- Email: [email protected]
Inhibition of Nitric Oxide Synthesis Reduces Intravenous Cocaine Self-administration in the Rat
Neurophannacology, Vol.35,No. 12,pp. 1811–1814, 1996
Copyright01997 ElsevierScienceLtd.All rightsreserved Printedin GreatBritain 0028-3908/96 $15.00+ 0.00
Pergamon @ PII: S0028-3908(96)00152-9
Rapid Communication Inhibition of Nitric Oxide Synthesis Reduces Intravenous Cocaine Self-administration in the Rat LUIGI PULVIRENTI,l’2*CLAUDIA BALDUCCI1and GEORGE F. KOOB1 IDepartment of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, U.S.A. and zFondazione Isti~to Neurologico ‘C. Mondino’, via palestro 3, pavia> Italy (Accepted 13 September 1996)
Summary-The effects of a blockade of nitric oxide synthesis were studied in rats trained to self-administer cocaine intravenously. Pretreatment with Ng-nitro-l-arginine methyl ester (l-NAME; 10-50 mgjkg, intraperitoneally, twice daily for 4 days), significantly and dose-dependentlysuppressed the maintenance of intravenous cocaine self-administrationand the absolute reward magnitude of cocaine. These results suggest that nitric oxide may play a role in cocaine abuse and dependence. @ 1997 Elsevier Science Ltd. Atl rights
reserved. Keywords-Cocaine,nitricoxide,drugdependence,l-NAME.
Intravenous cocaine self-administration in rodents has been used as a useful animal analog to study the neural substrates of cocaine dependence. Dopamine and excitatory amino acid neurotransmission,within the limbic system have been identified as critical neurochemical determinantsof cocaine-seekingbehavior (Maldonado et al., 1993; Pulvirenti et al., 1992) and antagonism of NMDA receptor function within the nucleus accumbens was shown to reduce the expressionof the psychostimulant and reinforcing properties of cocaine (Pulvirenti et al., 1992, 1994). Since activation of NMDA receptors in the central nervous system results in an increase in the activity of nitric oxide (NO) synthase(Garthwaite, 1991),the aim of the present studywas to evaluatethe effects of a blockade of NO synthesis,on intravenouscocaine self-administration in the rat. For this purpose, rats trained to selfadminister cocaine were treated with the NO synthesis inhibitor Ng-nitro-l-arginine methyl ester (l-NAME). In addition to a simple measurement of responding, for intravenous(iv.) cocaine self-administration,in order to
arrive at appropriate interpretationsof general increases or decreases in response rate, the absolute reward magnitude of cocaine was assessed using a progressive ratio schedule, an operant measure, tailored to establish the motivationalstrength of the animal to obtain cocaine (Roberts et al., 1989). Male Wistar rats (Charles River), weighing 200-225 g at the start of the experiment,were housed three to a cage, provided with ad libitum access to food and water and maintained on a 12 hr light~ark cycle (lights on 7arn– 7pm). All animals were surgically implanted with a chronic silastic jugular vein catheter under halothane anesthesia.The catheter passed subcutaneously(s.c.) to a piece of marlex mesh secured S.C.on the animal’s back. At the time of the self-administrationsession,the catheter was connected to a swivel system through a metal spring, which was in turn connected to an infusion pump, as previously described (Caine et al., 1993). Four days following surgery the animals were allowed 2 hr access every day to a metal lever mounted on the side wall of a standard operant-conditioning cage. The cages themselveswere housed insidesound attenuatingchambers. A lever press resulted in an intravenousinjection of 0.1 ml * To whomcorrespondence shouldbe addressedat: Centrodi of cocaine hydrochloride (0.25 mghjection), dissolved NeurobiologiaSperimentale‘Mondino-TorVergata’,Di- in 0.9% physiologicalsaline and delivered over a period partimentodi Biologia, Universitiidi Roma ‘Tor Vergata’, of 4 sec. A swivel system allowed free movement of the Via delta Ricerca Scientific, 00133 Roma, Italy. animal in the cage. Coincident with the onset of the
1812
L. Pulvirenti et al.
injection,a stimuluslight was turned on for 20 sec during which time the lever became inactive. Lever presses during the period when the signal light was not lit were reinforced on a continuous reinforcement schedule (fixed-ratio-1,FR-1). Once the animalshad demonstrated stable drug intakefor 3 days (a range of <15%of the daily intake over 3 days), the rats were subjected to a progressive ratio schedule where, for the first eight injections, the ratio requirement increased by one response per injection. For the next eight injections the ratio was raised by two, each successiveratio, for the next eight injectionsthe ratio was increasedby four and for the next eight injections the ratio was increased by eight responses, each successive injection until the ratio requirement reached an FR-120. The breaking point was defined as the last ratio attained by the rat prior to a 1 hr period during which a ratio was not completed.Rats
were probed with the progressive ratio schedule until a of the average of stable response was obtained ( t 1O$% three successive probes). Once stable responding was reached in the FR-1 and
progressive ratio schedules, this was taken as baseline and the study was begun. The rats were treated with 1NAME (10 and 50 mg/kg intraperitoneally (i.p.) twice daily for 4 days) based on previous results showing that brain nitric oxide synthase activity is reduced approximately 50-95% after this treatment schedule (Dwyer et al., 1991).The drug was prepared in a vehicle solutionof 0.9% physiological saline and injected in a volume of 1.0 ml/kg of body weight. The number of reinforcers earned during the 120 min session was recorded during the 4 days of drug treatment and compared with pretreatment intakes. Statistical analysis of the data was computed using a one-way factorial analysis of variance D L-Name50mgkg
9 L-NameIOmg/lcg 50
40”
1-
1-
140
-r*
** **
30
** -
7
** -i-
20
2 10”
10
.
0
o’
baseline
d]
d2
d3
baseline
d4 “Max FR
~& 120
d2
-r
d3
d4
2CSI
100
I
dl
150
T
80
* 60
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40 50 20 0
0 saline
L-Name
10 mglkg
saline
L-Name
50 mglkg
Fig. 1. Effects of treatment with l-NAME on iv. cocaine self-administration.ToP panel:number of self-injection of the daily 2 hr sessionsof cocaine self-administrationduringthe 4 day treatmen~with l-NAME.Valuesrepresent mean + SEM of seven animals for the dose of 10 mg/kg and nine animals for the dose of 50 mg/kg. *p c 0.05 **p<0.01 Newman–Keul’stest. Bottompanel: progressiveratio respondingfor IV cocaine self-administrationin rats pretreated with l-NAME (10 mg/kg, left and 50 mg/kg, right, twice daily for 4 days). Values represent the mean + SEM of the maximum FR for a single self-injectionof cocaine in seven and nine animals for the doses of 10 and 50 mg/kg, respectively. *p< 0.05 Student’s t-test.
Nitric oxide and cocaine self-administration
with repeated measures (ANOVA). Individual means comparisons were made using Newman–Keul’s a poster-iori test. On the fifth day, rats were probed with the progressive ratio schedule and the breaking points observed were compared to those recorded prior to treatment with l-NAME. The data were analysed using Students t-test for paired observations. Figure 1, top panel, shows the effects of treatment with l-NAME on cocaine self-administration. ANOVA revealed that during the 4 days of treatment with l-NAME there was a reduction of cocaine intake with both doses of l-NAME [F(4,24) = 3.52 p e 0.05 for the dose of
10 mg/kg and F(4,32) = 9.654 p <0.001 for the dose of 50 mg/kg]. Statistical significance vs baseline intake was reached at day 2 only for the dose of 10 mg/kg and at all days for the dose of 50 mg/kg. Figure 1, bottom panel, shows the effect of pretreatment with l-NAME on progressive ratio responding for cocaine self-administration. l-NAME significantly reduced the breaking point at the dose of 50 mg/kg (df = 8; t= 2.41p< 0.05) but not at the dose of 10 mg/kg (df = 6, t= 1.12 NS). The apparent variation between baseline breaking point before treatment in the two groups of rats (90t 13 for the rats which later were treated with 1NAME at the dose of 10 mg/kg and 150t34 for the rats which later received l-NAME at the dose of 50 mg/kg) is consistentwith the high variability shown by rats probed in the progressive ratio schedule and, in any case, the baselines of the two populationsdo not differ statistically (df = 14 t= –1.492 NS). The results show that treatment with l-NAME significantly and dose-dependentlyreduces iv. cocaine self-administrationand diminishes the absolute rewarding value of cocaine, as measuredby the progressiveratio procedure. Specifically,the breaking point in a progressive ratio schedule represents a sensitive operant measure, designed to assess the organism’s motivation to obtain the drug (Roberts et al., 1989).The progressive ratio schedule, besides revealing the antagonistic action of l-NAME on cocaine reinforcement, also provides evidencethat the effects inducedby l-NAME are not nonspecific motoric effects. Brain nitric oxide synthase activity has been shown to be inhibited by 95’%0after treatment with l-NAME at the dose of 50 mg/kg, twice daily for 4 days, while only 50% inhibitionwas reported at the dose of 5 mg/kg (Dwyer et al., 1991).The resultsof this study suggest that near-complete inhibition of nitric oxide synthase activity seems to be necessary for the reduction of the reinforcing properties of intravenously self-administeredcocaine in the rat. It has been recently suggested that excitatory amino acid neurotransmission may be involved in the natural history of cocaine dependence. More specifically, excitatory amino acid neurotransmission within the nucleusaccumbens,a critical structuremediatingcocaine self-administration in rodents (Pulvirenti et al., 1992; Maldonado et al., 1993), seems particularly important in this respect. Behavioral evidence suggests that the
1813
blockade of nucleus accumbens NMDA receptors, reduces cocaine reinforcement (Pulvirenti et al., 1992) and the full expressionof the psychostimulantproperties of cocaine and other psychostimulantdrugs (Pulvirenti et al., 1994).Neurochemicalstudies indicatethat excitatory amino acid within the nucleus accumbensmay modulate dopamine tone (Youngren et al., 1993) which has been shown to play a key role in cocaine-seeking behavior (Maldonado et al., 1993). NO is an important transduction mechanismfor NMDA receptors(Garthwaite, 1991). In agreement with previous observations, the present results confirmthat the blockade of NO synthesiswith 1NAME reduces the reinforcingproperties of cocaine and cocaine self-administration, in a similar way to the reduction of cocaine-induced dopaminergic behaviors, including conditioned place preference, recently observed in mice after inhibition of nitric oxide synthesis (Kim and Park, 1995). Although it is not possible to determine what the intimate neurochemical mechanisms leading to reduction of cocaine reward are, it has been shown that NO evokes the release of dopamine from striatal slices (Hanbauer et al., 1992).Therefore, it would also be of interest to determine whether the same mechanism occurs within the nucleus accumbens and, consequently, whether the suppressing effects of 1NAME on cocaine self-administration, depend upon a putative reduction of dopamine neurotransmission induced by a blockade of NO synthesis. Finally, considering the growing preclinical evidence suggesting a role for excitatory amino acids in cocaine dependence, as well as dependence to other drugs of abuse, including opiates and ethanol (Herman et al., 1996), the possibility that pharmacological intervention at the level of NO synthesis, might be a novel and effective means of modifying various aspects of the natural history of the addictive process, deserves rapid experimental and clinical attention. 102O2-NPof The Scripps Research Institute. This work was partially supported by NIDA grant DA 04398. L. Pulvirenti is a recipient of a Fellowship from the ‘C. Mondino’ Foundation (Italy).
Acknowledgements—This is manuscript number
REFERENCES Caine S. B., Lintz R. and Koob G. F. (1993) Intravenousdrug self-administration techniques in animals. In: Behavioral Neuroscience: A Practical Approach. (Sahgal A. Ed), pp.
117-143.OxfordUniversityPress,Oxford. DwyerM.A.,BredtD. S. andSnyderS. H. (1991)Nitricoxide synthase: irreversible inhibition by L-Ng-nitroarginine in brain in vitro and in vivo. Biochem. Biophys. Res. Commun. 176: 1136-1141.
Garthwaite J. (1991) Glutamate, nitric oxide and cell-cell signaling in the nervous system. Trends Neurosci. 14: 6& 67.
Hanbauer I., Wink D., Osawa Y., Edelman G. M. and Gaily J.
1814
L. Pulvirenti et al.
A. (1992) Role of nitric oxide in NMDA-evokedrelease of [3H]-dopaminefrom striatal slices. Neuroreport 3: 409-412. Herman B. H., Vocci F. and Bridge P. (1996) The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal. Neuropsychopharmacology 13: 269–293. Kim H. S. and Park W. K. (1995)Nitricoxidemediationof
receptors in the nucleus accumbens modulate intravenous cocaine, but not heroin self-administration in the rat. Brain Res. 594: 32’7-330.
Pulvirenti L., Berrier R., Kriefeldt M. and Koob G. F. (1994) Modulationof locomotoractivity by NMDA receptors in the nucleus accumbens core and shell regions of the rat. Brain Res. 664: 231–236.
cocaine-induced dopaminergic behaviors:ambulation-accel- Roberts D. C. S., I-oh E. A. and Vickers G. (1989) Selferating activity,reverse toleranceand conditionedplace administration of cocaine in a progressive ratio schedule. preferencein mice.J. Pharmacol. Exp. Ther. 275: 551–557. Maldonado R., RobledoP., ChoverA. J., Caine S. B. and Koob G. F. (1993) D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administrationin the rat. Pharmacol. Biochem. Behav. 45: 239–242.
Pulvirenti L., Maldonado R. and Koob G. F. (1992) NMDA
Psychopharmacology 97: 535–538.
Youngren K. D., Daly D. A. and Moghaddam B. (1993) Distinct actions of endogenousexcitatory aminoacids on the outflow of dopamine in the nucleus accumbens. J. PharmaCO1.Exp. Ther. 264: 289–293.
Copyright01997 ElsevierScienceLtd.All rightsreserved Printedin GreatBritain 0028-3908/96 $15.00+ 0.00
Pergamon @ PII: S0028-3908(96)00152-9
Rapid Communication Inhibition of Nitric Oxide Synthesis Reduces Intravenous Cocaine Self-administration in the Rat LUIGI PULVIRENTI,l’2*CLAUDIA BALDUCCI1and GEORGE F. KOOB1 IDepartment of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, U.S.A. and zFondazione Isti~to Neurologico ‘C. Mondino’, via palestro 3, pavia> Italy (Accepted 13 September 1996)
Summary-The effects of a blockade of nitric oxide synthesis were studied in rats trained to self-administer cocaine intravenously. Pretreatment with Ng-nitro-l-arginine methyl ester (l-NAME; 10-50 mgjkg, intraperitoneally, twice daily for 4 days), significantly and dose-dependentlysuppressed the maintenance of intravenous cocaine self-administrationand the absolute reward magnitude of cocaine. These results suggest that nitric oxide may play a role in cocaine abuse and dependence. @ 1997 Elsevier Science Ltd. Atl rights
reserved. Keywords-Cocaine,nitricoxide,drugdependence,l-NAME.
Intravenous cocaine self-administration in rodents has been used as a useful animal analog to study the neural substrates of cocaine dependence. Dopamine and excitatory amino acid neurotransmission,within the limbic system have been identified as critical neurochemical determinantsof cocaine-seekingbehavior (Maldonado et al., 1993; Pulvirenti et al., 1992) and antagonism of NMDA receptor function within the nucleus accumbens was shown to reduce the expressionof the psychostimulant and reinforcing properties of cocaine (Pulvirenti et al., 1992, 1994). Since activation of NMDA receptors in the central nervous system results in an increase in the activity of nitric oxide (NO) synthase(Garthwaite, 1991),the aim of the present studywas to evaluatethe effects of a blockade of NO synthesis,on intravenouscocaine self-administration in the rat. For this purpose, rats trained to selfadminister cocaine were treated with the NO synthesis inhibitor Ng-nitro-l-arginine methyl ester (l-NAME). In addition to a simple measurement of responding, for intravenous(iv.) cocaine self-administration,in order to
arrive at appropriate interpretationsof general increases or decreases in response rate, the absolute reward magnitude of cocaine was assessed using a progressive ratio schedule, an operant measure, tailored to establish the motivationalstrength of the animal to obtain cocaine (Roberts et al., 1989). Male Wistar rats (Charles River), weighing 200-225 g at the start of the experiment,were housed three to a cage, provided with ad libitum access to food and water and maintained on a 12 hr light~ark cycle (lights on 7arn– 7pm). All animals were surgically implanted with a chronic silastic jugular vein catheter under halothane anesthesia.The catheter passed subcutaneously(s.c.) to a piece of marlex mesh secured S.C.on the animal’s back. At the time of the self-administrationsession,the catheter was connected to a swivel system through a metal spring, which was in turn connected to an infusion pump, as previously described (Caine et al., 1993). Four days following surgery the animals were allowed 2 hr access every day to a metal lever mounted on the side wall of a standard operant-conditioning cage. The cages themselveswere housed insidesound attenuatingchambers. A lever press resulted in an intravenousinjection of 0.1 ml * To whomcorrespondence shouldbe addressedat: Centrodi of cocaine hydrochloride (0.25 mghjection), dissolved NeurobiologiaSperimentale‘Mondino-TorVergata’,Di- in 0.9% physiologicalsaline and delivered over a period partimentodi Biologia, Universitiidi Roma ‘Tor Vergata’, of 4 sec. A swivel system allowed free movement of the Via delta Ricerca Scientific, 00133 Roma, Italy. animal in the cage. Coincident with the onset of the
1812
L. Pulvirenti et al.
injection,a stimuluslight was turned on for 20 sec during which time the lever became inactive. Lever presses during the period when the signal light was not lit were reinforced on a continuous reinforcement schedule (fixed-ratio-1,FR-1). Once the animalshad demonstrated stable drug intakefor 3 days (a range of <15%of the daily intake over 3 days), the rats were subjected to a progressive ratio schedule where, for the first eight injections, the ratio requirement increased by one response per injection. For the next eight injections the ratio was raised by two, each successiveratio, for the next eight injectionsthe ratio was increasedby four and for the next eight injections the ratio was increased by eight responses, each successive injection until the ratio requirement reached an FR-120. The breaking point was defined as the last ratio attained by the rat prior to a 1 hr period during which a ratio was not completed.Rats
were probed with the progressive ratio schedule until a of the average of stable response was obtained ( t 1O$% three successive probes). Once stable responding was reached in the FR-1 and
progressive ratio schedules, this was taken as baseline and the study was begun. The rats were treated with 1NAME (10 and 50 mg/kg intraperitoneally (i.p.) twice daily for 4 days) based on previous results showing that brain nitric oxide synthase activity is reduced approximately 50-95% after this treatment schedule (Dwyer et al., 1991).The drug was prepared in a vehicle solutionof 0.9% physiological saline and injected in a volume of 1.0 ml/kg of body weight. The number of reinforcers earned during the 120 min session was recorded during the 4 days of drug treatment and compared with pretreatment intakes. Statistical analysis of the data was computed using a one-way factorial analysis of variance D L-Name50mgkg
9 L-NameIOmg/lcg 50
40”
1-
1-
140
-r*
** **
30
** -
7
** -i-
20
2 10”
10
.
0
o’
baseline
d]
d2
d3
baseline
d4 “Max FR
~& 120
d2
-r
d3
d4
2CSI
100
I
dl
150
T
80
* 60
Iou
40 50 20 0
0 saline
L-Name
10 mglkg
saline
L-Name
50 mglkg
Fig. 1. Effects of treatment with l-NAME on iv. cocaine self-administration.ToP panel:number of self-injection of the daily 2 hr sessionsof cocaine self-administrationduringthe 4 day treatmen~with l-NAME.Valuesrepresent mean + SEM of seven animals for the dose of 10 mg/kg and nine animals for the dose of 50 mg/kg. *p c 0.05 **p<0.01 Newman–Keul’stest. Bottompanel: progressiveratio respondingfor IV cocaine self-administrationin rats pretreated with l-NAME (10 mg/kg, left and 50 mg/kg, right, twice daily for 4 days). Values represent the mean + SEM of the maximum FR for a single self-injectionof cocaine in seven and nine animals for the doses of 10 and 50 mg/kg, respectively. *p< 0.05 Student’s t-test.
Nitric oxide and cocaine self-administration
with repeated measures (ANOVA). Individual means comparisons were made using Newman–Keul’s a poster-iori test. On the fifth day, rats were probed with the progressive ratio schedule and the breaking points observed were compared to those recorded prior to treatment with l-NAME. The data were analysed using Students t-test for paired observations. Figure 1, top panel, shows the effects of treatment with l-NAME on cocaine self-administration. ANOVA revealed that during the 4 days of treatment with l-NAME there was a reduction of cocaine intake with both doses of l-NAME [F(4,24) = 3.52 p e 0.05 for the dose of
10 mg/kg and F(4,32) = 9.654 p <0.001 for the dose of 50 mg/kg]. Statistical significance vs baseline intake was reached at day 2 only for the dose of 10 mg/kg and at all days for the dose of 50 mg/kg. Figure 1, bottom panel, shows the effect of pretreatment with l-NAME on progressive ratio responding for cocaine self-administration. l-NAME significantly reduced the breaking point at the dose of 50 mg/kg (df = 8; t= 2.41p< 0.05) but not at the dose of 10 mg/kg (df = 6, t= 1.12 NS). The apparent variation between baseline breaking point before treatment in the two groups of rats (90t 13 for the rats which later were treated with 1NAME at the dose of 10 mg/kg and 150t34 for the rats which later received l-NAME at the dose of 50 mg/kg) is consistentwith the high variability shown by rats probed in the progressive ratio schedule and, in any case, the baselines of the two populationsdo not differ statistically (df = 14 t= –1.492 NS). The results show that treatment with l-NAME significantly and dose-dependentlyreduces iv. cocaine self-administrationand diminishes the absolute rewarding value of cocaine, as measuredby the progressiveratio procedure. Specifically,the breaking point in a progressive ratio schedule represents a sensitive operant measure, designed to assess the organism’s motivation to obtain the drug (Roberts et al., 1989).The progressive ratio schedule, besides revealing the antagonistic action of l-NAME on cocaine reinforcement, also provides evidencethat the effects inducedby l-NAME are not nonspecific motoric effects. Brain nitric oxide synthase activity has been shown to be inhibited by 95’%0after treatment with l-NAME at the dose of 50 mg/kg, twice daily for 4 days, while only 50% inhibitionwas reported at the dose of 5 mg/kg (Dwyer et al., 1991).The resultsof this study suggest that near-complete inhibition of nitric oxide synthase activity seems to be necessary for the reduction of the reinforcing properties of intravenously self-administeredcocaine in the rat. It has been recently suggested that excitatory amino acid neurotransmission may be involved in the natural history of cocaine dependence. More specifically, excitatory amino acid neurotransmission within the nucleusaccumbens,a critical structuremediatingcocaine self-administration in rodents (Pulvirenti et al., 1992; Maldonado et al., 1993), seems particularly important in this respect. Behavioral evidence suggests that the
1813
blockade of nucleus accumbens NMDA receptors, reduces cocaine reinforcement (Pulvirenti et al., 1992) and the full expressionof the psychostimulantproperties of cocaine and other psychostimulantdrugs (Pulvirenti et al., 1994).Neurochemicalstudies indicatethat excitatory amino acid within the nucleus accumbensmay modulate dopamine tone (Youngren et al., 1993) which has been shown to play a key role in cocaine-seeking behavior (Maldonado et al., 1993). NO is an important transduction mechanismfor NMDA receptors(Garthwaite, 1991). In agreement with previous observations, the present results confirmthat the blockade of NO synthesiswith 1NAME reduces the reinforcingproperties of cocaine and cocaine self-administration, in a similar way to the reduction of cocaine-induced dopaminergic behaviors, including conditioned place preference, recently observed in mice after inhibition of nitric oxide synthesis (Kim and Park, 1995). Although it is not possible to determine what the intimate neurochemical mechanisms leading to reduction of cocaine reward are, it has been shown that NO evokes the release of dopamine from striatal slices (Hanbauer et al., 1992).Therefore, it would also be of interest to determine whether the same mechanism occurs within the nucleus accumbens and, consequently, whether the suppressing effects of 1NAME on cocaine self-administration, depend upon a putative reduction of dopamine neurotransmission induced by a blockade of NO synthesis. Finally, considering the growing preclinical evidence suggesting a role for excitatory amino acids in cocaine dependence, as well as dependence to other drugs of abuse, including opiates and ethanol (Herman et al., 1996), the possibility that pharmacological intervention at the level of NO synthesis, might be a novel and effective means of modifying various aspects of the natural history of the addictive process, deserves rapid experimental and clinical attention. 102O2-NPof The Scripps Research Institute. This work was partially supported by NIDA grant DA 04398. L. Pulvirenti is a recipient of a Fellowship from the ‘C. Mondino’ Foundation (Italy).
Acknowledgements—This is manuscript number
REFERENCES Caine S. B., Lintz R. and Koob G. F. (1993) Intravenousdrug self-administration techniques in animals. In: Behavioral Neuroscience: A Practical Approach. (Sahgal A. Ed), pp.
117-143.OxfordUniversityPress,Oxford. DwyerM.A.,BredtD. S. andSnyderS. H. (1991)Nitricoxide synthase: irreversible inhibition by L-Ng-nitroarginine in brain in vitro and in vivo. Biochem. Biophys. Res. Commun. 176: 1136-1141.
Garthwaite J. (1991) Glutamate, nitric oxide and cell-cell signaling in the nervous system. Trends Neurosci. 14: 6& 67.
Hanbauer I., Wink D., Osawa Y., Edelman G. M. and Gaily J.
1814
L. Pulvirenti et al.
A. (1992) Role of nitric oxide in NMDA-evokedrelease of [3H]-dopaminefrom striatal slices. Neuroreport 3: 409-412. Herman B. H., Vocci F. and Bridge P. (1996) The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal. Neuropsychopharmacology 13: 269–293. Kim H. S. and Park W. K. (1995)Nitricoxidemediationof
receptors in the nucleus accumbens modulate intravenous cocaine, but not heroin self-administration in the rat. Brain Res. 594: 32’7-330.
Pulvirenti L., Berrier R., Kriefeldt M. and Koob G. F. (1994) Modulationof locomotoractivity by NMDA receptors in the nucleus accumbens core and shell regions of the rat. Brain Res. 664: 231–236.
cocaine-induced dopaminergic behaviors:ambulation-accel- Roberts D. C. S., I-oh E. A. and Vickers G. (1989) Selferating activity,reverse toleranceand conditionedplace administration of cocaine in a progressive ratio schedule. preferencein mice.J. Pharmacol. Exp. Ther. 275: 551–557. Maldonado R., RobledoP., ChoverA. J., Caine S. B. and Koob G. F. (1993) D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administrationin the rat. Pharmacol. Biochem. Behav. 45: 239–242.
Pulvirenti L., Maldonado R. and Koob G. F. (1992) NMDA
Psychopharmacology 97: 535–538.
Youngren K. D., Daly D. A. and Moghaddam B. (1993) Distinct actions of endogenousexcitatory aminoacids on the outflow of dopamine in the nucleus accumbens. J. PharmaCO1.Exp. Ther. 264: 289–293.