European Journal of Pharmacofogv, 191 (1990) 497-499 Elsevier
497
EfP 0281 R
Rapid communication
epeated stimulation of dopamine s enhances of dopamine receptor agonists Francis J. White, Xiu-Ti Hu and Richard J. Brooderson Cellular and Clinical Neurobiology Program, Department of Psychiatry, Wayne State University School of Medicine, Neuropsychopharmacolow Laboratory, Lafayette Clinic, 951 East Lafayette, Detroit. MI 48207, U.S.A. Received 1 November 1990, accepted 2 November
Behavioral sensitization refers to the enhanced motor effects of psychomotor stimulants observed following their repeated administration. Efforts to elucidate underlying mechanisms of this phenomenon have revealed conflicting findings although increased dopamine (DA) release appears to be involved (Robinson and Becker, 1986). We have reported that repeated cocaine administration results in enhanced responsiveness of ventral striatal neurons to iontophoretically administered DA (Henry et al., 1989) due to enhanced sensitivity of DA D, receptors (Henry and White, in preparation). These findings led us to examine the effects of repeated selective stimulation of the DA D, receptor. Male Sprague-Dawley rats (200-250 g) received either twice daily injections of the selective D, agonist SKF 38393 (8.0 mg/kg s-c.) or saline for 21 days. For the last injection, both groups received SKF 38393 and were observed (30 mm) for D, receptor-mediated grooming behavior (White et al., 1988). As compared to controls (440 + 60 s), SKF 38393-pretreated rats groomed themselves significantly less (222 f 33 s), indicating tolerance development. However, following a 7 day withdrawal period, SKF 38393-pretreated rats exhibited significantly more grooming behavior than
Correspondence to: F.J. White, Lafayette Lafayette, Detroit, MI 48207, U.S.A. 0014.2999/91/$03.50
Clinic,
951 E.
1990
control rats when challenged with SKF 38393 (table 1). A separate group of SKF 38393-pretreated and withdrawn rats was challenged with the D, selective agonist quinpirole (2.0 mg/kg s-c.) and were scored continuously for six 5 mm bins (beginning 5 mm post-injection) for the presence of stereo-
TABLE 1 Effects of repeated stimulation of the dopamine D, receptor on the behavioral and electrophysiological effects of D, and Da agonists when administered 7 days following the cessation of treatment. Grooming behavior is expressed in number of seconds spent grooming (mean + S.E.M.) whereas stereotyped behavior is expressed as the percentage of rats exhibiting either licking or biting in at least four of six 5 mm bins during a 30 mm observation period (n = 8 rats/group). Electrophysiological data refer to the percentage of inhibition (means+S.E.M.) below basal rates (determined during a 5 mm pre-drug period) produced by a 1 mm iontophoretic ejection (16 nA) of the test compound onto glutamate-driven neurons within the dorsolateral caudate-putamen (n = 8 cells/group). Repeated treatment
Test
Behavior SKF 38393-induced grooming Quinpirole-induced oral stereotypy Electrophysiology SFK 38393-induced inhibition Quinpirole-induced inhibition
Saline
SKF 38393
419 f45 12.5%
717 557” 87.5% ’
Xc)+_lOW 11.6f 9%
58.6f 42.9+
8% b 8% b
a Significantly greater than control (P c 0.01, ttest). b Significantly greater than control (P c 0.05. t-test). ’ Significantly greater than control (P -z 0.01. Chi-square test).
0 1991 Elsevier Science Publishers B.V. (Biomedical
Division)
aviors including both ‘low component’ stereotype (sniffing, rearing, motility) and oral stereotypy (bcking, gnawing), as described by Amt et a~. (1987). For simplification, the data are presented as the percentage of rats engaging in oral steratypy (defined as present during at least four of six bins) during the 30 min observation period. s previously reported (Amt et al., 1987; White et 1988). while quinpirole (given alone) readily .. produced low component stereotypy in normal (saline-control) rats, oral stereotyped behaviors (Licking and gnawing) were almost never observed. However. in rats that were withdrawn from repeated SKF 38393 treatment, quinpirole almost always produced oral stereotypy, primarily licking (table 1). To determine whether similar alterations in D, receptor sensitivity were evident at the cellular level. rats with&awn from either SKF 38393 or saline treatment were prepared for extracellular single cell recording. Methods for electrophysiologica! recording and microiontophoretic drug administration have been detailed previously (Henry et al.. 1959). Briefly, rats were anesthetized with cbloral hydrate (400 mg/kg i.p.) and mounted in a stereotaxic frame. A burr hole was drilled over the head of the caudate-putamen (CPU: 8.7-8.9 mm A to lambda, 3-O-3.3 mm L to the midline). Ficle barrel micropipettes were used to record the activity of CPU neurons while SKF 38393 HCl and quinpirole HCl (both at 10 mM, pH 4) were applied by cationic iontophoresis (16 nA current) using appropriate balancing and retaining of currents. All CPU neurons were driven by iontophoretic application (anionic) of glutamatic acid (100 m&I. pH 8) to achieve firing rates of 4-7
ty
spikes/s. In rats that were pretreated with SKF 38393, the inhibitory effects of both SKF 38393 and quinpirole on CPU neurons were significantly enhanced as compared to controls (table 1). Thus, both the behavioral and electrophysiological results suggest that repeated selective stimulation of D, receptors leads to a sensitization of DA receptor-mediated functions. The enhanced effect of quinpirole in these animals was likely due to a greater enabling effect of D, receptors on D2mediated functions (Wachtel et al., 1989) rather
in D, receptors since oral stereotyped behaviors are only observed when selective D, agonists are administered during enhanced stimulation of the D, receptor (Amt et al., 1987; White et al., 1988), in this case provided by endogenous DA stimulation of supersensitive D, receptors. It is interesting that the sensitized behavioral response to SKF 38393 following repeated selective stimulation of the D, receptor required a withdrawal period before becoming manifest. In fact, behavioral tolerance was observed after the last injection of SKF 38393. This contrasts to behavioral sensitization observed following repeated psychomotor stimulant administration which is often evident both during the treatment regimen and following various withdrawal periods (Robinson and Becker, 1986). Therefore, while our previous findings with cocaine (Henry et al., 1989; Henry and White, in preparation) and the present results with SKF 38393 suggest that an increased responsiveness of DA D, receptors is a likely mediating component in the phenomenon of behavioral sensitization, alterations in other aspects of dopaminergic systems, which are affected by indirect and non-selective DA agonists such as than a direct
change
cocaine, must also be involved and may regulate temporal parameters of its expression.
Acknowledgements We ihank Vernice Davis for technical assistance and Eli Lilly and Co. for the generous gift of quinpirole. This study was supported by USPHS Grants DA-04093 and MH-40832.
References Amt J.. J. Hyttel and J. Perregaard. 1987, Dopamine D-l receptor agonists combined with the selective D-2 agonist quinpirole facilitate the expression of oral stereotyped behavior in rats, European J. Pharmacol. 133, 137. Henry, D.J., M.A. Greene and F.J. White, 1989, Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: Repeated administration, J. Pharmacol. Exp. Ther. 251, 839. Robinson, T.E. and J.B. Becker, 1986. Enduring changes in brain and behavior produced by chronic amphetamine ad-
499 ministration: a review and evaluation of animal models of amphetamine psychosis, Brain Res. Rev. 11, 57. Wachtel, S.R., X.-T. Hu, M.P. Galloway and F.J. White, 1989, Dl dopamine receptor stimulation enables the postsynaptic. but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems, Synapse 4. 327.
White, F.J., L.M. Bednan, S.R. Wachtel, S. Hjorth and R.J. Brooderson, 1988, Is stimulation of Dl dopamine receptors necessary for the expression of dopamine-mediated behaviors?, Pharmacol. B&hem. Behav. 30, 189.
497
EfP 0281 R
Rapid communication
epeated stimulation of dopamine s enhances of dopamine receptor agonists Francis J. White, Xiu-Ti Hu and Richard J. Brooderson Cellular and Clinical Neurobiology Program, Department of Psychiatry, Wayne State University School of Medicine, Neuropsychopharmacolow Laboratory, Lafayette Clinic, 951 East Lafayette, Detroit. MI 48207, U.S.A. Received 1 November 1990, accepted 2 November
Behavioral sensitization refers to the enhanced motor effects of psychomotor stimulants observed following their repeated administration. Efforts to elucidate underlying mechanisms of this phenomenon have revealed conflicting findings although increased dopamine (DA) release appears to be involved (Robinson and Becker, 1986). We have reported that repeated cocaine administration results in enhanced responsiveness of ventral striatal neurons to iontophoretically administered DA (Henry et al., 1989) due to enhanced sensitivity of DA D, receptors (Henry and White, in preparation). These findings led us to examine the effects of repeated selective stimulation of the DA D, receptor. Male Sprague-Dawley rats (200-250 g) received either twice daily injections of the selective D, agonist SKF 38393 (8.0 mg/kg s-c.) or saline for 21 days. For the last injection, both groups received SKF 38393 and were observed (30 mm) for D, receptor-mediated grooming behavior (White et al., 1988). As compared to controls (440 + 60 s), SKF 38393-pretreated rats groomed themselves significantly less (222 f 33 s), indicating tolerance development. However, following a 7 day withdrawal period, SKF 38393-pretreated rats exhibited significantly more grooming behavior than
Correspondence to: F.J. White, Lafayette Lafayette, Detroit, MI 48207, U.S.A. 0014.2999/91/$03.50
Clinic,
951 E.
1990
control rats when challenged with SKF 38393 (table 1). A separate group of SKF 38393-pretreated and withdrawn rats was challenged with the D, selective agonist quinpirole (2.0 mg/kg s-c.) and were scored continuously for six 5 mm bins (beginning 5 mm post-injection) for the presence of stereo-
TABLE 1 Effects of repeated stimulation of the dopamine D, receptor on the behavioral and electrophysiological effects of D, and Da agonists when administered 7 days following the cessation of treatment. Grooming behavior is expressed in number of seconds spent grooming (mean + S.E.M.) whereas stereotyped behavior is expressed as the percentage of rats exhibiting either licking or biting in at least four of six 5 mm bins during a 30 mm observation period (n = 8 rats/group). Electrophysiological data refer to the percentage of inhibition (means+S.E.M.) below basal rates (determined during a 5 mm pre-drug period) produced by a 1 mm iontophoretic ejection (16 nA) of the test compound onto glutamate-driven neurons within the dorsolateral caudate-putamen (n = 8 cells/group). Repeated treatment
Test
Behavior SKF 38393-induced grooming Quinpirole-induced oral stereotypy Electrophysiology SFK 38393-induced inhibition Quinpirole-induced inhibition
Saline
SKF 38393
419 f45 12.5%
717 557” 87.5% ’
Xc)+_lOW 11.6f 9%
58.6f 42.9+
8% b 8% b
a Significantly greater than control (P c 0.01, ttest). b Significantly greater than control (P c 0.05. t-test). ’ Significantly greater than control (P -z 0.01. Chi-square test).
0 1991 Elsevier Science Publishers B.V. (Biomedical
Division)
aviors including both ‘low component’ stereotype (sniffing, rearing, motility) and oral stereotypy (bcking, gnawing), as described by Amt et a~. (1987). For simplification, the data are presented as the percentage of rats engaging in oral steratypy (defined as present during at least four of six bins) during the 30 min observation period. s previously reported (Amt et al., 1987; White et 1988). while quinpirole (given alone) readily .. produced low component stereotypy in normal (saline-control) rats, oral stereotyped behaviors (Licking and gnawing) were almost never observed. However. in rats that were withdrawn from repeated SKF 38393 treatment, quinpirole almost always produced oral stereotypy, primarily licking (table 1). To determine whether similar alterations in D, receptor sensitivity were evident at the cellular level. rats with&awn from either SKF 38393 or saline treatment were prepared for extracellular single cell recording. Methods for electrophysiologica! recording and microiontophoretic drug administration have been detailed previously (Henry et al.. 1959). Briefly, rats were anesthetized with cbloral hydrate (400 mg/kg i.p.) and mounted in a stereotaxic frame. A burr hole was drilled over the head of the caudate-putamen (CPU: 8.7-8.9 mm A to lambda, 3-O-3.3 mm L to the midline). Ficle barrel micropipettes were used to record the activity of CPU neurons while SKF 38393 HCl and quinpirole HCl (both at 10 mM, pH 4) were applied by cationic iontophoresis (16 nA current) using appropriate balancing and retaining of currents. All CPU neurons were driven by iontophoretic application (anionic) of glutamatic acid (100 m&I. pH 8) to achieve firing rates of 4-7
ty
spikes/s. In rats that were pretreated with SKF 38393, the inhibitory effects of both SKF 38393 and quinpirole on CPU neurons were significantly enhanced as compared to controls (table 1). Thus, both the behavioral and electrophysiological results suggest that repeated selective stimulation of D, receptors leads to a sensitization of DA receptor-mediated functions. The enhanced effect of quinpirole in these animals was likely due to a greater enabling effect of D, receptors on D2mediated functions (Wachtel et al., 1989) rather
in D, receptors since oral stereotyped behaviors are only observed when selective D, agonists are administered during enhanced stimulation of the D, receptor (Amt et al., 1987; White et al., 1988), in this case provided by endogenous DA stimulation of supersensitive D, receptors. It is interesting that the sensitized behavioral response to SKF 38393 following repeated selective stimulation of the D, receptor required a withdrawal period before becoming manifest. In fact, behavioral tolerance was observed after the last injection of SKF 38393. This contrasts to behavioral sensitization observed following repeated psychomotor stimulant administration which is often evident both during the treatment regimen and following various withdrawal periods (Robinson and Becker, 1986). Therefore, while our previous findings with cocaine (Henry et al., 1989; Henry and White, in preparation) and the present results with SKF 38393 suggest that an increased responsiveness of DA D, receptors is a likely mediating component in the phenomenon of behavioral sensitization, alterations in other aspects of dopaminergic systems, which are affected by indirect and non-selective DA agonists such as than a direct
change
cocaine, must also be involved and may regulate temporal parameters of its expression.
Acknowledgements We ihank Vernice Davis for technical assistance and Eli Lilly and Co. for the generous gift of quinpirole. This study was supported by USPHS Grants DA-04093 and MH-40832.
References Amt J.. J. Hyttel and J. Perregaard. 1987, Dopamine D-l receptor agonists combined with the selective D-2 agonist quinpirole facilitate the expression of oral stereotyped behavior in rats, European J. Pharmacol. 133, 137. Henry, D.J., M.A. Greene and F.J. White, 1989, Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: Repeated administration, J. Pharmacol. Exp. Ther. 251, 839. Robinson, T.E. and J.B. Becker, 1986. Enduring changes in brain and behavior produced by chronic amphetamine ad-
499 ministration: a review and evaluation of animal models of amphetamine psychosis, Brain Res. Rev. 11, 57. Wachtel, S.R., X.-T. Hu, M.P. Galloway and F.J. White, 1989, Dl dopamine receptor stimulation enables the postsynaptic. but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems, Synapse 4. 327.
White, F.J., L.M. Bednan, S.R. Wachtel, S. Hjorth and R.J. Brooderson, 1988, Is stimulation of Dl dopamine receptors necessary for the expression of dopamine-mediated behaviors?, Pharmacol. B&hem. Behav. 30, 189.
