6 women, mean age 33 ± 6 years) were examined. All subjects signed a consent form approved by the Yale University and the VA-Connecticut Healthcare System Human Investigations Committees.
Based on a clinical interview all cocaine-dependent subjects met DSM-IV criteria for dependence on cocaine but without meeting criteria for dependence on other
Results
Table 1lists the motor thresholds obtained from right and from left stimulation of the motor cortex of each subject.
The mean motor threshold, resulting from stimulation of the right motor cortical region was 65.4 ± 8.3 for the cocaine-dependent subjects and 41.2 ± 10.6 for the control subjects. The mean motor threshold resulting from stimulation of the left motor cortical region was 63.5 ± 10.3 for cocaine-dependent subjects and 42.5 ± 8.9 for control subjects. An analysis of variance (ANOVA)
Discussion
These pilot data suggest that the motor threshold is significantly elevated in chronic cocaine-dependent subjects who are at least 3 weeks abstinent from cocaine use. We hypothesize that this elevated motor threshold could reflect an adaptation to those effects of cocaine intoxication that promote cortical excitability and seizures and/or direct tissue damage rendering the stimulated region less responsive.
The MT is hypothesized to reflect sodium channel conductivity and neuronal membrane
Acknowledgements
A VA Merit Review Award to the senior author supported this work.
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