The differential projections from the dorsal raphe and median raphe nuclei of the midbrain were autoradiographically traced in the rat brain after 3H-proline micro-injections. Six ascending fiber tracts were identified, the dorsal raphe nucleus being the sole source of four tracts and sharing one with the median raphe nucleus. The tracts can be classified as those lying within the medial forebrain bundle (dorsal raphe forebrain tract and the median raphe forebrain tract) and those lying entirely outside (dorsal raphe arcuate tract, dorsal raphe periventricular tract, dorsal raphe cortical tract, and raphe medial tract). The dorsal raphe forebrain tract lies in the ventrolateral aspect of the medial forebrain bundle (MFB) and projects mainly to lateral forebrain areas (e.g., basal ganglion, amygdala, and the pyriform cortex). The median raphe forebrain tract lies in the ventromedial aspect of the MFB and projects to medial forebrain areas (e.g., cingulate cortex, medial septum, and hippocampus). The dorsal raphe cortical tract lies ventrolaterally to the medial longitudinal fasciculus and projects to the caudate-putamen and the parieto-temporal cortex. The dorsal raphe periventricular tract lies immediately below the midbrain aqueduct and projects rostrally to the periventricular region of the thalamus and hypothalamus. The dorsal raphe arcuate tract curves laterally from the dorsal raphe nucleus to reach the ventrolateral edge of the midbrain and projects to ventrolateral geniculate body nuclei and the hypothalamic suprachiasmatic nuclei. Finally, the raphe medial tract receives fibers from both the median and dorsal raphe nuclei and runs ventrally between the fasciculus retroflexus and projects to the interpeduncular nucleus and the midline mammillary body.



Further studies were done to test whether the fiber tracts travelling in the MFB contained 5-HT. Unilateral (left) injections of 5,7-dihydroxytryptamine (5 μgm/400 nl) 18 days before midbrain raphe microinjections of 3H-proline produced a reduction in the grain concentrations in all the ascending fibers within the MFB. Furthermore, pharmacological and behavioural evidence was obtained to show that the 5-HT system had been unilaterally damaged; these animals displayed preferential ipsilateral turning in a rotameter which was strongly reversed to contralateral turning after 5-hydroxytryptophan administration.



The results show that DR and MR nuclei have numerous ascending projections whose axons contain the transmitter 5-HT. The results agree with the neuroanatomical distribution of the 5-HT system previously determined biochemically, histochemically, and neurophysiologically. The midbrain serotonin system seems to be organized by a series of fiber pathways. The fast transport rate in these fibers was found to be about 108 mm/day.

An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat

The concept of impulsivity covers a wide range of ”actions that are poorly conceived, prematurely expressed, unduly risky, or inappropriate to the situation and that often result in undesirable outcomes”. As such it plays an important role in normal behaviour, as well as, in a pathological form, in many kinds of mental illness such as mania, personality disorders, substance abuse disorders and attention deficit/hyperactivity disorder. Although evidence from psychological studies of human personality suggests that impulsivity may be made up of several independent factors, this has not made a major impact on biological studies of impulsivity. This may be because there is little unanimity as to which these factors are. The present review summarises evidence for varieties of impulsivity from several different areas of research: human psychology, psychiatry and animal behaviour. Recently, a series of psychopharmacological studies has been carried out by the present author and colleagues using methods proposed to measure selectively different aspects of impulsivity. The results of these studies suggest that several neurochemical mechanisms can influence impulsivity, and that impulsive behaviour has no unique neurobiological basis. Consideration of impulsivity as the result of several different, independent factors which interact to modulate behaviour may provide better insight into the pathology than current hypotheses based on serotonergic underactivity.

Varieties of impulsivity.

http://psycnet.apa.org/journals/rev/91/2/251.pdf

Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants.

Neuroleptic drugs disrupt the learning and performance of operant habits motivated by a variety of positive reinforcers, including food, water, brain stimulation, intravenous opiates, stimulants, and barbiturates. This disruption has been demonstrated in several kinds of experiments with doses that do not significantly limit normal response capacity. With continuous reinforcement neuroleptics gradually cause responding to cease, as in extinction or satiation. This pattern is not due to satiation, however, because it also occurs with nonsatiating reinforcement (such as saccharin or brain stimulation). Repeated tests with neuroleptics result in earlier and earlier response cessation reminiscent of the kind of decreased resistance to extinction caused by repeated tests without the expected reward. Indeed, withholding reward can have the same effect on responding under later neuroleptic treatment as prior experience with neuroleptics themselves; this suggests that there is a transfer of learning (really unlearning) from nonreward to neuroleptic conditions. These tests under continuous reinforcement schedules suggest that neuroleptics blunt the ability of reinforcers to sustain responding at doses which largely spare the ability of the animal to initiate responding. Animals trained under partial reinforcement, however, do not respond as well during neuroleptic testing as animals trained under continuous reinforcement. Thus, neuroleptics can also impair responding (though not response capacity) that is normally sustained by environmental stimuli (and associated expectancies) in the absence of the primary reinforcer. Neuroleptics also blunt the euphoric impact of amphetamine in humans. These data suggest that the most subtle and interesting effect of neuroleptics is a selective attenuation of motivational arousal which is (a) critical for goal-directed behavior, (b) normally induced by reinforcers and associated environmental stimuli, and (c) normally accompanied by the subjective experience of pleasure. Because these drugs are used to treat schizophrenia and because they cause parkinsonian-like side effects, this action has implications for a better understanding of human pathology as well as normal motivational processes.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/S0140525X00010372

Neuroleptics and operant behavior: The anhedonia hypothesis

Animal research suggests that central serotonergic neurons are involved in behavioral suppression, particularly anxiety-related inhibition. The hypothesis linking decreased serotonin transmission to reduced anxiety as the mechanism in the anxiolytic activity of benzodiazepines conflicts with most clinical observations. Serotonin antagonists show no marked capacity to alleviate anxiety. On the other hand, clinical signs of reduced serotonergic transmission (low 5-HIAA levels in the cerebrospinal fluid) are frequently associated with aggressiveness, suicide attempts, and increased anxiety. The target article attempts to reconcile such human and animal findings by investigating whether anxiety reduction or increased impulsivity is more Likely to account for animal behavioral changes associated with decreased serotonergic transmission. The effects of manipulating central serotonin in experimental anxiety paradigms in animals (punishment, extinction, novelty) are reviewed and compared with the effects of antianxiety drugs. Anxiety seems neither necessary nor sufficient to induce control by serotonergic neurons on behavior. Further evidence suggests that behavioral effects of anxiolytics thought to be mediated by decreases in anxiety are not caused by the ability of these drugs to reduce serotonin transmission. Blockade of serotonin transmission, especially at the level of the substantia nigra, results in a shift of behavior toward facilitation of responding. This behavioral shift is particularly marked when there is competition between acting and restraining response tendencies and when obstacles prevent the immediate attainment of an anticipated reward. It is proposed that serotonergic neurons are involved not only in behavioral arousal but also in enabling the organism to arrange or tolerate delay before acting. Decreases in serotonin transmission seem to be associated with the increased performance of behaviors that are usually suppressed, though not necessarily because of the alleviation of anxiety, which might contribute to the suppression.

Reconciling the role of central serotonin neurons in human and animal behavior

Regional 5-hydroxytryptamine following selective midbrain raphe lesions in the rat

Behavioral effects of selective midbrain raphe lesions in the rat.

Morphine (5, 10, and 20 mg/kg, subcutaneously) both suppressed and elevated lateral hypothalamic self-stimulation response output. The duration of the depressant effect and the temporal appearance of the excitatory influence were dose dependent. With repeated daily injection tolerance developed to the suppressive effect while the facilitatory effect appeared ealier and tended to be enhanced. Thus the facilitatory action is not due simply to a rebound phenomenon. Finally, no correlation between the effects of morphine on self-stimulation behavior and on wheel-running activity was observed.

Influence of morphine on lateral hypothalamic self-stimulation in the rat.

Activity, avoidance learning and regional 5-hydroxytryptamine following intra-brain stem 5,7-dihydroxytryptamine and electrolytic midbrain raphe lesions in the rat.

The forebrain serotonin (5-HT) concentrations of rats with lesions in the median (M; n = 5), dorsal (D; n = 5), and both (DM; n = 6) midbrain raphe nuclei were, respectively, 22, 48 and 70% lower than in control animals (n = 10). The lesion and control groups, However, did not evidence differences in pain sensitivity as measured by the flinch-jump technique. On the other hand, of the animals tested, those with M (n = 3) and DM (n = 4) lesions required more trials than controls (n = 6) to acquire a one-way avoidance response. D lesion rats (n = 2) did not differ from controls in one-way avoidance learning, except in terms of prolonged escape latencies during the first three trials. The previously reported increased sensitivity to painful stimuli subsequent to medial forebrain bundle lesions or para-chlorophenylalanine administration, therefore, does not appear to be due exclusively to disruption of ascending 5-HT fibers originating in the dorsal and median raphe nuclei. The effects of midbrain raphe lesions on avoidance learning, furthermore, depend on lesion locus, and are not due to either hypo- or hyperalgesia.

Stanley A. Lorens

Papers

Regional 5-hydroxytryptamine following selective midbrain raphe lesions in the rat

Behavioral effects of selective midbrain raphe lesions in the rat.

Influence of morphine on lateral hypothalamic self-stimulation in the rat.

Activity, avoidance learning and regional 5-hydroxytryptamine following intra-brain stem 5,7-dihydroxytryptamine and electrolytic midbrain raphe lesions in the rat.

Response to electric shock in rats: effects of selective midbrain raphe lesions.