Benzodiazepine tolerance, physical dependence and withdrawal: electrophysiological study of spinal reflex function

The in situ segmental spinal reflex system of the rat was used to determine changes in excitatory and inhibitory synaptic function associated with benzodiazepine tolerance, physical dependence and withdrawal. Rats were made physically dependent on chlordiazepoxide using a chronically equivalent dosing method. After spinalization, dorsal and ventral lumbar roots (L5 or L6) were isolated for extracellular stimulation and recording. Testing of spinal function was performed during peak withdrawal (8 days) and at peak effect (4 hr) after first ("acute") and last ("chronic") dose of chronically equivalent chlordiazepoxide. There were no quantitative or qualitative differences in the acute and chronic spinal actions of chlordiazepoxide. Polysynaptic discharges were markedly augmented during withdrawal (159% above control) and diminished during treatment (44% below control). Recovery of the 2 N reflex measured by twin pulse was shortened during withdrawal (23% above control) and lengthened during treatment (28% below control). Recovery of the 2 N reflex analyzed by low-frequency (10 Hz) stimulation was also elevated at peak withdrawal (40% above control) and depressed in treatment (41% below control). At peak withdrawal spinal inhibitions were reduced below control; presynaptic-dorsal root reflex (60%) and recurrent (62%). In contrast, drug treatment enhanced presynaptic (72%) and recurrent (48%) inhibitions above control. Only those synaptic parameters chronically altered by continuous chlordiazepoxide administration were oppositely affected during withdrawal. Consequently, benzodiazepine withdrawal is associated with rebound alterations of profound reductions in inhibitory synaptic transmission, increased net polysynaptic activity and shortened monosynaptic recovery times.