The effects of putative 5-hydroxytryptamine receptor active agents ond-amphetamine self-administration in controls and rats with 5,7-dihydroxytryptamine median forebrain bundle lesion

Animals in which 5,7-dihydroxytryptamine (5,7-DHT) was bilaterally injected into the median forebrain bundle (MFB) and sham lesioned animals were allowed access to an apparatus which delivered, upon lever pressing, intravenousd-amphetamine injections. MFB lesioned rats achieved stable self-injections patterns and self-administered more drug per test session than controls. A number of agents known to either directly or indirectly affect 5-hydroxytryptamine (5-HT) receptor function were administered prior tod-amphetamine access. The responses to these pretreatments in lesioned vs non-lesioned rats were markedly different. Pretreatment withl-tryptophan reduced the number ofd-amphetamine self-injections in sham lesioned rats but had no effect in MFB lesioned animals. Fluoxetine pretreatment, likewise, reduced responding in non-lesioned rats and had no observable effect in lesioned animals. Quipazine markedy reduced self-injection in control rats but was not evaluated in the lesioned group. The putative 5-HT antagonists utilized, cyproheptadine and methysergide, unpredictably reduced self-injection frequency of non-lesioned animals in a dose related manner. When MFB lesioned animals were pretreated with cyproheptadine, rapid bursts of lever pressing were observed and 3 of 6 animals thus treated died as a result (presumably amphetamine overdose). In the remaining animals, methysergide produced a similar marked increase in self-injection rate. While these data may suggest that, in some instances, non-serotonergic mechanisms are involved, for the most part it would appear that 5-HT containing neurons are of major import in some aspect ofd-amphetamine self-administration.     

Intrahypothalamic 5,7-dihydroxytryptamine: Temporal analysis of effects on 5-hydroxytryptamine content in brain nuclei and on facilitated lordosis behavior

The long-term relationship between serotonin (5-HT) levels in discrete hypothalamic nuclei and female rat sexual behavior, the lordosis response, was examined following intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). One week following 5,7-DHT injection, 5-HT levels in the ventromedial hypothalamic nucleus, dorsomedial nucleus, anterior hypothalamic nucleus and the medial preoptic nucleus were approximately 90% depleted as compared to sham animals. Other hypothalamic and preoptic areas including the arcuate-median eminence, vertical nucleus of diagonal band and lateral septal nucleus showed smaller reductions in 5-HT, from 40 to 70% of sham values. At this time estrogen-dependent lordosis behavior in the lesioned group was facilitated. Behavioral facilitation was greatest at 4 weeks post lesion when depletion of 5-HT in the VMN was maximal. 5-HT levels increased at 57 days after 5,7-DHT treatment in most areas, and by 71 days post lesion, no significant differences in 5-HT levels were found between sham and 5,7-DHT-treated groups. Concomitant with the increases in 5-HT, facilitated lordosis behavior gradually decreased. Loss of behavioral facilitation appeared to be most closely related to increases in content of 5-HT in the ventromedial nucleus. These results further support the hypothesis that 5-HT endings in the hypothalamus exert tonic inhibitory regulation over hormone-dependent lordosis in the female rat. They also indicate that regenerating 5-HT fibers in the hypothalamus can reinstate a normal pattern of hormone-dependent behavioral function.     

Regeneration of serotonergic fibers in the rat hypothalamus following unilateral 5,7-dihydroxytryptamine injection

The time course of degeneration and regeneration of serotonin (5-HT) fibers in the rat hypothalamus was studied with 5-HT immunocytochemistry and [3H]5-HT uptake following unilateral injections of 5,7-dihydroxytryptamine (5,7-DHT) into the dorsolateral hypothalamus. Within 3 days of the lesion, 5-HT fibers in the ipsilateral hypothalamus were swollen and darkly stained for 5-HT. In the contralateral hypothalamus few swollen fibers were apparent and these were generally restricted to the area adjacent to the fornix. Swollen 5-HT fibers were evident in the ipsilateral hypothalamus 3-19 days post-lesion in the medial forebrain bundle (MFB) during which time there was a gradual decrease in their density. In the medial and periventricular areas of the ipsilateral hypothalamus there were essentially no 5-HT fibers 7-30 days post-lesion. Sprouting 5-HT fibers were observed 12-19 days post-lesion. Thirty days post-lesion the density of 5-HT fibers in the MFB appeared normal; however, medial and periventricular areas remained denervated. Fifty days post-lesion there was an apparent bilateral hyperinnervation in the lateral and dorsomedial hypothalamic areas of 5,7-DHT-injected animals as compared to sham-injected animals. The morphological data were paralleled by changes in [3H]5-HT uptake. Seven days post-lesion specific high affinity uptake was reduced to 27% of sham in the ipsilateral hypothalamus and to 53% of sham in the contralateral hypothalamus. By 50 days post-lesion, specific high affinity uptake of [3H]5-HT was 141% of sham in the ipsilateral hypothalamus and 96% of sham in the contralateral hypothalamus.     

Behavioural modification of bulbospinal serotonergic inhibition and morphine analgesia

Habituation to the stress of sham nociceptive testing enhances a rat's sensitivity to noxious thermal stimuli and reduces the antinociceptive effect of a subsequent acute dose of morphine. Since serotonin (5-hydroxytryptamine, 5-HT) mediates stress responses, experiments were designed to elucidate the role of 5-HT in these phenomena. Intrathecal methysergide or 5,7-dihydroxytryptamine (5,7-DHT) reduced baseline tail-flick latencies of novice rats to those of habituated animals. Morphine dose-response relationships were fitted to a 4 parameter sigmoidal function. Baseline latencies of novice animals were increased by 5-hydroxytryptophan (5-HTP) and reduced by parachlorophenylalanine (PCPA) in both reflex tests and in the hot-plate test, but latencies of habituated animals were unchanged by either treatment. In both reflex tests, the maximum effect due to morphine was increased by 5-HTP and reduced by PCPA in novice but not in habituated animals. We conclude that the serotonergic component of morphine's bulbospinal action represents the stress of the testing environment rather than an essential part of morphine's action.     

Temporal effects of intrahypothalamic 5,7-dihydroxytryptamine: relationship between serotonin levels and [H]serotonin binding

The relationship between serotonin (5-HT) levels and [³H]5-HT binding in discrete hypothalamic areas was examined in separate groups of animals at various times, following unilateral intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). Seven days post-5,7-DHT lesion, 5-HT levels were significantly decreased in both the ipsilateral and contralateral ventromedial and dorsomedial hypothalamic nuclei (VMN, DMN). In the lateral hypothalamic area (LHA), 5-HT levels were significantly decreased only ipsilaterally. Fifty days postlesion, 5-HT levels in the ipsilateral VMN remained significantly below sham, while the DMN and LHA returned to sham values. Seven days after 5,7-DHT there was a significant increase in [³H]5-HT labeling densities in the ipsilateral and contralateral ventromedial hypothalamic area as well as in the ipsilateral LHA. In contrast, in the dorsomedial hypothalamic area there was no increase in [³H]5-HT binding. Fifty days postlesion, no significant differences in [³H]5-HT binding between 5,7-DHT and sham were observed in any areas examined. This data provides further evidence for the regeneration of 5-HT fibers in the hypothalamus and demonstrates that the relationship between [³H]5-HT binding and 5-HT levels varies from one hypothalamic area to another.     

Modifications of the sexual activity in male rats following administration of antiserotoninergic drugs

The influence of cyproheptadine (CPH), methysergide and 5-hydroxytryptamine (5-HT) was studied on male sexual activity. Wistar rats from a colony of the Department were used. Measures of sexual parameters (number of ejaculations, initial latency, ejaculation latency, refractory period and neuromotor activity) indicate that cyproheptadine and methysergide facilitate male sexual activity. However, 5-HT inhibits male sexual reflex. Our experimental results suggest that the serotoninergic system exerts an inhibitory role on the sexual parameters which comprise the copulatory model of the male rat and also demonstrate that cyproheptadine facilitates sexual behavior of the male rat.     

Cardio-respiratory actions of substance P, TRH and 5-HT in the nucleus tractus solitarius of rats: evidence for functional interactions of neuropeptides and amine neurotransmitters

The cardiovascular and respiratory effects of Substance P (SP) and Thyrotrophin-Releasing Hormone (TRH) microinjections into the nucleus tractus solitarius (NTS) of urethane anaesthetized rats have been investigated. Dual injections of the peptides with serotonin (5-HT) were given to investigate possible functional interactions. In addition, SP and TRH were injected into rats in which 5-HT in the NTS area had been depleted by prior treatment with 5,7-Dihydroxytryptamine (5,7-DHT). SP (65pmol) did not elicit significant effects on blood pressure (BP) or heart rate (HR), but produced a marked, acute reduction in respiration rate (RR). TRH (110pmol) elicited a small but significant reduction in mean arterial pressure (MAP), whereas 5-HT (15nmol) caused a rise in MAP. Neither TRH nor 5-HT modified RR when given alone. A dual injection of SP (6.5pmol, ineffective alone) and 5-HT (15nmol) resulted in a rise in MAP which was insignificantly different from the effect of 5-HT alone. However, a prolonged fall in RR, unlike the effect of SP alone was also observed. A dual injection of TRH (11pmol, ineffective alone) and 5-HT (15nmol) resulted in a profound fall of RR but no significant changes in MAP or HR. SP elicited similar effects in 5,7-DHT lesioned animals as in sham operated controls. In contrast, TRH microinjections in lesioned rats were associated with a profound fall in RR, and a blood pressure response significantly different to that observed in the corresponding sham group. The results are discussed in relation to other evidence suggesting functional interactions between neuropeptides and amine neurotransmitters in the mammalian brainstem.     

Experimentally induced supersensitivity of neocortical neurons to microiontophoretically administered serotonin

Central serotonergic fiber systems of the rat were selectively lesioned by intraventricular injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At various times thereafter, the sensitivity of rostral cortical neurons to microiontophoretically administered serotonin (5-HT) was compared in groups of lesioned and sham-operated animals pretreated with the 5-HT uptake inhibitor CGP 6085. Twenty-four hours after the injection of 5,7-DHT, at which time the cortical 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were both reduced by 40%, there was no significant difference in the sensitivity of cortical neurons to 5-HT. However, 3 days after such treatment, when the cortical 5-HT and 5-HIAA levels were reduced by 52% and 53% respectively, pronounced supersensitivity to 5-HT was noted. The depressant action of 5-HT on neuronal firing was potentiated with regard to both maximal firing depression and duration of the firing inhibition. A similar potentiation of the 5-HT responses was observed 7 days after lesioning. Supersensitivity thus appears to develop between 1 and 3 days after the injection of 5,7-DHT. Seven days after lesioning, the sensitivity of rostral cortical neurons to gamma-aminobutyric acid was unchanged compared to that observed in sham-operated animals.     

5,7-Dihydroxytryptamine lesions enhance and serotonergic grafts normalize the evoked overflow of acetylcholine in rat hippocampal slices

Adult rats were subjected to intracerebroventricular injections of 5,7-dihydroxytryptamine (5,7-DHT; 150 micro g) and, 15 days later, to intrahippocampal grafts of fetal raphe cell suspensions. About 11 months later, we assessed baseline and electrically evoked release of tritium ([3H]) in hippocampal slices, preloaded with tritiated ([3H])choline or [3H]serotonin (5-HT), in the presence or absence of the 5-HT1B receptor agonist CP-93,129 and the 5-HT receptor antagonist methiothepine. HPLC determinations of monoamine concentrations were also performed. The lesions reduced the concentration of 5-HT (-90%) and the accumulation (-80%) as well as the evoked release (-90%) of [3H]5-HT. They also decreased the inhibitory effects of CP-93,129 on the evoked release of [3H]5-HT. Most interestingly, they facilitated the evoked release of [3H]acetylcholine (+20%). In slices from rats subjected to lesions and grafts, the responsiveness of the serotonergic autoreceptors (presumably located on the terminals of the grafted neurons) and the release of acetylcholine were close to normal. These results confirm that grafts rich in serotonergic neurons may partially compensate for the dramatic effects of 5,7-DHT lesions on serotonergic hippocampal functions. The lesion-induced reduction of the 5-HT1B autoreceptor-mediated inhibition of evoked 5-HT release may be an adaptation enhancing serotonergic transmission in the (few) remaining terminals. The facilitated release of acetylcholine is probably caused by a reduced serotonergic tone on the inhibitory 5-HT1B heteroreceptors of the cholinergic terminals. When related to data in the literature, this facilitation may be of particular interest in terms of transmitter-based strategies developed to tackle cognitive symptoms related to neurodegenerative diseases.     

6-Hydroxydopamine lesions of the ventral tegmentum abolish D-amphetamine and morphine analgesia in the formalin test but not in the tail flick test

The effect of bilateral 6-hydroxdopamine (with desipramine) lesions of the ventral tegmental area-substantia nigra region on analgesia produced by morphine and D-amphetamine was examined with the formalin and tail flick tests in rats. These lesions depleted dopamine, but not noradrenaline, in the ventral and anterior striatum. Morphine and D-amphetamine produced analgesia in the formalin test in sham lesioned rats but not in lesioned rats. In contrast, morphine produced the same degree of analgesia in the tail flick test in sham lesioned and lesioned rats while D-amphetamine did not produce analgesia in this test. These data suggest that morphine and D-amphetamine analgesia in the formalin test involves dopamine, whereas morphine analgesia in the tail flick test does not.     

Serotonergic modulation of 3,4-methylenedioxymethamphetamine (MDMA)-elicited reduction of response rate but not rewarding threshold in accumbal self-stimulation

In a fixed interval 5-s rate-frequency function paradigm with rats, 3,4-methylenedioxymethamphetamine (MDMA; 0.5, 2 and 4 mg/kg) dose-dependently decreased response rate for nucleus accumbens self-stimulation while both D-amphetamine (0.3 and 1 mg/kg) and cocaine (5 and 15 mg/kg) increased response rates. The highest dose of MDMA caused a cessation of responding in many of the rats tested, but in those rats that continued to respond a significant reduction in frequency threshold for self-stimulation was seen. Cocaine and amphetamine dose-dependently reduced frequency threshold in all rats tested. The non-specific serotonin antagonist, methysergide (5 mg/kg), reversed the inhibitory effects of MDMA on response rates and caused all rats to respond following MDMA (4 mg/kg). Methysergide did not affect MDMA's threshold-lowering properties and when administered alone methysergide had no effect on self-stimulation. These results suggest serotonergic involvement in the performance but not reinforcement-modulating effect of MDMA in the self-stimulation paradigm.     

Role of presynaptic serotonergic receptors on the mechanism of action of 5-HT1A and 5-HT1B agonists on masculine sexual behaviour: physiological and pharmacological implications

Summary In order to establish whether the 5-HT1A or the 5HT1B agonists, 8-OH-DPAT or TFMPP, produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving: (a) the serotonin synthesis or release; (b) the stimulation of presynaptic receptors, or (c) the stimulation of somatodendritic receptors, three series of experiments were performed. The administration of the serotonin synthesis inhibitor, p-chlorophenylalanine (p-CPA, 300mg/kg×3 days), facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP (0.5mg/kg) or 8-OH-DPAT (0.5 mg/kg), respectively. The icv or the intraraphé administration of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels. In lesioned animals TFMPP (0.5 mg/kg) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency. The inhibitory effect of this drug on mounting behaviour was not observed in 5,7-DHT treated rats. In lesioned animals 8-OH-DPAT (0.5 mg/kg) produced the same facilitatory effect. Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8-OH-DPAT in copulation. All data further support the idea that endogenous serotonin acts via the stimulation of 5-HT1B receptors to induce its inhibitory effects on masculine sexual behaviour.     

Dopamine and noradrenaline content in fish retina: modulation by serotonin

The presence of noradrenaline (NA) and the possible interaction of serotonin (5-HT) with dopaminergic and noradrenergic neuronal elements was studied in the retina of the teleost Eugerres plumieri. By means of a histofluorescent technique, paired amacrine cells can be visualized after intravitreal injection of NA or 5,6-dihydroxytriptamine, suggesting their probable catecholaminergic and indoleaminergic nature. With a high-performance liquid chromatographic (HPLC) method and after pargyline treatment of the animal, 6.86 ng/mg protein of dopamine (DA) was detected, while NA content was 0.50 ng/mg protein. The NA levels of the retina increased, whereas the DA levels decreased in a significant manner after in vivo treatment with 5-HT. 5-methoxy-N,N-dimethyltryptamine, a 5-HT agonist, was able to mimic this effect partially, while the agonists tryptamine and quipazine did not affect the levels of DA and NA. The antagonists methysergide, metergoline, and cyproheptadine significantly blocked the 5-HT-induced NA increase, whereas only the first two antagonists were effective in inhibiting the 5-HT-induced DA decrease. The 5-HT modulation of NA and DA is apparently receptor mediated and is not due to a hetero-exchange, since imipramine was not able to block the 5-HT effect. These findings support the suggested interaction between serotoninergic and dopaminergic cells [Negishi et al: J Neurosci Res 5:621-635, 1980; Neurosci Lett 25:1-5, 1981]. Furthermore, they demonstrate the possible modulation which 5-HT exerts on the endogenous levels of NA.     

Inhibition of pontine omnipauser neurons in the cat by 5-hydroxytryptophan

We assessed ocular motor nerve discharges and omnipause neuronal activity in six adult alert cats before and after intravenous infusion of the serotonin precursor 5-hydroxytryptophan (5-HTP). In all animals, 5-HTP inhibited omnipause neuron activity synchronously with a disappearance of high-frequency bursts of the ocular motor nerves associated with vestibular-induced fast components. This effect was rapidly reversed by the serotonin blocker, methysergide. Our findings are most consistent with an indirect effect of 5-HTP on omnipause neurons.     

Transplantation of serotonergic neurons into the 5,7-DHT-lesioned rat olfactory bulb restores the parameters of kindling

In order to restore a normal pattern of kindling, kindled rats, previously lesioned in the olfactory nuclei with 5,7-dihydroxytryptamine, were grafted with serotonin (5-HT) neurons in the right olfactory bulb and then implanted for kindling procedure. It was observed that complete 5-HT lesions accelerated the kindling profile, and that the transplants containing 5-HT neurons restored, in lesioned rats, quite normal parameters.     

Anxiogenic effect of median raphe nucleus lesion in stressed rats

Serotonin (5-HT) neurons located in the median raphe nucleus (MRN) may have a role in the development of behavioral changes to stress. The objective of the present work was to investigate the effects of a selective lesion of 5-HT neurons located in the MRN in previously stressed male Wistar rats submitted to the elevated plus maze (EPM). In an initial experiment, the animals (n=20-22) were submitted to one (acute) or seven (chronic) daily restraint stress periods (2 h) and tested in the EPM 24 h later. Results showed that acute restraint caused a significant decrease in the number of entries into the open arms, as compared to nonstressed controls. This effect disappeared when the animals were submitted to chronic restraint. In the next set of experiments, animals (n=6-8) received, 1 week before the behavioral studies, intra-MRN injection of 5,7-dihydroxytryptamine (5,7-DHT; 8 microg/1 microl). Neurochemical analysis showed that this treatment significantly decreases 5-HT and 5-hydroxy-indoleacetic acid (5-HIAA) levels in the hippocampus, but not in the striatum. No difference between lesioned and sham-operated animals in EPM performance was found in nonstressed animals or in those submitted to acute restraint. In chronically restrained animals, however, lesioned rats showed a significant decrease in the number of entries and time spent in the open arms. These results suggest that lesions of 5-HT neurons located in the MRN cause anxiogenic-like behavior in animals that have been chronically restrained.     

Serotonergic sprouting is induced by dopamine-lesion in substantia nigra of adult rat brain

We have previously extracted a serotonin (5-HT) neurotrophic supernatant from the 5,7-DHT lesioned hippocampus. The current study shows that a new 5-HT neurotrophic signal was monitored in the striatum and nigra after DA-denervation. Such a signal may be involved in the heterotypic sprouting. Dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA), was injected directly into the substantia nigra of adult rats. Two months after surgery, immunocytochemical staining showed that tyrosine hydroxylase (TH)-positive cell bodies had mostly disappeared in the substantia nigra, and TH-positive terminals in the striatum were almost completely depleted. Meanwhile, the 5-HT fibers, which exist in the same areas with low density, sprouted in the nigra as well as in the striatum and became dense. Normally 5-HT fibers innervate the striatum sparsely and the globus pallidus densely with sharp delineation (in the control side), and become dense across both areas with no appreciable delineation (in the lesion side). The increase of 5-HT fibers was more prominent in the posterior than in the anterior striatum. A significant increase in 5-HT and 5-HIAA levels was also evident in the posterior striatum when the decrease in DA level exceeded 90% in the nigra and striatum. In addition, we found that induction of 5-HT sprouting requires a greater than 90% decrease of DA level. Current data support that 6-OHDA injection in the substantia nigra of adult rats triggered a trophic signal or removed an inhibition for the growth of 5-HT neurons which responded with sprouting in the nigra as well as in the striatum.     

Differential pulse voltammetry in brain tissue. I. Detection of 5-hydroxyindoles in the rat striatum

In vitro, differential pulse voltammetry combined with electrochemically treated carbon fiber electrodes enabled detection, in different solution of 5-hydroxyindole compounds, of an oxidation peak 3 at +300 mV. In vivo, a striatal peak 3 was also recorded at this potential. Electrolytic or 5,7-dihydroxytryptamine lesions interrupting the medial forebrain bundle (MFB) were followed by a decrease of 65% and 64% in peak height, but not elimination of the peak. Biochemical determinations were significantly correlated to the peak 3 measurements. The existence of peak 3 as well as hydroxyindole compounds in blood suggested a blood contamination under the experimental conditions employed. This possibility is confirmed both by the complete disappearance of striatal peak 3 in animals with the MFB lesioned and surgically prepared a week before recordings, and by biochemical measurements in parachlorophenylalanine-treated or perfused (phosphate-buffered saline solution) animals.     

Serotoninergic denervation suppresses the sympathetic outflow induced by thyrotropin-releasing hormone in conscious rats.

Intrathecal administration of thyrotropin-releasing hormone (TRH) resulted in an increase in plasma epinephrine (E) and glucose levels in conscious rats. To elucidate the mechanisms by which TRH stimulates the release of E, the animals were pretreated with 5,7-dihydroxytryptamine, parachlorophenylalanine, methysergide or ketanserin. Serotoninergic denervation suppressed the TRH-induced increase in plasma E and glucose levels, whereas inhibition of serotonin (5-HT) synthesis or blockade of 5-HT receptors did not suppress the responses. These findings suggest that the serotoninergic neurons, but not 5-HT itself, are involved in stimulating the sympathetic outflow by TRH at the spinal level.     

Lesions of dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning

Habits are controlled by antecedent stimuli rather than by goal expectancy. Interval schedules of feedback have been shown to generate habits, as revealed by the insensitivity of behaviour acquired under this schedule to outcome devaluation treatments. Two experiments were conducted to assess the role of the dorsolateral striatum in habit learning. In Experiment 1, sham operated controls and rats with dorsolateral striatum lesions were trained to press a lever for sucrose under interval schedules. After training, the sucrose was devalued by inducing taste aversion to it using lithium chloride, whereas saline injections were given to the controls. Only rats given the devaluation treatment reduced their consumption of sucrose and this reduction was similar in both the sham and the lesioned groups. All rats were then returned to the instrumental chamber for an extinction test, in which the lever was extended but no sucrose was delivered. In contrast to sham operated controls, rats with dorsolateral striatum lesions refrained from pressing the lever if the outcome was devalued. To assess the specificity of the role of dorsolateral striatum in this effect a second experiment was conducted in which a group with lesions of dorsomedial striatum was added. In relation now to both the sham and the dorsomedial lesioned groups, only rats with lesions of dorsolateral striatum significantly reduced responding after outcome devaluation. In conclusion, this study provides direct evidence that the dorsolateral striatum is necessary for habit formation. Furthermore, it suggests that, when the habit system is disrupted, control over instrumental performance reverts to the system controlling the performance of goal-directed instrumental actions.