20
Neuroscience Letters, 123 (1991) 20-22 '~', 1991 Elsevier Scientific Publishers Ireland Ltd. 0304-3940/91/$ 03.50 ADONIS 0304394091000783
NSL 07522
Effect of modafinil and amphetamine on the rat catecholaminergic neuron activity Hid~o A k a o k a 1, Bernard Roussel 2, Jian-Sheng Lin 3, G u y Chouvet 1 and Michel Jouvet 3 I l N S E R M U 171, CNRS URA 1195, Centre Hospitalier Lyon-Sud, Pierre-B~nite (France), ZLaboratoire LAFON, Maisons Alfort (France) and 31NSERM U 52, CNRS URA 1195, Universitb Claude Bernard, Lyon (France) (Received 12 July 1990; Revised version received 29 October 1990; Accepted 29 October 1990) Key words:
Modafinil; Amphetamine; Single unit activity; Catecholaminergic neuron
We have studied the effect of modafinil and amphetamine, two waking drugs, on the electrical activity of central dopaminergic and noradrenergic neurons in the rat. Modafinil (128 mg/kg, i.p.) was unable to modify the firing pattern of these neurons, while amphetamine (2 or 5 mg/kg, i.p.) consistently inhibited their activity. A pretreatment with modafinil did not change thereafter the effect of amphetamine. Contrary to amphetamine, the waking effect of modafinil does not seem to be mediated by the catecholaminergic neuron activity per se.
Modafinil, chemically a benzhydrylsulfinylacetamid, induces behavioral long-lasting wakefulness in animal [5]. This property is used to treat succesfully narcoleptic and hypersomniac patients [3, 4]. Contrary to the classical treatment with amphetamines, dependance and tolerance phenomena are never observed in such patients [3]. Since central catecholamines, especially dopamine (DA), are involved in drug dependance mechanisms [8], we carfled out a comparative study on the effects of modafinil (MOD) and d-amphetamine (AMP) on the spontaneous activity of dopaminergic neurons of the mesencephalon and noradrenergic (NA) neurons of the locus coeruleus (LC) in the rat. Extracellular unit recordings were performed in Sprague Dawley rats anesthetized with chloral hydrate (400 mg/kg, i.p., supplemented continuously i.v.) or halothane (1% in air, through tracheal cannula) [2, 6]. Mesencephalic DA neurons (under chloral hydrate) and LC-NA neurons (under halothane) were identified by their characteristic waveform, firing pattern rate and histological location (post mortem examination of dye deposits) according to previously reported criteria [1, 2, 6, 7]. As MOD is not soluble in aqueous solution, drug administrations (dissolved or suspended in physiological saline containing 5% Arabic gum), were realized i.p. (1 ml/kg), except for piperoxan in saline which was administered intravenously via the femoral vein. After at Correspondence: B. Roussel, D6partement de M6decine Exp6rimentale, Facult6 de M6decine, Universit6 Claude Bernard, 8, avenue Rockefeller, 69373 Lyon Cedex 02, France.
least 5 min of baseline recording of a single neuron, MOD or AMP were administered i.p. Their effects on discharge rate were studied for over 1 h following their injection as it has been shown that such MOD administration induced at least 2 consecutive hours of wakefulness in rats (Roussel, unpublished results). At the end of the experiment, typical pharmacological responsiveness of recorded neurons was sometimes assessed by systemic administration of AMP, the DA antagonist haloperidol (HAL), and the ~2 antagonist piperoxan (PIP). For quantitative analysis, all spike counts were taken from computer records of integrated impulse activity. Because it was not possible to predict the recording time of a given cell after drug administration, discharge rates (in Hz) were determined over a 5-20 min period, prior to drug administration and within consecutive time periods following drug administration (t= 0): 0-20; 20-40; 40-60; 60-80 min. Comparisons of absolute firing rates of the same cells before and after drug administration, within each of these time periods, were performed using the two-tailed Student's t-test for paired observations, with a significance criterion of P = 0.05 or less. Results are given as mean___S.E.M. Mesencephalic DA neurons. As no difference was noted between pharmacological responsiveness of substantia nigra and ventral tegmental area DA neurons, pharmacological data obtained from the two populations were pooled for statistical analysis. We verified the high efficacy of systemic administration of AMP (5 mg/ kg, i.p.) [9] which consistently inhibited all DA neurons tested (n=7) with a latency of maximal inhibition
21
NA
DA 3"
-f I rJ) id.I
(18)
(11
(7)
(7)
¢7
e. (J)
C
M
A
1
uIj
0
C
M
A
Fig. 1. Mean discharge rate in spike/s (_ S.E.M.) of mesencephalic DA (left) and LC-NA (right) neurons in the first 20 min period after injection of modafinil (M) (128 mg/kg, i.p.) of d-amphetamine (A) (5 mg/ kg, i.p., for DA cells and 2 mg/kg, i.p., for NA cells) as compared to the 5 min preinjection basal rate (C). Number of sampled neurons is indicated in brackets. As baseline firing rates were not statistically different for the M and A group, they have been graphically grouped together (C). However, comparisons of firing rates of the same cells before and after drug administration were performed with the paired Student's t-test (see text); *P
Neuroscience Letters, 123 (1991) 20-22 '~', 1991 Elsevier Scientific Publishers Ireland Ltd. 0304-3940/91/$ 03.50 ADONIS 0304394091000783
NSL 07522
Effect of modafinil and amphetamine on the rat catecholaminergic neuron activity Hid~o A k a o k a 1, Bernard Roussel 2, Jian-Sheng Lin 3, G u y Chouvet 1 and Michel Jouvet 3 I l N S E R M U 171, CNRS URA 1195, Centre Hospitalier Lyon-Sud, Pierre-B~nite (France), ZLaboratoire LAFON, Maisons Alfort (France) and 31NSERM U 52, CNRS URA 1195, Universitb Claude Bernard, Lyon (France) (Received 12 July 1990; Revised version received 29 October 1990; Accepted 29 October 1990) Key words:
Modafinil; Amphetamine; Single unit activity; Catecholaminergic neuron
We have studied the effect of modafinil and amphetamine, two waking drugs, on the electrical activity of central dopaminergic and noradrenergic neurons in the rat. Modafinil (128 mg/kg, i.p.) was unable to modify the firing pattern of these neurons, while amphetamine (2 or 5 mg/kg, i.p.) consistently inhibited their activity. A pretreatment with modafinil did not change thereafter the effect of amphetamine. Contrary to amphetamine, the waking effect of modafinil does not seem to be mediated by the catecholaminergic neuron activity per se.
Modafinil, chemically a benzhydrylsulfinylacetamid, induces behavioral long-lasting wakefulness in animal [5]. This property is used to treat succesfully narcoleptic and hypersomniac patients [3, 4]. Contrary to the classical treatment with amphetamines, dependance and tolerance phenomena are never observed in such patients [3]. Since central catecholamines, especially dopamine (DA), are involved in drug dependance mechanisms [8], we carfled out a comparative study on the effects of modafinil (MOD) and d-amphetamine (AMP) on the spontaneous activity of dopaminergic neurons of the mesencephalon and noradrenergic (NA) neurons of the locus coeruleus (LC) in the rat. Extracellular unit recordings were performed in Sprague Dawley rats anesthetized with chloral hydrate (400 mg/kg, i.p., supplemented continuously i.v.) or halothane (1% in air, through tracheal cannula) [2, 6]. Mesencephalic DA neurons (under chloral hydrate) and LC-NA neurons (under halothane) were identified by their characteristic waveform, firing pattern rate and histological location (post mortem examination of dye deposits) according to previously reported criteria [1, 2, 6, 7]. As MOD is not soluble in aqueous solution, drug administrations (dissolved or suspended in physiological saline containing 5% Arabic gum), were realized i.p. (1 ml/kg), except for piperoxan in saline which was administered intravenously via the femoral vein. After at Correspondence: B. Roussel, D6partement de M6decine Exp6rimentale, Facult6 de M6decine, Universit6 Claude Bernard, 8, avenue Rockefeller, 69373 Lyon Cedex 02, France.
least 5 min of baseline recording of a single neuron, MOD or AMP were administered i.p. Their effects on discharge rate were studied for over 1 h following their injection as it has been shown that such MOD administration induced at least 2 consecutive hours of wakefulness in rats (Roussel, unpublished results). At the end of the experiment, typical pharmacological responsiveness of recorded neurons was sometimes assessed by systemic administration of AMP, the DA antagonist haloperidol (HAL), and the ~2 antagonist piperoxan (PIP). For quantitative analysis, all spike counts were taken from computer records of integrated impulse activity. Because it was not possible to predict the recording time of a given cell after drug administration, discharge rates (in Hz) were determined over a 5-20 min period, prior to drug administration and within consecutive time periods following drug administration (t= 0): 0-20; 20-40; 40-60; 60-80 min. Comparisons of absolute firing rates of the same cells before and after drug administration, within each of these time periods, were performed using the two-tailed Student's t-test for paired observations, with a significance criterion of P = 0.05 or less. Results are given as mean___S.E.M. Mesencephalic DA neurons. As no difference was noted between pharmacological responsiveness of substantia nigra and ventral tegmental area DA neurons, pharmacological data obtained from the two populations were pooled for statistical analysis. We verified the high efficacy of systemic administration of AMP (5 mg/ kg, i.p.) [9] which consistently inhibited all DA neurons tested (n=7) with a latency of maximal inhibition
21
NA
DA 3"
-f I rJ) id.I
(18)
(11
(7)
(7)
¢7
e. (J)
C
M
A
1
uIj
0
C
M
A
Fig. 1. Mean discharge rate in spike/s (_ S.E.M.) of mesencephalic DA (left) and LC-NA (right) neurons in the first 20 min period after injection of modafinil (M) (128 mg/kg, i.p.) of d-amphetamine (A) (5 mg/ kg, i.p., for DA cells and 2 mg/kg, i.p., for NA cells) as compared to the 5 min preinjection basal rate (C). Number of sampled neurons is indicated in brackets. As baseline firing rates were not statistically different for the M and A group, they have been graphically grouped together (C). However, comparisons of firing rates of the same cells before and after drug administration were performed with the paired Student's t-test (see text); *P
