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Noncontingent displacement of catecholamines by intraventricular tyramine: Biphasic dose-response effects on self-stimulation
Nrurophurmucoluy,v.
1977. 16. 53-55
Pergamon
Press. Printed in Gt. Britam
NONCONTINGENT DISPLACEMENT OF CATECHOLAMINES BY INTRAVENTRICULAR TYRAMINE: BIPHASIC DOSE-RESPONSE EFFECTS ON SELF-STIMULATION K. B. J. FRANKLIN and L. J. HERBERG Institute of Neurology, National Hospital, Queen Square, London WClN 3BG (Accepted 26 May 1976) Summary-It
has been proposed that the reinforcing effects of brain-stimulation reward are mediated by central catecholamine-containing pathways. If so, catecholamine release during self-stimulation would have to be contingent on relevant items of performance, and treatments causing a dissociation between responding and release of catecholamine should disrupt self-stimulation. This prediction was tested by comparison of two indirectly acting catecholamine stimulants: (1) tyramine, which causes a continuous displacement of catecholamine from nerve terminals independently of nerve impulses, and (2) amphetamine, which, in moderate doses, acts by potentiating the release of catecholamine by individual nerve impulses. Intraventricular injection of tyramine was found to depress self-stimulation except at near-threshold doses, whereas amphetamine facilitated it over a wide range of doses. A second dose of tyramine administered 60 min after the first was without significant effect. These results suggest that self-stimulation may be impaired if catecholamine is released in a manner unrelated to the rat’s lever-pressing performance. This finding is consistent with the hypothesis that catecholamine serves as a transmitter in a central reinforcement system.
Recent investigations have led to a hypothesis that rewarding events are signalled in the brain by catecholamine-dependent pathways, and that electrical activation of these pathways mediates the reinforcement process in electrical self-stimulation (Stein, 1968; Crow, 1973). It is known, however, that for operant behaviour to be maintained by conventional reinforcers, it is necessary for the receipt of the reward to be correlated in time with the emission of the relevant response (Skinner, 1948). In accordance with this principle it has been found that procedures which dissociate reinforcement from the rat’s response may have a disruptive effect on operant responding for food (Ahlenius, Anden and Engel, 1971; Sheldon and Williams, unpublished observations) or for brain-stimulation reward (Herberg, 1962). One condition in which responses may be dissociated from rewards is after treatment with stimulant drugs, certain of which have been shown to act by displacing catecholamine from nerve endings and delivering it to the catecholamine receptors independently of nerve impulses and without regard to the animal’s ongoing activities. Such drugs, though acting as stimulants of various autonomic nervous functions (Burn and Rand, 1958), would be predicted to randomize reward-response relationships in self-stimulation and disrupt performance (Crow, 1970; Wise, Berger and Stein, 1973; Herberg and Stephens, 1975). Any other result would raise doubts as to the proposed role of catecholamine in signalling reward. In the present study we sought to test the catecholamine hypothesis by examining the effect of tyramine on self-stimulation. Tyramine acts by releasing cat-
echolamine from nerve-endings in a continuous flow. It differs from amphetamine-like stimulants which release transmitter in discrete quanta emitted in time with ongoing nerve impulses (Smith, 1973; Von Voigtlander and Moore, 1973). On the catecholamine hypothesis, tyramine should depress self-stimulation, although amphetamine enhances it. METHODS
Subjects
Nineteen adult male Wistar rats were implanted with a guide cannula aimed at the lateral ventricle (de Groot coordinates: bregma 0.0, 1.8, 4.2 below brain surface), and a stimulating electrode in either the lateral hypothalamus (monopolar, - 1.0, 1.8, 8.7) or the substantia nigra (bipolar, -2.7, 1.8, 8.7). The cannula served as an indifferent electrode when required. After recovery, the rats were trained to operate a pedal for 0.5~set 50-Hz sinewave pulses which were available on a variable interval reinforcement schedule at randomly varied intervals of 10 set mean duration. Use of this schedule’ ensures a steady, seizure-free rate of responding on which stimulant or depressive effects can be imposed without appreciable effect on the rate at which reinforcing shocks are received. Training continued for at least three 2-hr sessions before testing began. Procedure
On test days rats were allowed to self-stimulate for 30 min or until stable, and injected intraventricularly with isotonic saline or one of four doses of tyramine 53
54
K. B. J. FRANKLIN and L. J. HERBERG
hydrochloride (Sigma) or (+)-amphetamine sulphate (Smith, Kline and French), and allowed to self-stimulate for a further 40 min. Response rates were recorded at IO-min intervals on print-out counters. Tyramine was administered to nine rats in doses of 200, 600, 1800 and 4160 nmol. The lowest point on this range exceeded a dose (67 nmol) which had proved to be without apparent effect on self-stimulation or general behaviour in preliminary trials. (+)-Amphetamine was given to 6 rats in doses of 133. 400, 1200 and 3600 nmol, overlapping the range of doses of tyramine. Saline, and the largest doses of tyramine and amphetamine, were injected in a volume of 6 ~1, the other doses in 4 /*I. Injections were given in random order at intervals of not less than 48 hr. Four additional rats were each given two consecutive 1800-nmol injections of tyramine 60 min apart in a single test session, and results from these rats are treated separately. After completion of the experiment, surviving rats were anaesthetized, injected with 4 ~1 india ink, and killed. The position of electrodes and cannulae in all rats, and the presence of ink in the ventricular system were determined from photographic enlargements of 50-pm frozen sections. RESULTS Histology
Three rats dislodged their electrodes before testing was completed and were discarded. In 15 rats the cannula tips penetrated the lateral ventricles, and rats injected with ink (n = 12) showed spread of ink to the third ventricle or beyond. In the sixteenth rat the cannula ended above and lateral to the ventricle and +100 r
I
I
_
z
NPCI
B O %
L Z
25 T
I’
-too’
1
2
4 DOSE
8 (nmol
16 x
32
64
100)
Fig. 1. Self-stimulation rates during the first 30 intraventricular injection of various doses of expressed (H-W) or amphetamine (M) centage of the rate in the 30 min before injection. bars and the shaded panel indicate standard
min after tyramine as a perVertical errors.
I =300 2 0 ti uJ200 g
R
-
-
100 -
I
I
I
I
I
b
I
I
I
2
3
4
5
6
7
a
9
IO-mm
I
IO
I
II
I
12
PERIODS
Fig. 2. Self-stimulation rates of four rats recorded at IO-min intervals during two consecutive intraventricular injections of 1800 nmol tyramine (marked by arrows), demonstrating the protective effect conferred by the initial dose.
ink was limited to the cortical surfaces after reflux along the cannula track. Electrodes in all rats were located in the near-and mid-lateral hypothalamus.
Doseeresponse curves for tyramine and amphetamine are plotted in Figure 1. Response rates after the lowest dose of tyramine (100 nmol) were slightly higher than after saline (+ 1794; t = 3.7, d.f. = 6. P < 0.05) but all other doses of tyramine were either without effect or strongly depressant, and the overall dose-response curve showed a significantly negative slope (Friedman x,’ = 19.3, d.J = 3, P < 0.001). Depressant effects were rapid in onset and commonly reached maximal levels within the first 10 min after injection. At this time the rats’ posture and behaviour often appeared abnormal. They lay with their abdomens held close to the floor, sometimes making rapid repetitive movements of their limbs in brief bursts. Full recovery occurred within the ensuing 60 min. and Figure 2 shows that administration of a second dose of tyramine at this stage was much less effective than the first in its action on self-stimulation (1 = 3.8, d:f: = 3, P < 0.05). The effect of increasing doses of amphetamine was in the opposite direction to that of tyramine, giving a significant positive slope (Friedman 1,’ = 10.1, d:f: = 3. P < 0.02) but even the least effective dose of amphetamine (133 nmol) increased self-stimulation rates more strongly than the 200-nmol dose of tyramine (40 vs. 17’/,. t = 2.8, dJ = 7, P < 0.05). Behavioural changes after amphetamine generally included increased locomotor activity, rearing and sniffing, except with the 3600-nmol dose, which evoked stereotyped sniffing of the floor of the cage. DISCUSSION It was predicted. on the catecholamine-reinforcement hypothesis, that the differing modes of action
Tyramine
and self-stimulation
of tyramine and amphetamine would lead to opposite effects on self-stimulatton. Our results appear to be consistent with this prediction except for the mild stimulant effect observed after the lowest dose of tyramine. The stimulant effect, however, is not necessarily in conflict with the hypothesis, since a suitably low dose of tyramine would be expected to cause subliminal excitation of reinforcement units, rendering more units subject to response-contingent recruitment by the stimulating current (cf. Creed, Denny-Brown, Liddel and Sherrington, 1932, p. 119). Thus, disruption of responding would be expected only with higher doses that were supraliminal for nerve firing. Another possible explanation of the stimulant effect of tyramine is that it could also be acting, at low doses, on a central mechanism for drive or arousal not forming part of the reinforcement system proper. A similar explanation (Herberg, Stephens and Franklin, 1976) has recently been proposed for the reported facilitation of self-stimulation by the direct dopaminereceptor stimulant, apomorphine (Broekkamp and Van Rossum, 1974; Wauquier and Niemegeers, 1973). At all higher doses tyramine was depressant. It is necessary to consider, however, whether the predicted depression of self-stimulation by tyramine may have in fact been caused by toxic side-effects, as might seem from the abnormal behaviour seen at the height of its action. Tyramine is an important precursor of octopamine (Fischer, Horst and Kopin, 1965) a false transmitter which could cause general disturbance of behaviour, including depression of self-stimulation. But the virtual absence of any change in self-stimulation rate after a second dose of tyramine argues against this possibility and suggests that the initial depression, like other known effects of tyramine (Axelrod, Gordon, Hertling, Kopin and Potter, 1962) was mediated by a small cytoplasmic pool of catecholamine which suffered exhaustion after the first dose. If the depression had depended on the formation of octopamine, or on a direct toxic effect of tyramine, one would have expected a cumulative depression with repeated doses, rather than a tachyphyllaxis. The motor disturbances which accompanied the tyramine injections equally showed tachyphyllaxis to a second dose and seem equally dependent on tyramine-induced release of catecholamine, which occurs perhaps at the terminals of the bulbospinal noradrenergic pathways of Dahlstrom and Fuxe (1975). The presence of these motor disturbances does not necessarily rule out or preempt noncontingency of catecholamine receptor activity as a possible explanation of the accompanying behavioural effects, and it is even possible that the motor disturbances themselves are to be explained in the same way. Acknowledgements-The authors thank Research Council and the Brain Research port.
N.P. 16/l--~
the Trust
Medical for sup-
55 REFERENCES
Ahlenius, S., Anden, N. E. and Engel, J. (1971). Importance of catecholamine release by nerve impulses for free operant behaviour. Physiol. B&au. 7: 931-934. Axelrod, J. Gordon, E., Hertting, G., Kopin, I. J. and Potter, L. T. (1962). On the mechanism of tachyphylaxis to tyramine in the isolated rat heart. Er. J. Pharmac. 19: 56-63. Broekkamp, C. L. E. and Van Rossum, J. M. (1974) Effects of apomorphine on self-stimulaiton behaviour. Psychopharmacologia 34: 71-80. Burn, J. H. and Rand, M. J. (1958). The action of sympathomimetic amines in animals treated with reserpine. Br. J. Pharmac. 144: 314-336. Creed, R. S., Denny-Brown, D., Eccles, J. C., Liddell, E. G. T. and Sherrington, C. S. (1932). Rejex Actioity of the Spinal Cord. Oxford University Press, London. Crow, T. J. (1970) Enhancement by cocaine of intracranial self-stimulation in the rat. Life Sci. 9: 3755381. Crow, T. J. (1973) Catecholamine-containing neurones and electrical self-stimulation: 2. A theoretical interpretation and some psychiatric implications. Psychol. Med. 3: 66-73. Dahlstrom, A. and Fuxe, K. (1965) Evidence for the existence of monoamine neurons in the central nervous system. II. Experimentally induced changes in intraneuronal amine levels of bulbospinal neuron systems. Acta physiol. stand. 64: Suvvl. 247. 1-36. Fischer, J. E., Horst. WI b. and Kopin, I. J. (1965) p-Hydroxylated sympathomimetic amines as false neurotransmitters. Br. J. Pharmac. 24: 477484. Herberg, L. J. (1962) Dissociating reward from response in electrical self-stimulation in the rat. Nature, Land. 195: 628. Herberg, L. J. and Stephens, D. N. (1975). Catecholamines and self-stimulation: the action of amantadine and its interaction with amphetamine. Pharmac. Biochem. Behav. 3: 263-269. Herberg, L. J., Stephens, D. N. and Franklin, K. B. J. (1976). Catecholamines and self-stimulation: evidence suggesting a reinforcing role for noradrenaline and a motivating role for dopamine. Pharmac. Biochem. Behav. 4: 575-582. Skinner, B. F. (1948). ‘Superstition’ in the pigeon. J. exp. Psychoi. 38: 168-172. Smith, A. D. (1973). Mechanisms involved in the release of noradrenaline from sympathetic nerves. Br. med. Bull. 29: 123-129. Von Voigtlander, P. F. and Moore. K. E. (1973) Involvement of nigrostriatal neurons in the in uiuo release of dopamine by amphetamine, amantadine, and tyramine. J. Pharmac. exp. Ther. 184: 542-552. Stein, L. (1968). Chemistry of reward and punishment. In: Psychopharmacology: A Review of Progress 1957-1967 (Efron, D. H., Ed.) pp. 105-123, US. Government Printing OfIke. Washingtom, DC. Wauquier, A. and Niemegeers, C. J. E. (1973). Intracranial self-stimulation in rats as a function of various stimulus parameters: III. Influence of apomorphine on medial forebrain bundle stimulation with monopolar electrodes. Psychopharmacologia 30: 163-l 72. Wise, C. D., Berger, B. D. and Stein, L. (1973). Evidence of r-noradrenergic reward receptors and serotonergic punishment receptors in the rat brain. Biol. Psychiat. 6: 3-21.
1977. 16. 53-55
Pergamon
Press. Printed in Gt. Britam
NONCONTINGENT DISPLACEMENT OF CATECHOLAMINES BY INTRAVENTRICULAR TYRAMINE: BIPHASIC DOSE-RESPONSE EFFECTS ON SELF-STIMULATION K. B. J. FRANKLIN and L. J. HERBERG Institute of Neurology, National Hospital, Queen Square, London WClN 3BG (Accepted 26 May 1976) Summary-It
has been proposed that the reinforcing effects of brain-stimulation reward are mediated by central catecholamine-containing pathways. If so, catecholamine release during self-stimulation would have to be contingent on relevant items of performance, and treatments causing a dissociation between responding and release of catecholamine should disrupt self-stimulation. This prediction was tested by comparison of two indirectly acting catecholamine stimulants: (1) tyramine, which causes a continuous displacement of catecholamine from nerve terminals independently of nerve impulses, and (2) amphetamine, which, in moderate doses, acts by potentiating the release of catecholamine by individual nerve impulses. Intraventricular injection of tyramine was found to depress self-stimulation except at near-threshold doses, whereas amphetamine facilitated it over a wide range of doses. A second dose of tyramine administered 60 min after the first was without significant effect. These results suggest that self-stimulation may be impaired if catecholamine is released in a manner unrelated to the rat’s lever-pressing performance. This finding is consistent with the hypothesis that catecholamine serves as a transmitter in a central reinforcement system.
Recent investigations have led to a hypothesis that rewarding events are signalled in the brain by catecholamine-dependent pathways, and that electrical activation of these pathways mediates the reinforcement process in electrical self-stimulation (Stein, 1968; Crow, 1973). It is known, however, that for operant behaviour to be maintained by conventional reinforcers, it is necessary for the receipt of the reward to be correlated in time with the emission of the relevant response (Skinner, 1948). In accordance with this principle it has been found that procedures which dissociate reinforcement from the rat’s response may have a disruptive effect on operant responding for food (Ahlenius, Anden and Engel, 1971; Sheldon and Williams, unpublished observations) or for brain-stimulation reward (Herberg, 1962). One condition in which responses may be dissociated from rewards is after treatment with stimulant drugs, certain of which have been shown to act by displacing catecholamine from nerve endings and delivering it to the catecholamine receptors independently of nerve impulses and without regard to the animal’s ongoing activities. Such drugs, though acting as stimulants of various autonomic nervous functions (Burn and Rand, 1958), would be predicted to randomize reward-response relationships in self-stimulation and disrupt performance (Crow, 1970; Wise, Berger and Stein, 1973; Herberg and Stephens, 1975). Any other result would raise doubts as to the proposed role of catecholamine in signalling reward. In the present study we sought to test the catecholamine hypothesis by examining the effect of tyramine on self-stimulation. Tyramine acts by releasing cat-
echolamine from nerve-endings in a continuous flow. It differs from amphetamine-like stimulants which release transmitter in discrete quanta emitted in time with ongoing nerve impulses (Smith, 1973; Von Voigtlander and Moore, 1973). On the catecholamine hypothesis, tyramine should depress self-stimulation, although amphetamine enhances it. METHODS
Subjects
Nineteen adult male Wistar rats were implanted with a guide cannula aimed at the lateral ventricle (de Groot coordinates: bregma 0.0, 1.8, 4.2 below brain surface), and a stimulating electrode in either the lateral hypothalamus (monopolar, - 1.0, 1.8, 8.7) or the substantia nigra (bipolar, -2.7, 1.8, 8.7). The cannula served as an indifferent electrode when required. After recovery, the rats were trained to operate a pedal for 0.5~set 50-Hz sinewave pulses which were available on a variable interval reinforcement schedule at randomly varied intervals of 10 set mean duration. Use of this schedule’ ensures a steady, seizure-free rate of responding on which stimulant or depressive effects can be imposed without appreciable effect on the rate at which reinforcing shocks are received. Training continued for at least three 2-hr sessions before testing began. Procedure
On test days rats were allowed to self-stimulate for 30 min or until stable, and injected intraventricularly with isotonic saline or one of four doses of tyramine 53
54
K. B. J. FRANKLIN and L. J. HERBERG
hydrochloride (Sigma) or (+)-amphetamine sulphate (Smith, Kline and French), and allowed to self-stimulate for a further 40 min. Response rates were recorded at IO-min intervals on print-out counters. Tyramine was administered to nine rats in doses of 200, 600, 1800 and 4160 nmol. The lowest point on this range exceeded a dose (67 nmol) which had proved to be without apparent effect on self-stimulation or general behaviour in preliminary trials. (+)-Amphetamine was given to 6 rats in doses of 133. 400, 1200 and 3600 nmol, overlapping the range of doses of tyramine. Saline, and the largest doses of tyramine and amphetamine, were injected in a volume of 6 ~1, the other doses in 4 /*I. Injections were given in random order at intervals of not less than 48 hr. Four additional rats were each given two consecutive 1800-nmol injections of tyramine 60 min apart in a single test session, and results from these rats are treated separately. After completion of the experiment, surviving rats were anaesthetized, injected with 4 ~1 india ink, and killed. The position of electrodes and cannulae in all rats, and the presence of ink in the ventricular system were determined from photographic enlargements of 50-pm frozen sections. RESULTS Histology
Three rats dislodged their electrodes before testing was completed and were discarded. In 15 rats the cannula tips penetrated the lateral ventricles, and rats injected with ink (n = 12) showed spread of ink to the third ventricle or beyond. In the sixteenth rat the cannula ended above and lateral to the ventricle and +100 r
I
I
_
z
NPCI
B O %
L Z
25 T
I’
-too’
1
2
4 DOSE
8 (nmol
16 x
32
64
100)
Fig. 1. Self-stimulation rates during the first 30 intraventricular injection of various doses of expressed (H-W) or amphetamine (M) centage of the rate in the 30 min before injection. bars and the shaded panel indicate standard
min after tyramine as a perVertical errors.
I =300 2 0 ti uJ200 g
R
-
-
100 -
I
I
I
I
I
b
I
I
I
2
3
4
5
6
7
a
9
IO-mm
I
IO
I
II
I
12
PERIODS
Fig. 2. Self-stimulation rates of four rats recorded at IO-min intervals during two consecutive intraventricular injections of 1800 nmol tyramine (marked by arrows), demonstrating the protective effect conferred by the initial dose.
ink was limited to the cortical surfaces after reflux along the cannula track. Electrodes in all rats were located in the near-and mid-lateral hypothalamus.
Doseeresponse curves for tyramine and amphetamine are plotted in Figure 1. Response rates after the lowest dose of tyramine (100 nmol) were slightly higher than after saline (+ 1794; t = 3.7, d.f. = 6. P < 0.05) but all other doses of tyramine were either without effect or strongly depressant, and the overall dose-response curve showed a significantly negative slope (Friedman x,’ = 19.3, d.J = 3, P < 0.001). Depressant effects were rapid in onset and commonly reached maximal levels within the first 10 min after injection. At this time the rats’ posture and behaviour often appeared abnormal. They lay with their abdomens held close to the floor, sometimes making rapid repetitive movements of their limbs in brief bursts. Full recovery occurred within the ensuing 60 min. and Figure 2 shows that administration of a second dose of tyramine at this stage was much less effective than the first in its action on self-stimulation (1 = 3.8, d:f: = 3, P < 0.05). The effect of increasing doses of amphetamine was in the opposite direction to that of tyramine, giving a significant positive slope (Friedman 1,’ = 10.1, d:f: = 3. P < 0.02) but even the least effective dose of amphetamine (133 nmol) increased self-stimulation rates more strongly than the 200-nmol dose of tyramine (40 vs. 17’/,. t = 2.8, dJ = 7, P < 0.05). Behavioural changes after amphetamine generally included increased locomotor activity, rearing and sniffing, except with the 3600-nmol dose, which evoked stereotyped sniffing of the floor of the cage. DISCUSSION It was predicted. on the catecholamine-reinforcement hypothesis, that the differing modes of action
Tyramine
and self-stimulation
of tyramine and amphetamine would lead to opposite effects on self-stimulatton. Our results appear to be consistent with this prediction except for the mild stimulant effect observed after the lowest dose of tyramine. The stimulant effect, however, is not necessarily in conflict with the hypothesis, since a suitably low dose of tyramine would be expected to cause subliminal excitation of reinforcement units, rendering more units subject to response-contingent recruitment by the stimulating current (cf. Creed, Denny-Brown, Liddel and Sherrington, 1932, p. 119). Thus, disruption of responding would be expected only with higher doses that were supraliminal for nerve firing. Another possible explanation of the stimulant effect of tyramine is that it could also be acting, at low doses, on a central mechanism for drive or arousal not forming part of the reinforcement system proper. A similar explanation (Herberg, Stephens and Franklin, 1976) has recently been proposed for the reported facilitation of self-stimulation by the direct dopaminereceptor stimulant, apomorphine (Broekkamp and Van Rossum, 1974; Wauquier and Niemegeers, 1973). At all higher doses tyramine was depressant. It is necessary to consider, however, whether the predicted depression of self-stimulation by tyramine may have in fact been caused by toxic side-effects, as might seem from the abnormal behaviour seen at the height of its action. Tyramine is an important precursor of octopamine (Fischer, Horst and Kopin, 1965) a false transmitter which could cause general disturbance of behaviour, including depression of self-stimulation. But the virtual absence of any change in self-stimulation rate after a second dose of tyramine argues against this possibility and suggests that the initial depression, like other known effects of tyramine (Axelrod, Gordon, Hertling, Kopin and Potter, 1962) was mediated by a small cytoplasmic pool of catecholamine which suffered exhaustion after the first dose. If the depression had depended on the formation of octopamine, or on a direct toxic effect of tyramine, one would have expected a cumulative depression with repeated doses, rather than a tachyphyllaxis. The motor disturbances which accompanied the tyramine injections equally showed tachyphyllaxis to a second dose and seem equally dependent on tyramine-induced release of catecholamine, which occurs perhaps at the terminals of the bulbospinal noradrenergic pathways of Dahlstrom and Fuxe (1975). The presence of these motor disturbances does not necessarily rule out or preempt noncontingency of catecholamine receptor activity as a possible explanation of the accompanying behavioural effects, and it is even possible that the motor disturbances themselves are to be explained in the same way. Acknowledgements-The authors thank Research Council and the Brain Research port.
N.P. 16/l--~
the Trust
Medical for sup-
55 REFERENCES
Ahlenius, S., Anden, N. E. and Engel, J. (1971). Importance of catecholamine release by nerve impulses for free operant behaviour. Physiol. B&au. 7: 931-934. Axelrod, J. Gordon, E., Hertting, G., Kopin, I. J. and Potter, L. T. (1962). On the mechanism of tachyphylaxis to tyramine in the isolated rat heart. Er. J. Pharmac. 19: 56-63. Broekkamp, C. L. E. and Van Rossum, J. M. (1974) Effects of apomorphine on self-stimulaiton behaviour. Psychopharmacologia 34: 71-80. Burn, J. H. and Rand, M. J. (1958). The action of sympathomimetic amines in animals treated with reserpine. Br. J. Pharmac. 144: 314-336. Creed, R. S., Denny-Brown, D., Eccles, J. C., Liddell, E. G. T. and Sherrington, C. S. (1932). Rejex Actioity of the Spinal Cord. Oxford University Press, London. Crow, T. J. (1970) Enhancement by cocaine of intracranial self-stimulation in the rat. Life Sci. 9: 3755381. Crow, T. J. (1973) Catecholamine-containing neurones and electrical self-stimulation: 2. A theoretical interpretation and some psychiatric implications. Psychol. Med. 3: 66-73. Dahlstrom, A. and Fuxe, K. (1965) Evidence for the existence of monoamine neurons in the central nervous system. II. Experimentally induced changes in intraneuronal amine levels of bulbospinal neuron systems. Acta physiol. stand. 64: Suvvl. 247. 1-36. Fischer, J. E., Horst. WI b. and Kopin, I. J. (1965) p-Hydroxylated sympathomimetic amines as false neurotransmitters. Br. J. Pharmac. 24: 477484. Herberg, L. J. (1962) Dissociating reward from response in electrical self-stimulation in the rat. Nature, Land. 195: 628. Herberg, L. J. and Stephens, D. N. (1975). Catecholamines and self-stimulation: the action of amantadine and its interaction with amphetamine. Pharmac. Biochem. Behav. 3: 263-269. Herberg, L. J., Stephens, D. N. and Franklin, K. B. J. (1976). Catecholamines and self-stimulation: evidence suggesting a reinforcing role for noradrenaline and a motivating role for dopamine. Pharmac. Biochem. Behav. 4: 575-582. Skinner, B. F. (1948). ‘Superstition’ in the pigeon. J. exp. Psychoi. 38: 168-172. Smith, A. D. (1973). Mechanisms involved in the release of noradrenaline from sympathetic nerves. Br. med. Bull. 29: 123-129. Von Voigtlander, P. F. and Moore. K. E. (1973) Involvement of nigrostriatal neurons in the in uiuo release of dopamine by amphetamine, amantadine, and tyramine. J. Pharmac. exp. Ther. 184: 542-552. Stein, L. (1968). Chemistry of reward and punishment. In: Psychopharmacology: A Review of Progress 1957-1967 (Efron, D. H., Ed.) pp. 105-123, US. Government Printing OfIke. Washingtom, DC. Wauquier, A. and Niemegeers, C. J. E. (1973). Intracranial self-stimulation in rats as a function of various stimulus parameters: III. Influence of apomorphine on medial forebrain bundle stimulation with monopolar electrodes. Psychopharmacologia 30: 163-l 72. Wise, C. D., Berger, B. D. and Stein, L. (1973). Evidence of r-noradrenergic reward receptors and serotonergic punishment receptors in the rat brain. Biol. Psychiat. 6: 3-21.