Rapid EEG desynchronization and EMG activation induced by intravenous cocaine in freely moving rats: a peripheral, nondopamine neural triggering

Abstract

Many important physiological, behavioral, and psychoemotional effects of intravenous (IV) cocaine (COC) are too fast and transient compared with pharmacokinetic predictions, suggesting a possible involvement of peripheral neural mechanisms in their triggering. In the present study, we examined changes in cortical electroencephalogram (EEG) and neck electromyogram (EMG) induced in freely moving rats by IV COC administration at low, reinforcing doses (0.25-1.0 mg/kg) and compared them with those induced by an auditory stimulus and IV COC methiodide, which cannot cross the blood-brain barrier. We found that COC induces rapid, strong, and prolonged EEG desynchronization, associated with decrease in alpha and increase in beta and gamma activities, and EMG activation and that both begin within 2-6 s following the start of a 10-s injection; immediate components of this effect were dose independent. The rapid COC-induced changes in EEG and EMG resembled those induced by an auditory stimulus; the latter effects had shorter onset latencies and durations and were fully blocked during urethane anesthesia. Although urethane anesthesia completely blocked COC-induced EMG activation and rapid components of EEG response, COC still induced EEG desynchronization that was much weaker, greatly delayed (approximately 60 s), and associated with tonic decreases in delta and increases in alpha, beta, and gamma activities. Surprisingly, IV saline delivered during slow-wave sleep (but not quite wakefulness) also induced a transient EEG desynchronization but without changes in EMG activity; these effects were also fully blocked during anesthesia. Peripherally acting COC methiodide fully mimicked rapid EEG and EMG effects of regular COC, but the effects at an equimolar dose were less prolonged than those with regular COC. These data suggest that in awake animals IV COC, like somato-sensory stimuli, induces cortical activation and a subsequent motor response via its action on peripheral neural elements and involving rapid neural transmission. By providing a rapid neural signal and triggering transient neural activation, such an action might play a crucial role in the sensory effects of COC, thus contributing to the learning and development of drug-taking behavior.

Fig. 1.

Phasic and tonic changes in electroencephalogram (EEG; top) and electromyogram (EMG; bottom) total powers after intravenous cocaine (COC) administration at different doses. Mean ± SE values are shown in percents vs. preinjection baseline. Vertical hatched lines (0 s) show the start of injections and horizontal hatched lines show basal values (100%). Black symbols show values significantly different (Fisher F-test) from baseline (n = number of tests). ANOVA values for the effect of cocaine on EEG and EMG, respectively, are 0.25 mg/kg, F_12.402 = 20.86, 9.41; 0.50 mg/kg, F_19,610 = 19.48, 15.63; 1.0 mg/kg, F_11,371 = 37.30, 11.10; each P < 0.001.

Fig. 2.

Original examples of EEG and EMG activity (μV at final amplification) recorded in freely moving rats following clap, intravenous COC, and saline injections. Onset (on) and offset (off) of the injection (15 s) is shown with vertical hatched lines. Data were obtained in 3 different rats (S75B7, S78D1, S77B3; first 3 symbols show rat number, the next symbol is session number, and the last symbol is the test number). While intravenous saline injection in many cases did not induce evident EEG changes, the example (S77B3) demonstrates a typical desynchronization when the injection was performed during a prolonged episode of slow-wave sleep.

Fig. 3.

Mean changes in individual EEG frequencies [total power for delta, theta, alpha, beta, and gamma waves] following intravenous COC administration. Similar to Fig. 1, vertical and horizontal hatched lines in each graph show the starts of injections and basal values, respectively. ANOVA values for COC at 0.25 mg/kg [delta: F_13,433 = 1.08, nonsignificant (NS); theta = 3.79, P < 0.001; alpha = 1.90, P < 0.01; beta = 2.85; P < 0.001; gamma = 8.59, P < 0.001]. ANOVA values for COC at 0.50 mg/kg (delta: F_21,681 = 0.88, NS; theta = 3.40, P < 0.001; alpha = 1.93, P < 0.01; beta = 4.00; P < 0.001; gamma = 8.24, P < 0.001). ANOVA values for COC at 1.0 mg/kg (delta: F_11.371 = 1.44, P = 0.06; theta = 4.61, P < 0.001; alpha = 3.32, P < 0.001; beta = 5.64; P < 0.001; gamma = 8.86, P < 0.001).

Fig. 4.

Mean changes in EEG (A and C) and EMG (B and D) total powers induced by intravenous COC (0.5 mg/kg) in drug-free, freely moving conditions (n = 11), during dopamine (DA) receptor blockade (SCH 23390 + eticlopride at 0.2 mg/kg sc, each; n = 18), and urethane anesthesia (1.25 g/kg ip, n = 11). Left: EEG and EMG effects of COC during DA receptor blockade and drug-free control. Right: effects of COC during urethane anesthesia and drug-free control. Black symbols show values significantly different from baseline. ANOVA values for EEG total power are: control, F_10,240 = 7.81, P < 0.001; DA receptor blockade, F_17,557 = 4.07, P < 0.01; anesthesia, F_8,279 = 3.52, P < 0.01. ANOVA values for EMG total power are: control, F_10,240 = 11.37, P < 0.001; DA receptor blockade, F_17,557 = 7.11, P < 0.001; anesthesia, F_8,279 = 0.78, NS.

Fig. 5.

Mean ± SE changes in individual EEG frequencies (delta, theta, alpha, beta, and gamma) following IV COC administration (0.5 mg/kg) in 3 conditions: drug-free control (left), DA receptor blockade (middle), and urethane anesthesia (right). Similar to Fig. 1, vertical and horizontal hatched lines in each graph show the start of injections and basal values, respectively. ANOVA values for the effect of COC in drug-free control (delta: F_10,340 = 0.77, NS; theta = 1.94, P < 0.01; alpha = 1.62, P < 0.05; beta = 3.75; P < 0.001; gamma = 4.04, P < 0.001), following DA receptor blockade (delta: F_17,557 = 1.00, P = 0.47; theta = 1.44, P = 0.06; alpha = 1.70, P < 0.02; beta = 1.10; NS; gamma = 4.57, P < 0.001), and during urethane anesthesia (delta: F_8,278 = 2.84, P < 0.001; theta = 2.42, P < 0.001; alpha = 1.70, P < 0.02; beta = 1.39; NS; gamma = 1.20, NS).

Fig. 6.

Mean changes in EEG (A and C) and EMG (B and D) total powers (%) induced by clap in drug-free, freely moving conditions (A and B) and during urethane anesthesia (C and D). Vertical hatched lines (0 s) show the moments of sound presentation, and horizontal hatched lines show basal values (100% for both EEG and EMG). As assessed by ANOVA with repeated measures (for 120 s poststimulation with a basal value = mean for 60 s prestimulus), clap induced significant and strong effects on EEG and EMG in freely moving conditions (F_20,650 = 6.98 and 11.43; both P < 0.001) but no effect on either parameter during general anesthesia (F_10,340 = 0.94 and 0.84; P = 0.55 and 0.71, respectively). Black symbols show values significantly different (Fischer test) from baseline (mean for 1 min preceding stimulation). Data were compiled from 21 and 11 clap presentations.

Fig. 7.

Mean changes in individual EEG frequencies (delta, theta, alpha, beta, and gamma) following clap and IV saline administration in drug-free, freely moving conditions. Similar to Fig. 2, vertical and horizontal hatched lines in each graph show moments of stimulation and basal values, respectively. ANOVA values for clap are delta power: F_20,650 = 1.26, NS; theta power = 1.98, P < 0.05; alpha power = 2.25, P < 0.01; beta power = 2.48, P < 0.01; gamma power = 10.54; P < 0.001. ANOVA values for IV saline are delta power: F_29,929 = 1.60; theta power = 1.43, NS; delta power = 0.64, NS; alpha power = 2.86, P < 0.01; beta power = 0.97, NS; gamma power = 15.94; P < 0.001.

Fig. 8.

Mean changes in EEG and EMG total powers induced by intravenous administration of COC methiodide (0.67 mg/kg or 1.4 μM) shown together with those induced by regular COC-HCl at equimolar dose (reproduced from Fig. 4 for comparison). For clarity, standard errors are shown only for COC methiodide. Vertical hatched lines (0 s) show the start of injections, and horizontal hatched lines show basal values. ANOVA values for the effect of cocaine methiodide on EEG and EMG are F_18,588 = 6.32, 8.63; each P < 0.001. COC methiodide data represent the average of 13 responses obtained in 4 rats. Interrupted hatched lines at 300–360 s in both graphs show mean values of EEG and EMG total powers for 5th min postinjection. *Significant between-group difference.

Fig. 9.

Mean changes in individual EEG frequencies (%total power for delta, theta, alpha, beta, and gamma waves) following intravenous administration of COC methiodide shown together with those induced by regular COC-HCl at equimolar dose (reproduced from Fig. 5 for comparison). Similar to Fig. 3, vertical and horizontal hatched lines in each graph show the start of injections and basal values, respectively. ANOVA values for the effect of COC methiodide are delta: F_18,588 = 0.78, NS; theta = 3.25, P < 0.001; alpha = 2.08, P < 0.01; beta = 2.84; P < 0.001; gamma = 3.82, P < 0.001. Values significantly different from baseline are shown by black symbols.

Fig. 10.

Mean changes in EEG (A and C) and EMG (B and D) total powers (%) induced by intravenous saline administration in drug-free, freely moving conditions (A and B) and during urethane anesthesia (C and D). Vertical hatched lines (0 s) show the moments of injection start, and horizontal hatched lines show basal values (100% for both EEG and EMG). As assessed by ANOVA with repeated measures (for 120 s poststimulation with a basal value = mean for 60 s prestimulus), intravenous saline administration induced a significant effect on EEG in freely moving conditions (F_29,929 = 2.96) but no effect during anesthesia (F_10,340 = 0.96, P = 0.59). The effect of intravenous saline on EMG was not significant in both conditions (F_29,929 = 0.96, P = 0.54 for freely moving and F_11,371 = 1.02, P = 0.44 for anesthetized conditions). Black symbols show values significantly different (Fischer test) from baseline (mean for 1 min preceding stimulation). Data were compiled from 30 and 12 saline injections.