- Email: [email protected]
Stressor-like effects of FG-7142 on medial prefrontal cortex self-stimulation
171 operant chambers. Following stabilization of response rates on CRF, the rats were then switched to a fixed interval 5 (FI-5) schedule of reinforcement. It has previously been shown that this schedule minimizes the confounding influence of non-specific effects of stimulation on performance whilst being sensitive to drug and stress-induced alterations in reinforcement2'15. Following stabilization on the FI-5 schedule, rate-intensity curves were computed for each rat to determine the current intensity yielding half maximal response rates. One rat failed to reach a predefined response criterion of 10 lever-presses per minute at half-maximal FI-5 responding and was eliminated from the study. Extreme care was taken to avoid stressing the animals during this pretreatment. The rats were then run daily on the FI-5 schedule until individual response rates did not vary more than 5% across 3 consecutive days of testing. The last of these 3 days was used as a baseline against which the effects of stress were evaluated. On the following day, the rats were stressed prior to their usual self-stimulation session. They were taken from their cages and manually restrained for a period of one minute. The restraint procedure consisted of firmly gripping the torso of the rat and resisting any attempt by the rat to escape. The high incidence of vocalization and attempted escape during restraint suggested the aversiveness of the procedure. The rats were then placed in their home cages for 3 min after which they were given a standard 20-min selfstimulation session. Further standard daily tests (in the absence of restraint stress) were given daily for the following week after which drug testing commenced. FG-7142 (Research Biochemicals Ltd., U.S.A.) (3, 10 or 20 mg/kg) or its vehicle (0.05 ml distilled water containing 2% Tween 80) was injected i.p. 5 min prior to self-stimulation testing. Drug injections were made using a volume of 1 ml/kg. Each drug treatment and the vehicle treatment was followed by 3 consecutive days where the rats were given i.p. vehicle injections. As uncontrollable stress significantly elevates MPC self-stimulation 0, 24 and 48, but not 72 h later (see Fig. 1), self-stimulation was measured at these intervals following administration of FG-7142. Testing occurred over 16 consecutive days with each rat receiving each dose of FG-7142 and a vehicle treatment followed in each case by 3 days of vehicle injection. The order of drug presentation was randomized across rats with 7 of the 24 possible drug presentation sequences selected randomly and allocated randomly to subjects. Rates of self-stimulation were automatically computed for the 20-min sessions using a customized data collection and analysis program. Drugand stress-induced changes in response rates were analyzed by means of paired Student's t-test comparisons
(two-tailed). Data for 24, 48 and 72 h following each drug treatment were compared with the equivalent data for 24, 48 and 72 h following vehicle. Following the conclusion of testing the rats were sacrificed with an overdose of barbiturate and the brains removed and examined microscopically for verification of electrode positions. All rats completing the study were found to have electrodes located within the prelimbic region of the MPC. It can be seen from Fig. 1. that one minute of restraint stress produced an immediate facilitation of mean MPC self-stimulation rates of about 20%. This effect was highly consistent across rats, with every subject, except one, increasing responding to greater than 110% of baseline. Further, a significant elevation was also present 24 and 48 h following stress. Interestingly, mean rates were still elevated, although not significantly, on the last day of measurement (168 h following stress). This was due to 3 rats still showing an elevation of greater than 10% relative to baseline at this time following stress. Overall, these data parallel the previous finding of a mean 20% increase in MPC self-stimulation immediately and 24 h following exposure to uncontrollable footshock, with a tendency towards elevation at 168 h following treatment 15. The effects of FG-7142 on MPC self-stimulation were unusual in their dose-response characteristics (Fig. 2). Immediately following injection, 3 mg/kg and 20 mg/kg FG-7142 decreased MPC self-stimulation. The 10 mg/kg dose, however, produced an immediate facilitation (mean 19%) in 5 of the 7 rats tested. The remaining two
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Fig. 1. The effect of one minute of restraint stress on MPC self-stimulation. Numbers on the abscissa represent hours before and after restraint stress when self-stimulation sessions were given. Baseline response measures were taken 24 h prior to restraint stress. The mean baseline response rate ( + S.E.M.) was 13.2 + 0.56 presses per minute (ppm). This increased to 15.86 + 0.74 ppm immediately following stress (0 hours on the figure). Values are expressed as mean percentage change in individual baselines + 1 S.E.M. (**P < 0.02).
172 rats showed a complete cessation of responding 6-8 min following administration. This cessation continued until the end of the session. At 24 h following the 10 mg/kg dose, MPC self-stimulation was facilitated in all subjects tested, including the two animals that stopped responding immediately following the 10 mg/kg dose. Similarly, at 48 h a significant facilitation was still present, although of lesser magnitude (12%) than at 24 h. By 72 h following the 10 mg/kg dose, mean response rates had further decreased, although a small facilitation was still evident in most rats. No significant effects were seen at 24, 48 or 72 h following either 3 mg/kg or 20 mg/kg FG-7142, although there was a strong but non-significant tendency towards facilitation at 48 h following the 20 mg/kg dose. It is important to note that mean self-stimulation rates were extremely stable 24, 48 and 72 h following vehicle treatment (see Fig. 2 legend for values). Thus the significant effects seen at 24, 48 and 72 h following FG-7142 are unlikely to be due to inherent variability in MPC self-stimulation performance. The present results confirm and extend the previous finding that stress causes specific elevation of rates of MPC self-stimulation 15. Whereas stress-induced facilitation of MPC self-stimulation was originally demonstrated with relatively intense stress (sixty, 0.6-mA footshocks of mean 26 s duration15), the present results indicate that an equivalent facilitation effect can be seen with much milder uncontrollable stress. This is consistent with previous reports that mild stress or conditioned fear can
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Fig. 2. Effects of vehicle and 3, 10 and 20 mg/kg FG-7142 on MPC self-stimulation measured immediately, 24, 48, and 72 h following administration. Drug-induced changes in responding are expressed as mean percentage change in individual baselines (+ 1 S.E.M.). Responding immediately, 24, 48, and 72 h following each drug treatment was compared with responding immediately, 24, 48 and 72 h followingvehicle respectively. Absolute rates of responding in vehicle condition are as follows: vehicle 14.32 _+0.59, 24 h 14.59 + 0.63, 48 h 14.17 + 0.71, and 72 h 14.58 + 0.95 bar-presses/minute. The values shown for 10 and 20 mg/kg immediately following administration represent n = 5 as two subjects failed to respond under these conditions. All other values represent n = 7. (*P < 0.05; **P < 0.01).
increase D A turnover in the MPC 3'6. Indeed, Claustre et al. 3 noted that merely exposing rats to an intracranial injection procedure (which involves a degree of manual restraint) produced significant elevations in MPC D A turnover. The present results are thus consistent with the theory that the stress-induced facilitation of MPC selfstimulation is associated with increased MPC D A turnover. Further, the exceptional sensitivity of MPC selfstimulation to stressor effects indicates that future studies of MPC self-stimulation should carefully control for this factor to avoid confounding results. In the present study, FG-7142 produced effects on MPC self-stimulation that were consistent with the proposal that it is a 'chemical stressor'. However, this consistency was dose-dependent, in that only 10 mg/kg FG-7142 produced a clear stress-like effect on selfstimulation. Even then, only 5 of 7 rats showed response increases immediately following the 10 mg/kg dose, whereas two rats stopped responding completely. These two rats also ceased responding following a higher 20 mg/kg dose, whereas the other rats typically showed a 40% decrease in responding. Interestingly, of the two rats that ceased responding after FG-7142, one showed no facilitation of self-stimulation after restraint stress and the other only showed a small facilitation (10%). This suggests that differential responsivity to stress in these two subjects may have determined their inhibitory responses to FG-7142. Another factor that may have led to differences in the immediate response of FG-7142 is possible variations in drug uptake across subjects. Large differences in the magnitude and time course of plasma FG-7142 elevation have been demonstrated in human subjects following administration of identical doses. This is thought to account for the variability in anxiogenic effects produced by FG-7142 in humans 4. The clearest parallel between FG-7142 (10 mg/kg) and mild stress was the demonstration that both consistently elevated MPC self-stimulation 24 and 48 h following administration. Indeed, the magnitude of the elevation 24 h following FG-7142 was almost identical to that seen 24 h following either mild restraint (present study) or inescapable footshock stress 15, suggesting involvement of a common mechanism. It is notable that the facilitation (20%) seen here 0 and 24 h after one minute of manual restraint was almost identical to that reported 0 and 24 h following 60 long duration uncontrollable footshocks 15. It appears from this that controllability, rather than intensity, of stress may be important in determining the extent of the stress-induced facilitation of MPC self-stimulation. Such a hypothesis is also strongly indicated by the previous observation that controllable footshock produces a much greater facilitation (100%) of MPC self-stimulation than uncontrollable footshock (20%) 15.
173 In the present study FG-7142 produced a facilitation of MPC self-stimulation that was similar in magnitude to that produced by uncontrollable rather than controllable stress. This finding is consistent with the fact that an equivalent dose of FG-7142 (10 mg/kg) mimics exposure to uncontrollable stress by producing a learned helplessness effect 24 h following administration 5. Controllable stress, on the other hand, does not produce learned helplessness 12. Further, uncontrollable shock produced FG-7142-appropriate responding in a drug discrimination paradigm 11. The combination of such findings with the present results thus strongly suggests that FG-7142, albeit across a limited dose range, produces interoceptive cues and specific behavioural sequelae that are nearly identical to those produced by uncontrollable stress. The facilitation effect seen in the present study following exposure to 10 mg/kg FG-7142 is especially striking since an equivalent dose of FG-7142 was found to produce an 80% inhibition of 10-s variable interval self-stimulation of the lateral hypothalamus TM. In the same study, 5 mg/kg FG-7142 produced a 60% decrease and 20 mg/kg FG-7142 produced an 80% decrease in response rates ~s. Further, a number of studies employing reinforcers other than brain stimulation have similarly shown that FG-7142 inhibits lever-pressing in a dosedependent manner without depressing locomotor activity per se (see ref. 23 for review). The reason why this operant depression is produced by FG-7142 is presently unknown, although a general anhedonic effect of FG7142 has been considered possible 23. From this, it is apparent that the unusual doseresponse effects obtained in the present study may reflect an interaction between FG-7142's inhibitory effects on lever-pressing and its facilitatory effects on MPC DA turnover across the dose range investigated. Thus MPC DA is only slightly affected by 5 mg/kg FG-7142, whereas both 10 and 20 mg/kg produce robust elevations in MPC DA turnover 22. However, 5 mg/kg FG-7142 depresses lever-pressing behaviour in both rats ~9 and primates 25. It is thus likely that in the present study 3 mg/kg FG-7142 had little effect on MPC DA turnover and therefore only slight reinforcement-enhancing effects, but produced a mild depression of lever-pressing. This would explain the mild decrease in MPC self-stimulation observed. On the other hand, 20 mg/kg FG-7142 probably produced a powerful inhibition of lever-pressing in addition to a marked increased release of MPC DA. This increased DA release would tend to increase MPC self-stimulation and counteract, to a certain extent, the powerful inhib-
itory effects of this dose on lever-pressing. Indeed, the fact that 20 mg/kg FG-7142 inhibited MPC self-stimulation far less than lateral hypothalamic self-stimulation suggests the presence of a residual reinforcement-enhancing effect with MPC self-stimulation. With 10 mg/kg FG-7142, however, it is likely that the operant depression was less severe than after 20 mg/kg, and the facilitatory effect of enhanced DA release on MPC self-stimulation performance may have completely counteracted the inhibition of lever-pressing to produce a net facilitation of responding. This model may also explain the differences in the facilitation of MPC self-stimulation produced by controllable versus uncontrollable stress by proposing that both stressor-types produce similar increased release of MPC DA, but that, in addition, uncontrollable stress depresses operant behaviour and thus counteracts the facilitatory effects of increased MPC DA release on MPC self-stimulation. Whereas the immediate effects of stress and FG-7142 on MPC self-stimulation may perhaps be accounted for by the enhanced synthesis 9"1° and release 1'8 of MPC DA, the longer term effects on self-stimulation reported here following both stress and FG-7142 may involve other neurochemical mechanisms. In particular, the recent report that footshock stress increases the density of D 2 DA receptors in the MPC measured 27, but not 3, h following stress 13, suggests that the longer term facilitation (i.e. 24 h or more) of MPC self-stimulation reported here may involve changes in the number and/or sensitivity of MPC D A receptors. Such a hypothesis is consistent with the observation that chronic neuroleptic administration produces a progressive and long-lasting enhancement of MPC self-stimulation, an effect thought due to the increased numbers of MPC DA receptors 2°. Although administration of FG 7142 has recently been shown to produce long-lasting increases in cortical fladrenoceptor density 2~, possible long-term effects of MPC DA receptors have yet to be investigated. The present results would suggest that FG-7142 may, like stress, cause increased DA receptor density at relatively long durations following administration. However, the mechanism by which alterations in GABAergic transmission in the MPC affect catecholamine synthesis, release and receptor density remains, at present, uncertain.
1 Abercrombie, E.D., Keefe, K.A, DiFrischia, D.S. and Zigmond, M.J., Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal
cortex, J. Neurochem., 52 (1989) 1655-1658. 2 Atrens, D.M., Self-stimulationand psychotropic drugs: a methodological and conceptual critique. In N. Bond (Ed.), Animal
Research supported by a University of Sydney Postgraduate Scholarship to I.S.M. Mr. Philip Healey is thanked for his excellent technical assistance.
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Models of Psychopathology, Academic Press, Sydney, 1984, pp. 227-256. Claustre, Y., Rivy, J.P., Dennis, T. and Scatton, B., Pharmacological studies on stress-induced increase in frontal cortical dopamine metabolism in the rat, J. Pharm. Exp. Ther., 238 (1986) 693-700. Dorow, R., FG-7152 and its anxiety-inducing effects in humans, Br. J. Clin. Pharmacol., 23 (1987) 781-782. Drugan, R.C., Maier, S., Skolnick, E, Paul, S.M. and Crawley, J.N., An anxiogenic benzodiazepine receptor ligand induces learned helplessness, Eur. J. Pharmacol., 113 (1985) 453-457. Herman, J.P., Guillonneau, D., Dantzer, R., Scatton, B., Semerdijian-Rouquier, L. and Le Moal, M., Differential effects of inescapable footshocks and of stimuli previously paired with inescapable footshocks on dopamine turnover in cortical and limbic areas of the rat, Life Sci., 30 (1982) 2207-2214. Ida, Y. and Roth, R.H., The activation of mesoprefrontal dopamine neurones by FG 7142 is absent in rats treated chronically with diazepam, Eur. J. Pharmacol., 137 (1987) 185-190. Imperato, A., Puglisi-AUegra, S., Casolini, P., Zocchi, A. and Angelucci, L., Stress-induced enhancement of dopamine and acetylcholine release in limbic structures: role of corticosterone, Eur. J. Pharmacol., 165 (1989) 337-338. Knorr, A.M., Deutch, A.Y. and Roth, R.H., The anxiogenic fl-carboline FG-7142 increases in vivo and in vitro tyrosine hydroxylation in the prefrontal cortex, Brain Research, 495 (1989) 355-361. Kramercy, N.R., Delanoy, R.L. and Dunn, A.J., Footshock treatment activates catecholamine synthesis in slices of mouse brain regions, Brain Research, 290 (1984) 311-319. Leidenheimer, N.J. and Schechter, M.D., Discriminative stimulus control by the anxiogenic fl-carboline FG 7142: generalization to a physiological stressor, Pharmacol. Bioehem. Behav., 30 (1988) 351-355. Maier, S.E and Seligman, M.E.E, Learned helplessness: theory and evidence, J. Exp. Psych. Gen., 105 (1976) 3-46. MacLennan, A.J., Pelleymounter, M.A., Atmadja, S., Jakubovic, A., Maier, S.E and Fibiger, H.C., D 2 dopamine receptors in the rat prefrontal cortex: characterization and alteration by stress, Brain Research, 477 (1989) 300-307. Mantz, J., Thierry, A.M. and Glowinski, J., Effect of noxious
tail pinch on the discharge rate of mesocortical and mesolimbic neurons: selective activation of the mesocortical system, Brain Research, 476 (1989) 377-381. 15 McGregor, I.S., Balleine, B.W. and Atrens, D.M., Footshock stress facilitates self-stimulation of the medial prefrontal cortex but not the lateral hypothalamus in the rat, Brain Research, 490 (1989) 397-403. 16 Mora, E and Ferrer, J.M.R., Neurotransmitters, pathways and circuits as the neural substrates of self-stimulation of the prefrontal cortex: facts and speculations, Behav. Brain Res., 22 (1986) 127-140. 17 Paxinos, G. and Watson, C., The Rat Brain in Stereotaxic Co-oordinates, 2nd edn., Academic Press, Sydney, 1986. 18 PeUow, S., Herberg, L.J. and File, S.E., The effects of the fl-carboline FG 7142 on intracranial self-stimulation in the rat, Pharmacol. Biochem. Behav., 21 (1984) 667-669. t9 Quintero, S., Henney, S., Lawson, P., Mellanby, J. and Gray, J.A., The effects of compounds related to gamma-aminobutyrate and benzodiazepine receptors on behavioural responses to anxiogenic stimuli in the rat: punished bar-pressing, Psychopharmacology, 85 (1985) 244-251. 20 Robertson, A. and Mogenson, G.J., Facilitation of self-stimulation of the prefrontal cortex in rats following chronic administration of spiroperidol or amphetamine, Psychopharmacology, 65 (1979) 149-154. 21 Stanford, S.C., Baldwin, H.A. and File, S.E., Effects of single or repeated administration of the benzodiazepine inverse agonist FG-7142 on behaviour and cortical adrenoceptor binding in the rat, Psychopharmacology, 98 (1989) 417-424. 22 Tam, S.-Y. and Roth, R.H., Selective increase in dopamine metabolism in the prefrontal cortex by the anxiogenic betacarboline FG 7142, Biochem. Pharmacol., 34 (1985) 1595-1598. 23 Thiebot, M.H., Soubrie, P. and Sanger, D., Anxiogenic properties of beta-CCE and FG 7142: a review of promises and pitfalls, Psychopharmacology, 94 (1988) 452-463. 24 Thierry, A.M., Tassin, J.P., Blanc, G. and GIowinski, J., Selective activation of the mesocortical DA system by stress, Nature (Lond.), 263 (1976) 242-243. 25 Wettstein, J.G., Behavioural studies with the fl-carboline FG 7142 combined with related drugs in monkeys, Eur. J. Pharmacol., 163 (1989) 219-225.
(two-tailed). Data for 24, 48 and 72 h following each drug treatment were compared with the equivalent data for 24, 48 and 72 h following vehicle. Following the conclusion of testing the rats were sacrificed with an overdose of barbiturate and the brains removed and examined microscopically for verification of electrode positions. All rats completing the study were found to have electrodes located within the prelimbic region of the MPC. It can be seen from Fig. 1. that one minute of restraint stress produced an immediate facilitation of mean MPC self-stimulation rates of about 20%. This effect was highly consistent across rats, with every subject, except one, increasing responding to greater than 110% of baseline. Further, a significant elevation was also present 24 and 48 h following stress. Interestingly, mean rates were still elevated, although not significantly, on the last day of measurement (168 h following stress). This was due to 3 rats still showing an elevation of greater than 10% relative to baseline at this time following stress. Overall, these data parallel the previous finding of a mean 20% increase in MPC self-stimulation immediately and 24 h following exposure to uncontrollable footshock, with a tendency towards elevation at 168 h following treatment 15. The effects of FG-7142 on MPC self-stimulation were unusual in their dose-response characteristics (Fig. 2). Immediately following injection, 3 mg/kg and 20 mg/kg FG-7142 decreased MPC self-stimulation. The 10 mg/kg dose, however, produced an immediate facilitation (mean 19%) in 5 of the 7 rats tested. The remaining two
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Fig. 1. The effect of one minute of restraint stress on MPC self-stimulation. Numbers on the abscissa represent hours before and after restraint stress when self-stimulation sessions were given. Baseline response measures were taken 24 h prior to restraint stress. The mean baseline response rate ( + S.E.M.) was 13.2 + 0.56 presses per minute (ppm). This increased to 15.86 + 0.74 ppm immediately following stress (0 hours on the figure). Values are expressed as mean percentage change in individual baselines + 1 S.E.M. (**P < 0.02).
172 rats showed a complete cessation of responding 6-8 min following administration. This cessation continued until the end of the session. At 24 h following the 10 mg/kg dose, MPC self-stimulation was facilitated in all subjects tested, including the two animals that stopped responding immediately following the 10 mg/kg dose. Similarly, at 48 h a significant facilitation was still present, although of lesser magnitude (12%) than at 24 h. By 72 h following the 10 mg/kg dose, mean response rates had further decreased, although a small facilitation was still evident in most rats. No significant effects were seen at 24, 48 or 72 h following either 3 mg/kg or 20 mg/kg FG-7142, although there was a strong but non-significant tendency towards facilitation at 48 h following the 20 mg/kg dose. It is important to note that mean self-stimulation rates were extremely stable 24, 48 and 72 h following vehicle treatment (see Fig. 2 legend for values). Thus the significant effects seen at 24, 48 and 72 h following FG-7142 are unlikely to be due to inherent variability in MPC self-stimulation performance. The present results confirm and extend the previous finding that stress causes specific elevation of rates of MPC self-stimulation 15. Whereas stress-induced facilitation of MPC self-stimulation was originally demonstrated with relatively intense stress (sixty, 0.6-mA footshocks of mean 26 s duration15), the present results indicate that an equivalent facilitation effect can be seen with much milder uncontrollable stress. This is consistent with previous reports that mild stress or conditioned fear can
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Fig. 2. Effects of vehicle and 3, 10 and 20 mg/kg FG-7142 on MPC self-stimulation measured immediately, 24, 48, and 72 h following administration. Drug-induced changes in responding are expressed as mean percentage change in individual baselines (+ 1 S.E.M.). Responding immediately, 24, 48, and 72 h following each drug treatment was compared with responding immediately, 24, 48 and 72 h followingvehicle respectively. Absolute rates of responding in vehicle condition are as follows: vehicle 14.32 _+0.59, 24 h 14.59 + 0.63, 48 h 14.17 + 0.71, and 72 h 14.58 + 0.95 bar-presses/minute. The values shown for 10 and 20 mg/kg immediately following administration represent n = 5 as two subjects failed to respond under these conditions. All other values represent n = 7. (*P < 0.05; **P < 0.01).
increase D A turnover in the MPC 3'6. Indeed, Claustre et al. 3 noted that merely exposing rats to an intracranial injection procedure (which involves a degree of manual restraint) produced significant elevations in MPC D A turnover. The present results are thus consistent with the theory that the stress-induced facilitation of MPC selfstimulation is associated with increased MPC D A turnover. Further, the exceptional sensitivity of MPC selfstimulation to stressor effects indicates that future studies of MPC self-stimulation should carefully control for this factor to avoid confounding results. In the present study, FG-7142 produced effects on MPC self-stimulation that were consistent with the proposal that it is a 'chemical stressor'. However, this consistency was dose-dependent, in that only 10 mg/kg FG-7142 produced a clear stress-like effect on selfstimulation. Even then, only 5 of 7 rats showed response increases immediately following the 10 mg/kg dose, whereas two rats stopped responding completely. These two rats also ceased responding following a higher 20 mg/kg dose, whereas the other rats typically showed a 40% decrease in responding. Interestingly, of the two rats that ceased responding after FG-7142, one showed no facilitation of self-stimulation after restraint stress and the other only showed a small facilitation (10%). This suggests that differential responsivity to stress in these two subjects may have determined their inhibitory responses to FG-7142. Another factor that may have led to differences in the immediate response of FG-7142 is possible variations in drug uptake across subjects. Large differences in the magnitude and time course of plasma FG-7142 elevation have been demonstrated in human subjects following administration of identical doses. This is thought to account for the variability in anxiogenic effects produced by FG-7142 in humans 4. The clearest parallel between FG-7142 (10 mg/kg) and mild stress was the demonstration that both consistently elevated MPC self-stimulation 24 and 48 h following administration. Indeed, the magnitude of the elevation 24 h following FG-7142 was almost identical to that seen 24 h following either mild restraint (present study) or inescapable footshock stress 15, suggesting involvement of a common mechanism. It is notable that the facilitation (20%) seen here 0 and 24 h after one minute of manual restraint was almost identical to that reported 0 and 24 h following 60 long duration uncontrollable footshocks 15. It appears from this that controllability, rather than intensity, of stress may be important in determining the extent of the stress-induced facilitation of MPC self-stimulation. Such a hypothesis is also strongly indicated by the previous observation that controllable footshock produces a much greater facilitation (100%) of MPC self-stimulation than uncontrollable footshock (20%) 15.
173 In the present study FG-7142 produced a facilitation of MPC self-stimulation that was similar in magnitude to that produced by uncontrollable rather than controllable stress. This finding is consistent with the fact that an equivalent dose of FG-7142 (10 mg/kg) mimics exposure to uncontrollable stress by producing a learned helplessness effect 24 h following administration 5. Controllable stress, on the other hand, does not produce learned helplessness 12. Further, uncontrollable shock produced FG-7142-appropriate responding in a drug discrimination paradigm 11. The combination of such findings with the present results thus strongly suggests that FG-7142, albeit across a limited dose range, produces interoceptive cues and specific behavioural sequelae that are nearly identical to those produced by uncontrollable stress. The facilitation effect seen in the present study following exposure to 10 mg/kg FG-7142 is especially striking since an equivalent dose of FG-7142 was found to produce an 80% inhibition of 10-s variable interval self-stimulation of the lateral hypothalamus TM. In the same study, 5 mg/kg FG-7142 produced a 60% decrease and 20 mg/kg FG-7142 produced an 80% decrease in response rates ~s. Further, a number of studies employing reinforcers other than brain stimulation have similarly shown that FG-7142 inhibits lever-pressing in a dosedependent manner without depressing locomotor activity per se (see ref. 23 for review). The reason why this operant depression is produced by FG-7142 is presently unknown, although a general anhedonic effect of FG7142 has been considered possible 23. From this, it is apparent that the unusual doseresponse effects obtained in the present study may reflect an interaction between FG-7142's inhibitory effects on lever-pressing and its facilitatory effects on MPC DA turnover across the dose range investigated. Thus MPC DA is only slightly affected by 5 mg/kg FG-7142, whereas both 10 and 20 mg/kg produce robust elevations in MPC DA turnover 22. However, 5 mg/kg FG-7142 depresses lever-pressing behaviour in both rats ~9 and primates 25. It is thus likely that in the present study 3 mg/kg FG-7142 had little effect on MPC DA turnover and therefore only slight reinforcement-enhancing effects, but produced a mild depression of lever-pressing. This would explain the mild decrease in MPC self-stimulation observed. On the other hand, 20 mg/kg FG-7142 probably produced a powerful inhibition of lever-pressing in addition to a marked increased release of MPC DA. This increased DA release would tend to increase MPC self-stimulation and counteract, to a certain extent, the powerful inhib-
itory effects of this dose on lever-pressing. Indeed, the fact that 20 mg/kg FG-7142 inhibited MPC self-stimulation far less than lateral hypothalamic self-stimulation suggests the presence of a residual reinforcement-enhancing effect with MPC self-stimulation. With 10 mg/kg FG-7142, however, it is likely that the operant depression was less severe than after 20 mg/kg, and the facilitatory effect of enhanced DA release on MPC self-stimulation performance may have completely counteracted the inhibition of lever-pressing to produce a net facilitation of responding. This model may also explain the differences in the facilitation of MPC self-stimulation produced by controllable versus uncontrollable stress by proposing that both stressor-types produce similar increased release of MPC DA, but that, in addition, uncontrollable stress depresses operant behaviour and thus counteracts the facilitatory effects of increased MPC DA release on MPC self-stimulation. Whereas the immediate effects of stress and FG-7142 on MPC self-stimulation may perhaps be accounted for by the enhanced synthesis 9"1° and release 1'8 of MPC DA, the longer term effects on self-stimulation reported here following both stress and FG-7142 may involve other neurochemical mechanisms. In particular, the recent report that footshock stress increases the density of D 2 DA receptors in the MPC measured 27, but not 3, h following stress 13, suggests that the longer term facilitation (i.e. 24 h or more) of MPC self-stimulation reported here may involve changes in the number and/or sensitivity of MPC D A receptors. Such a hypothesis is consistent with the observation that chronic neuroleptic administration produces a progressive and long-lasting enhancement of MPC self-stimulation, an effect thought due to the increased numbers of MPC DA receptors 2°. Although administration of FG 7142 has recently been shown to produce long-lasting increases in cortical fladrenoceptor density 2~, possible long-term effects of MPC DA receptors have yet to be investigated. The present results would suggest that FG-7142 may, like stress, cause increased DA receptor density at relatively long durations following administration. However, the mechanism by which alterations in GABAergic transmission in the MPC affect catecholamine synthesis, release and receptor density remains, at present, uncertain.
1 Abercrombie, E.D., Keefe, K.A, DiFrischia, D.S. and Zigmond, M.J., Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal
cortex, J. Neurochem., 52 (1989) 1655-1658. 2 Atrens, D.M., Self-stimulationand psychotropic drugs: a methodological and conceptual critique. In N. Bond (Ed.), Animal
Research supported by a University of Sydney Postgraduate Scholarship to I.S.M. Mr. Philip Healey is thanked for his excellent technical assistance.
174
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