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Association of the mesencephalic locomotor region with locomotor activity induced by injections of amphetamine into the nucleus accumbens
Abstract
Injections of amphetamine into the nucleus accumbens increased locomotor activity of rats. Subsequent injections of procaine into the midbrain, in the region of the pedunculopontine nucleus, significantly reduced the amphetamine-induced locomotor activity. Control experiments showed that procaine injections into the contralateral pedunculopontine nucleus had little or no effect, as well as ipsilateral injections dorsal and ventral to the pedunculopontine nucleus. These findings suggest that release of dopamine from amphetamine injections into the accumbens gives rise to ipsilateral descending influences on the region of the pedunculopontine nucleus, a major component of the mesencephalic locomotor region. Descending influences from the nucleus accumbens to mesencephalic locomotor region may serve as a link for limbic-motor integration in behavioral response initiation.
... The findings of Experiment 1 confirm previous observations that PPI is modulated by decreased GABAergic activity in the subpallidum, and the findings of Experiments 2 and 3 suggest the possibility that the decrease in PPI after subpallidal GABA blockade is effected via subpallidal efferents to the PPTg. It has been proposed previously that subpallidal efferents to the PPTg are a critical substrate for the locomotor-activating effects of d-amphetamine (AMPH; Brudzynski & Mogenson, 1985) and presumably translate the effects of AMPH-induced changes in NAC and subpallidal activity to lower motor circuitry. In this last experiment, we measured basal and AMPH-stimulated locomotor activity in the sham-and PPTglesioned rats that were tested in Experiment 3. If these PPTg lesions reduce PPI by disrupting the subpallidal input to the PPTg, then we would predict that these lesions would also disrupt the locomotor-activating effects of AMPH. ...
... reported to disrupt AMPH-stimulated locomotion (Brudzynski & Mogenson, 1985). ...
... A post hoc ANOVA for the 20-90-min post-AMPH interval revealed a significant effect of lesion, F(i, 14) = 4.57, p = .05. These findings suggest that lesions of the PPTg that disrupt PPI also disrupt AMPH-stimulated locomotion; the latter effect has been reported previously (Brudzynski & Mogenson, 1985) and attributed to the destruction of PPTg cells that constitute the terminal field of fibers originating within the subpallidum. ...
Prepulse inhibition (PPI) of startle is impaired in schizophrenics, which suggests they have disturbances in circuitry that controls PPI. How activity in forebrain circuitry is communicated to the primary startle circuit to modulate PPI was explored. Subpallidal cells innervate the pedunculopontine tegmental nucleus (PPTg). Infusion of the γ-aminobutyric acid antagonist picrotoxin into the subpallidum impaired PPI. In other rats, electrolytic PPTg lesions decreased or eliminated PPI, potentiated startle amplitude, and did not alter habituation. The disruption of PPI correlated significantly with the extent of PPTg damage. PPTg lesions reduced PPI when startle stimuli were weak or intense (104 or 120 dB) and when prepulse stimuli ranged from 2 to 17 dB above background but were most profound with prepulses 5–8 dB above background. The PPTg modulates sensorimotor gating and may process and transmit information from forebrain structures to the primary startle circuit.
... Spontaneous LA is one indicator of motivated, goal-directed activity (Brudzynski & Mogenson, 1985;Mogenson, Jones, & Yim, 1980). LA is nonspecific as an indicator of goal-directed behavior and, therefore, is more ambiguous (and perhaps more contaminated) than distinct forms of motivated behavior (e.g., active avoidance). ...
... motor programming phase or execution phase). A considerable body of evidence indicates that the initiation of spontaneous LA is achieved specifically by DA activation in the A-10 mesolimbic pathway from the ventral tegmental area (VTA) to the NAS (Brudzynski & Mogenson, 1985;Costall, Domeney, & Naylor, 1984;Grabowska, 1974;Jones, Mogenson, & Wu, 1981;Kalivas & Miller, 1985;Kelly, 1977;Mogenson et al, 1980), although DA inhibition of the prefrontal cortex's tonic inhibition over the NAS is a necessary correlate under natural physiologic conditions. The nigrostriatal DA pathway is also involved in motor behavior, but this pathway appears to be more associated with sensorimotor integration, posture, and rseponse selection and coordination than with the actual initiation of LA (Freed & Yamamoto, 1985). ...
... DA has been proposed as having a switching function in neurophysiologic information systems (Oades, 1985). Increases in DA activity are associated with the initiation of new responses, such as LA and exploratory behavior (Brudzynski & Mogenson, 1985), as well as switching between alternate responses (Evenden & Robbins, 1983). Serotonin appears to impede this switching-initiation function of DA. ...
Investigation of the role of 5-hydroxytryptophan (5-HT), which functions as a modulator in the central nervous system, across behavioral contexts suggests that a general principle of transmitter function may be derived that is independent of specific behaviors and specific neural loci. A functional principle of 5-HT action in neural information processing in the central nervous system is proposed. Extremes deviations in 5-HT activity result in biases in information processing that may have direct effects on behavior. Such biases may predispose to pathological conditions such as violent suicide and aggression.
... While electrical and chemical stimulation experiments pointed to the sufficiency of CnF and/or PPN for locomotor initiation, lesions aimed at establishing the necessity for locomotor initiation of these regions provided unclear and conflicting results (see Jordan 1998, Ryczko & Dubuc 2013, Winn 2006. In some studies, lesions of the PPN or the CnF did not affect spontaneous locomotion (Allen et al. 1996, Inglis et al. 1994, while in other studies, similar lesions of PPN caused reduced locomotor activity (Aziz et al. 1998, Brudzynski & Mogenson 1985 or gait disturbances (Karachi et al. 2010). So, after decades of research, studies to functionally define MLR pointed to two different regions in the brainstem: CnF and PPN. ...
Locomotion is a universal motor behavior that is expressed as the output of many integrated brain functions. Locomotion is organized at several levels of the nervous system, with brainstem circuits acting as the gate between brain areas regulating innate, emotional, or motivational locomotion and executive spinal circuits. Here we review recent advances on brainstem circuits involved in controlling locomotion. We describe how delineated command circuits govern the start, speed, stop, and steering of locomotion. We also discuss how these pathways interface between executive circuits in the spinal cord and diverse brain areas important for context-specific selection of locomotion. A recurrent theme is the need to establish a functional connectome to and from brainstem command circuits. Finally, we point to unresolved issues concerning the integrated function of locomotor control.
Expected final online publication date for the Annual Review of Neuroscience, Volume 45 is July 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... The areas within both the ventral (nucleus accumbens) and dorsal striatum appear to be involved in the control of locomotion. An activation of D1R striatal projection neurons with local administration of dopamine in the ventral striatum can elicit locomotor activity, which is blocked by inactivating MLR, showing that the effects from the ventral striatum are channeled via MLR (66,67,272,344,475). ...
The vertebrate control of locomotion involves all levels of the nervous system from cortex to the spinal cord. Here, we aim at covering all main aspects of this complex behavior - from the operation of the microcircuits in the spinal cord to the systems and behavioral levels and extend from mammalian locomotion to the basic undulatory movements of lamprey and fish. The cellular basis of propulsion represents the core of the control system and it involves the spinal central pattern generator networks (CPGs) controlling the timing of different muscles, the sensory compensation for perturbations and the brainstem command systems controlling the level of activity of the CPGs and the speed of locomotion. The forebrain and in particular the basal ganglia are involved in determining which motor programs should be recruited at a given point of time and can both initiate and stop locomotor activity. The propulsive control system needs to be integrated with the postural control system to maintain body orientation. Moreover, the locomotor movements need to be steered so that the subject approaches the goal of the locomotor episode, or avoids colliding with elements in the environment or simply escapes at high speed. These different aspects will all be covered in the review.
... Microinjections of cobalt chloride, which can block synaptic transmission, and application of toxic doses of excitatory amino acid into subregions of the MLR significantly decrease locomotion induced by dopamine injections into the nucleus accumbens or picrotoxin injections into the subpallidal region (Brudzynski et al. 1993). Locomotor activity elicited by injections of picrotoxin into the subpallidal region and amphetamine into the nucleus accumbens is reduced by administration of procaine into the PPTg (Brudzynski and Mogenson 1985;Mogenson and Wu 1988). Suppression of induced and spontaneous locomotion was obtained in the precollicular-postmammilary decerebrate and decorticate animals after injections of muscimol, diazepam, and GABA into the MLR (Garcia-Rill et al. 1985;Pointis and Borenstein 1985). ...
Orexins/hypocretins are synthesized in neurons of the perifornical, dorsomedial, lateral, and posterior hypothalamus. A loss of hypocretin neurons has been found in human narcolepsy, which is characterized by sudden loss of muscle tone, called cataplexy, and sleepiness. The normal functional role of these neurons, however, is unclear. The medioventral medullary region, including gigantocellular reticular nucleus, alpha (GiA) and ventral (GiV) parts, participates in the induction of locomotion and muscle tone facilitation in decerebrate animals and receives moderate orexinergic innervation. In the present study, we have examined the role of orexin-A (OX-A) in muscle tone control using microinjections (50 μM, 0.3 μl) into the GiA and GiV sites in decerebrate rats. OX-A microinjections into GiA sites, previously identified by electrical stimulation as facilitating hindlimb muscle tone bilaterally, produced a bilateral increase of muscle tone in the same muscles. Bilateral lidocaine microinjections (4%, 0.3 μl) into the dorsolateral mesopontine reticular formation decreased muscle rigidity and blocked muscle tone facilitation produced by OX-A microinjections into the GiA sites. The activity of cells related to muscle rigidity, located in the pedunculopontine tegmental nucleus and adjacent reticular formation, was correlated positively with the extent of hindlimb muscle tone facilitation after medullary OX-A microinjections. OX-A microinjections into GiV sites were less effective in muscle tone facilitation, although these sites produced a muscle tone increase during electrical stimulation. In contrast, OX-A microinjections into the gigantocellular nucleus (Gi) sites and dorsal paragigantocellular nucleus (DPGi) sites, previously identified by electrical stimulation as inhibitory points, produced bilateral hindlimb muscle atonia. We propose that the medioventral medullary region is one of the brain stem target for OX-A modulation of muscle tone. Facilitation of muscle tone after OX-A microinjections into this region is linked to activation of intrinsic reticular cells, causing excitation of midbrain and pontine neurons participating in muscle tone facilitation through an ascending pathway. Moreover, our results suggest that OX-A may also regulate the activity of medullary neurons participating in muscle tone suppression. Loss of OX function may, therefore, disturb both muscle tone facilitatory and inhibitory processes at the medullary level.
... The sub-populations of GABAergic neurons from the structure have outstanding projections to diverse motor cores in the brainstem [49]. As these neurons are tonically energetic at rest, they can sustain the incessant inhibitory drive [50][51][52][53][54][55][56]. ...
Objectives: The basal ganglia (BG) controls different patterns of behavior by receiving
inputs from sensory-motor and pre-motor cortex and projecting it to pre-frontal, pre-motor
and supplementary motor areas. As the exact role of BG in swallowing process has not been
fully determined, we aimed at reviewing the published data on neurological control in the
swallowing technique to have a better understanding of BG’s role in this performance.
Methods: English-language articles, which were published before December 2015 and eligible
for the present research, were extracted from databases according to the inclusion criteria, i.e.
articles related to “neurological aspects of swallowing” and/or “lesions of sub-cortical or BG
relevant to swallowing disorders”.
Results: This systematic review indicates that BG is a complicated neurological structure
with indistinct functions and that swallowing is a sophisticated process with several unknown
aspects.
Discussion: Swallowing is a multifaceted performance that needs contribution of the tongue,
larynx, pharynx, and esophagus as well as the neurological structures such as neocortex and
subcortical regions - BG and brainstem.
... The sub-populations of GABAergic neurons from the structure have outstanding projections to diverse motor cores in the brainstem [49]. As these neurons are tonically energetic at rest, they can sustain the incessant inhibitory drive [50][51][52][53][54][55][56]. ...
Objectives: The purpose of this study is to examine the use of assistive technology, social
support in everyday life and psychological existential orientation for individuals with physical
disabilities.
Methods: Forty-six elderly persons with physical disabilities (aged 73.7±10.6 years, range
53-93 years) were examined with regard to the use of assistive technology, social support
in everyday life and psychological existential orientation by an extensive questionnaire
set (questionnaire for assistive technology (AT-24), questionnaire for social support
(F-SOZU-K-22) and Brief Symptom Inventory (BSI).
Results: The subjects stated that they needed aid and social support in order to carry out their
daily indoor/outdoor activities (for e.g. dressing, having a bath / shower, using toilet, eating,
going up / down the stairs, shopping, or going out). The most commonly used mobility aid
was the walking frame that accounted for 61.9%, followed by the walking stick with 40.5%
and a bathtub lift with 21.4%. The results also showed the psychopathological symptoms in
the sample.
Discussion: Assistive technologies together with the support of relatives and care services
help people to cope with a variety of activities in their daily lives with fewer restrictions. The
effectiveness of the aids differs between participants because it depends on several factors such
as health, knowledge, and information about aids, as well as the appropriate selection of aids.
... The sub-populations of GABAergic neurons from the structure have outstanding projections to diverse motor cores in the brainstem [49]. As these neurons are tonically energetic at rest, they can sustain the incessant inhibitory drive [50][51][52][53][54][55][56]. ...
Objectives: The basal ganglia (BG) controls different patterns of behavior by receiving inputs from sensory-motor and pre-motor cortex and projecting it to pre-frontal, pre-motor and supplementary motor areas. As the exact role of BG in swallowing process has not been fully determined, we aimed at reviewing the published data on neurological control in the swallowing technique to have a better understanding of BG’s role in this performance.
Methods: English-language articles, which were published before December 2015 and eligible for the present research, were extracted from databases according to the inclusion criteria, i.e. articles related to “neurological aspects of swallowing” and/or “lesions of sub-cortical or BG relevant to swallowing disorders”.
Results: This systematic review indicates that BG is a complicated neurological structure with indistinct functions and that swallowing is a sophisticated process with several unknown aspects.
Discussion: Swallowing is a multifaceted performance that needs contribution of the tongue, larynx, pharynx, and esophagus as well as the neurological structures such as neocortex and subcortical regions - BG and brainstem.
... Microinjections of AMPH into the NAc increased locomotor activity in rats, which is consistent with previous studies [39][40][41][42]. IWP-2 did not block this effect revealing dissociation between the effects of Wnt inhibition on CPP and locomotor activity. ...
... In fact, behavioral studies indicated a modulatory function of the PPTg in locomotion (Brudzynski and Mogenson 1985;Milner and Mogenson 1988;Mogenson et al. 1989; Bechara and van der Kooy 1992) as well as in stimulus reward association Satorra-Marín et al. 2001), but the exact role of the PPTg is far from clear Inglis and Winn 1995;). Since anatomical data reveal direct input from midbrain dopaminergic neurons, behavior modulated by the PPTg might be controlled by DA transmission. ...
... Open-field locomotion produced by dopamine activation in nucleus accumbens may in part be mediated through efferent connections to the PPT. For example, amphetamine-induced locomotion was blocked by either reversible inactivation of the PPT with procaine (Brudzynski & Mogenson, 1985) or irreversible ibotenate lesions . However, others have since found that PPT ibotenate lesions did not affect locomotion by either systemic amphetamine (Inglis et al., 1994a;Olmstead & Franklin, 1994) or intra-accumbens injection of 32 amphetamine (Inglis, Dunbar, & Winn, 1994b), so on the whole the evidence is mixed, and the pathways involved are not clearly understood. ...
... Indeed, the firing of LPO neurons is predominantly increased during sleep (Kaitin 1984: Szymusiak et al. 1998) and predominantly decreased under the influence of stimulants (present data). It has also been shown that administration of the GABA antagonist bicuculine into the LPH produces behavioral arousal (Zahm et al. 2013), perhaps via downstream effects on the mesencephalic locomotor region Swanson et al. 1984;Brudzynski and Mogenson 1985). ...
The lateral preoptic-rostral lateral hypothalamic continuum (LPH) receives projections from the nucleus accumbens and is believed to be one route by which nucleus accumbens signaling affects motivated behaviors. While accumbens firing patterns are known to be modulated by fluctuating levels of cocaine, studies of the LPH's drug-related firing are absent from the literature. The present study sought to electrophysiologically test whether drug-related tonic and slow-phasic patterns exist in the firing of LPH neurons during a free-access cocaine self-administration task. Results demonstrated that a majority of neurons in the LPH exhibited changes in both tonic and slow-phasic firing rates during fluctuating drug levels. During the maintenance phase of self-administration, 69.6 % of neurons exhibited at least a twofold change in tonic firing rate when compared to their pre-drug firing rates. Moreover, 54.4 % of LPH neurons demonstrated slow-phasic patterns, specifically "progressive reversal" patterns, which have been shown to be related to pharmacological changes across the inter-infusion interval. Firing rate was correlated with calculated drug level in 58.7 % of recorded cells. Typically, a negative correlation between drug level and firing rate was observed, with a majority of neurons showing decreases in firing during cocaine self-administration. A small percentage of LPH neurons also exhibited correlations between locomotor behavior and firing rate; however, correlations with drug level in these same neurons were always stronger. Thus, the weak relationships between LPH firing and locomotor behaviors during cocaine self-administration do not account for the observed changes in firing. Overall, these findings suggest that a proportion of LPH neurons are sensitive to fluctuations in cocaine concentration and may contribute to neural activity that controls drug taking.
... There are data on a connection between the MLR and the locomotor activity caused by injection of amphetamine into the accumbens nucleus [46]. in a review concerning the connections of the basal ganglia with the locomotor regions it is pointed out that the MLR is under the tonic inhibitory control of the GABA-ergic neurons of the substantia nigra; the entopeduncular nucleus, the efferent fibers of which contain substance P and GABA, also directly or indirectly controls this region [57]. The nuclei of the basal ganglia exert a much greater influence on the neurons of the reticular formation [84] than was previously thought. ...
Conclusion This overview of the brainstem pathways of the initiation of locomotion can be summarized as follows. There are locomotor regions (hypothalamic and mesencephalic) whose stimulation leads to the appearance of rhythmic stepping movements. These regions are nonuniform in composition: transient fibers as well as cells are found. The locomotor effects of electrical stimulation of these regions can largely be explained on the basis of the presence of efferent projections of the neurons to the medial reticular formation, as well as the activation of the transient fibers of other brain systems. The ventromedial parts of the reticular formation of the medulla oblongata, including areas of the macrocellular and (to a lesser extent) gigantocellular nuclei, form the final element in the suprasegmental system of locomotion initiation. The inconclusive data of different scientists who have used chemical microinjections into the locomotor regions make it impossible at present to specify precisely the neurochemical mechanisms underlying the initiation of locomotion. NMDA has been found to play an important role. The activation of the reticular formation during the triggering of stepping movements can take place either from the locomotor regions or by means of signals coming from the collaterals of the ascending sensory tracts. The wide spectrum of possible pathways of the initiation of locomotion apparently affords the organism a choice of ways by which to realize this process and is an important factor in its adaptation to its environment.
... The effect of lesion of the PPN in locomotion generated by experimental manipulation of the basal ganglia led to puzzling results. The locomotor activity induced by dopamine or amphetamine injection into the nucleus accumbens was reduced by injection in the PPN of an excitotoxin or cobalt lysine [197], procaine or kainic acid [198]. In contrast, lesion of the PPN with ibotenate [191] or NMDA [199] did not modify the locomotion respectively induced by injection of amphetamine into the nucleus accumbens or by subcutaneous amphetamine, but disrupted conditioned reinforcement paradigm, thus suggesting a role for the PPN in terms of response selection (see also [192]). ...
In 1966, Shik, Severin and Orlovskii discovered that electrical stimulation of a region at the junction between the midbrain and hindbrain elicited controlled walking and running in the cat. The region was named Mesencephalic Locomotor Region (MLR). Since then, this locomotor center was shown to control locomotion in various vertebrate species, including the lamprey, salamander, stingray, rat, guinea-pig, rabbit or monkey. In human subjects asked to imagine they are walking, there is an increased activity in brainstem nuclei corresponding to the MLR (i.e. pedunculopontine, cuneiform and subcuneiform nuclei). Clinicians are now stimulating (deep brain stimulation) structures considered to be part of the MLR to alleviate locomotor symptoms (i.e. axial symptoms) of patients with Parkinson's disease. However, the anatomical constituents of the MLR still remain a matter of debate, especially relative to the pedunculopontine, cuneiform and subcuneiform nuclei. Furthermore, recent studies in lampreys have revealed that the MLR is more complex than a simple relay in a serial descending pathway activating the spinal locomotor circuits. It has multiple functions. Our goal is to review the current knowledge relative to the anatomical constituents of the MLR, and its physiological role, from lamprey to man. We will discuss these results in the context of the recent clinical studies involving stimulation of the MLR in patients with Parkinson's disease.
... Similarly, behavioral effects of mesolimbic dopaminergic stimulation appear to be mediated via outflow from ventral pallidum to the mesencephalic locomotor region adjacent to the nigrotegmental projection field (Swanson et al., 1984). locomotion elicited by intra-accumbens amphetamine infusion can be blocked by procaine infused into this region (Brudzyrfski & Mogenson, 1985). ...
... A similar effect of ATP was also demonstrated in frog embryos (Dale and Gilday 1996). The effect of 2-MeSATP in our system showed close similarities with the motor activation produced by the intra-accumbens injection of dopamine itself or of drugs known to release dopamine in the NAc such as amphetamine and large doses of cocaine (Pijnenburg and van Rossum 1973;Kuczenski et al. 1983;Brudzynski and Mogenson 1985). There is considerable evidence indicating that the alteration of locomotor activity appears to be mediated by mesolimbic structures, whereas stereotypic behaviour is more closely related to the nigrostriatal system in rats (Kelly et al. 1975;Costall et al. 1977). ...
Rationale: Previous experiments have shown that P2 receptor activation increases the release of dopamine in the mesolimbic mesocortical system. Objective: In order to investigate the functional correlates of dopaminergic stimulation, EEG and behavioural responses to injection
of the P2 receptor agonist 2-methylthio ATP (2-MeSATP) into the nucleus accumbens (NAc) of rats were investigated. Methods: EEG electrodes were positioned into the NAc together with the guide cannula for intracerebral injection. Behavioural analysis
was performed in an open field cage and was evaluated by a video activity measurement system. Rats were assigned to separate
groups that were given artificial cerebrospinal fluid (aCSF) or drug treatment. Results: 2-MeSATP significantly extended the period of locomotor activity in the novel environment. The quantitative EEG was characterized
by an elevation of the power in the alpha-1 range and a decrease in power in the delta range. The P2 receptor antagonists reactive blue 2 but not pyridoxalphosphate-6-azophenyl-2'4'-disulphonic acid (PPADS) also enhanced locomotion
when given alone, and elevated the alpha-1 and beta-2 bands. Both antagonists abolished the locomotor and EEG responses to
2-MeSATP. The dopamine D1 receptor antagonist SCH 23390 and the D2/D3 receptor antagonist sulpiride did not alter locomotor activity when given either alone or in combination. Only sulpiride
and especially sulpiride in combination with SCH 23390 prevented the effect of 2-MeSATP. Sulpiride produced a selective increase
in the alpha-1 band of the power spectrum whereas SCH 23390 elevated the power of the alpha-1, alpha-2 and beta-1 activities.
Neither antagonist inhibited the effect of 2-MeSATP on the EEG when applied separately; however, the co-administration of
SCH 23390 and sulpiride abolished the 2-MeSATP-induced alteration of power distribution. After a 6-hydroxydopamine (6-OHDA)-induced
lesion of the accumbal dopaminergic terminals, 2-MeSATP failed to enhance the locomotor activity and to induce the characteristic
EEG changes. Conclusions: The observed alterations in open field behaviour and quantitative EEG after injection of 2-MeSATP into the NAc may be mostly
due to P2 receptor-mediated dopamine release and subsequent receptor activation.
... There are data on a connection between the MLR and the locomotor activity caused by injection of amphetamine into the accumbens nucleus [46]. in a review concerning the connections of the basal ganglia with the locomotor regions it is pointed out that the MLR is under the tonic inhibitory control of the GABA-ergic neurons of the substantia nigra; the entopeduncular nucleus, the efferent fibers of which contain substance P and GABA, also directly or indirectly controls this region [57]. The nuclei of the basal ganglia exert a much greater influence on the neurons of the reticular formation [84] than was previously thought. ...
The data about structural organization, connections and different ways of activation of the brain stem locomotor regions are offered in the review. The specificity of the locomotor regions and pathways of their influence on the spinal locomotor generator is discussed, the role of the reticular formation is elucidated. It is suggested that side by side with the multilevel system of the locomotion initiation, which has an output on the spinal cord via medial reticular formation, nonspecific afferent activation of the brain stem is also very significant.
Investigation of the role of 5-hydroxytryptophan (5-HT), which functions as a modulator in the central nervous system, across behavioral contexts suggests that a general principle of transmitter function may be derived that is independent of specific behaviors and specific neural loci. A functional principle of 5-HT action in neural information processing in the central nervous system is proposed. Extremes deviations in 5-HT activity result in biases in information processing that may have direct effects on behavior. Such biases may predispose to pathological conditions such as violent suicide and aggression.
One purpose of this paper is to show that the concepts of locomotor physiology as they have been expressed in this symposium are useful for the analysis of motor disorders of basal ganglia diseases such as Parkinson’s disease.
It is more than 18 years since Jim Stevenson and I observed a strong and persistent drinking response in rats receiving electrical stimulation of the lateral hypothalamus1. We had, according to the Zeitgeist of the mid-1960’s, activated the hypothalamic “thirst center”. It turned out, after some reflection, that there was a good deal of vagueness about this interpretation. However, the assumption was that by stimulating the so-called hypothalamic “thirst center” we activated a brain site concerned with integrating thirst signals and with generating “command signals” for the procurement and ingestion of water2.
Locomotion-a fundamental patterned movement expressed as a result of multiple behavior and emotional states-arises due to complex forebrain, diencephalic, and brainstem networks converging on the relative automatism of the spinal central pattern generator. Over 100. years ago, Sherrington and Graham-Brown provided some of the most important breakthroughs, sparking vigorous research activity in subsequent decades, from anatomical organization of brain systems to elegant genetic tools that are leading to precise identification of neuronal circuitries fundamental to the basic mechanisms of locomotor control in various species, terrestrial or aquatic; during development and in adults; and in normal and in pathology states. We are now in a period of exponential discovery that is beginning to unravel many of the mysteries of this complex system. New neuronal components of the brain and spinal networks are rapidly emerging, and these developments are superimposed on the fundamental knowledge collected over the last century in this chapter.
The lateral part of the mesopontine tegmentum contains functionally important structures involved in the control of posture and gait. Specifically, the mesencephalic locomotor region, which may consist of the cuneiform nucleus and pedunculopontine tegmental nucleus (PPN), occupies the interest with respect to the pathophysiology of posture-gait disorders. The purpose of this article is to review the mechanisms involved in the control of postural muscle tone and locomotion by the mesopontine tegmentum and the pontomedullary reticulospinal system. To make interpretation and discussion more robust, the above issue is considered largely based on our findings in the experiments using decerebrate cat preparations in addition to the results in animal experimentations and clinical investigations in other laboratories. Our investigations revealed the presence of functional topographical organizations with respect to the regulation of postural muscle tone and locomotion in both the mesopontine tegmentum and the pontomedullary reticulospinal system. These organizations were modified by neurotransmitter systems, particularly the cholinergic PPN projection to the pontine reticular formation. Because efferents from the forebrain structures as well as the cerebellum converge to the mesencephalic and pontomedullary reticular formation, changes in these organizations may be involved in the appropriate regulation of posture-gait synergy depending on the behavioral context. On the other hand, abnormal signals from the higher motor centers may produce dysfunction of the mesencephalic-reticulospinal system. Here we highlight the significance of elucidating the mechanisms of the mesencephalic-reticulospinal control of posture and locomotion so that thorough understanding of the pathophysiological mechanisms of posture-gait disorders can be made.
The gamma-aminobutyric acid (GABA) projection from the nucleus accumbens to the ventral pallidum (VP) is important in the regulation of locomotion. Thus, stimulation and inhibition of GABAA receptors in the VP can alter locomotor activity. To determine whether the GABAA receptors are located presynaptically on accumbens efferents to the VP or postsynaptically on neurons intrinsic to the VP two experiments were performed. In the first, quinolinic acid lesions of the nucleus accumbens did not alter [3H]muscimol binding in the VP, while lesions in the VP significantly reduced (60-80%) binding as measured by light microscopic receptor autoradiography. In the second experiment, in situ hybridization with oligonucleotide probes for mRNAs of the alpha 1 and beta 2 subunits of the GABAA receptor was examined in the nucleus accumbens and VP. No mRNA for either subunit was observed in the nucleus accumbens, although many positively labeled neurons were present within the VP. By contrast, a moderate to high density of cells in both the nucleus accumbens and VP contained mRNA for glutamic acid decarboxylase. These data argue that the majority of GABAA receptors in the VP are not located presynaptically on axonal terminals originating from neurons in the nucleus accumbens.
The group of nuclei within the basal ganglia of the forebrain is central to the control of movement. We present data showing that the structure and function of the basal ganglia has been conserved throughout vertebrate evolution over some 560 million years. The interaction between the different nuclei within the basal ganglia is conserved as well as the cellular and synaptic properties and transmitters. We consider the role of the conserved basal ganglia circuitry for basic patterns of motor behaviour controlled via brainstem circuits. The output of the basal ganglia consists of tonically active GABAergic neurones, which target brainstem motor centres responsible for different patterns of behaviour, such as eye and locomotor movements, posture, and feeding. A prerequisite for activating or releasing a motor program is that this GABAergic inhibition is temporarily reduced. This can be achieved through activation of GABAergic projection neurons from striatum, the input level of the basal ganglia, given an appropriate synaptic drive from cortex, thalamus and the dopamine system. The tonic inhibition of the motor centres at rest most likely serves to prevent the different motor programs from becoming active when not intended. Striatal projection neurones are subdivided into one group with dopamine 1 receptors that provides increased excitability of the direct pathway that can initiate movements, while inhibitory dopamine 2 receptors are expressed on neurones that instead inhibit movements and are part of the "indirect loop" in mammals as well as lamprey. We review the evidence showing that all basic features of the basal ganglia have been conserved throughout vertebrate phylogeny, and discuss these findings in relation to the role of the basal ganglia in selection of behaviour.
The major central cholinergic systems include (1) the projection neurons of the medial septum and diagonal band of Broca (MS/DB) to the hippocampus; (2) the projection neurons of the nucleus basalis magnocellularis (NBM) to the amygdala and cerebral cortex; (3) the inter-neurons of the striatum. Although the basal forebrain projection neurons have been implicated in learning and memory, and the striatal inter-neurons in motor behaviors, it still is not clear how and to what extent the central cholinergic neurons are involved in specific behaviors. Similarly, relatively little is known about the cellular and molecular mechanisms that regulate animal behaviors mediated by the central cholinergic systems. Although acetylcholine (ACh) was the first neurotransmitter discovered in the central nervous system, it remains unclear how the synthesis, storage, and release of ACh are regulated, or how ACh neurochemistry might be altered by environmental stimuli or synaptic experience, both of which would impact on cholinergically mediated behaviors. The central cholinergic systems are particularly dysfunctional in Alzheimer's disease. Thus, our animal research on the regulation of central cholinergic transmission and behavior has focused on the deficits in the systems associated with senescence and the potential amelioration of age-related deficits by the administration of the neurotrophic protein, nerve growth factor (NGF). This chapter describes the current understanding of the regional regulation of ACh synthesis and release in young and old rats, and illustrates several correlations between age-related and NGF-induced alterations in cholinergic neurochemistry, electrophysiology, morphology, and behavior.
The central nucleus of the amygdala (CeA) receives a dopaminergic (DA) innervation from the midbrain. Among its many efferent projections, the CeA innervates the substantia nigra. The possibility that the CeA influences the activity of nigral DA neurons was evaluated. The effects of electrical stimulation of the CeA on the firing rate and pattern of nigral DA neurons were investigated in anesthetized rats. Poststimulus time histograms revealed that nigral DA cells were either inhibited (N = 15), excited (N = 13), or unresponsive (N = 17) to CeA stimulation (250 stimuli a t 0.5 Hz). The mean (±SEM) latency to inhibition (24 ± 9 msec) was significantly shorter than that for excitation (65 ± 10 msec); the duration of inhibition (200 ± 29 msec) was also significantly greater than the duration of excitation (86 ± 11 msec) (P < 0.01 for both). DA cells that were excited had basal firing rates significantly lower than those of the inhibited or unresponsive cells (P < 0.05). Preliminary data suggest that DA cell burst-firing increases or decreases, respectively, in association with stimulation-evoked increases or decreases in firing rate. The relatively long latencies for stimulation-evoked responses suggest that CeA projection neurons indirectly affect nigral DA neurons via polysynaptic pathways. These results demonstrate that the CeA has the ability to influence the activity of nigral DA neurons, consistent with the putative role of the CeA as an interface between the limbic and extrapyramidal systems. Given the crucial role of the amygdala in anxiety states, these findings suggest that DA cell function may also be affected in such disorders. © 1995 Wiley-Liss, Inc.
The cataleptic and locomotor depressant effects of morphine are mediated by a series of neural structures, all of which project to the pedunculopontine tegmental nucleus (PPTg). To test the idea that the PPTg is also involved in mediating morphine's effect on these behaviours, we examined catalepsy and spontaneous motor activity following bilateral lesions of the PPTg (0.5 μl of 0.1 M infused over 10 min). We also examined the effect of PPTg lesions on motor functioning by observing sensorimotor responses, limb use, muscle tone and locomotion. PPTg lesions completely abolished the catalepsy and decreased activity that normally follows morphine administration. In addition lesioned animals exhibited increased muscle tone, and impairments in limb use and righting reflexes. Although the deficits were subtle, these results confirm that damage to the PPTg is associated with motor abnormalities.
Microinjection of the indirect GABAA antagonist, picrotoxin, or the μ opioid agonist, Tyr-d-Ala-Gly-NMe-Phe-Gly-ol (DAGO), into the ventral pallidum and substantia innominata (VP/SI) increases locomotor activity in rats. The VP/SI has direct and indirect projections to the region of the ventral mesencephalon containing dopamine perikarya, and to certain dopamine terminal fields, including the nucleus accumbens. Thus, it is possible that modulation of the mesocorticolimbic dopamine system by pharmacological stimulation in the VP/SI may play a role in the locomotor stimulant response. It was shown that pretreatment with dopamine receptor antagonists, either peripherally or microinjected into the nucleus accumbens significantly attenuated the motor stimulant effect of DAGO or picrotoxin injection into the VP/SI. Injection of either picrotoxin or DAGO into the VP/SI increased the levels of dopamine metabolites in the nucleus accumbens and prefrontal cortex. Thus, the motor stimulant response following pharmacological stimulation of the VP/SI appears to be mediated by increased dopamine neurotransmission via feedback mechanisms to the mesocorticolimbic dopamine system.
The emotional-defensive response (EDR) and accompanied neurotoxic and electroencephalographic (EEG) effects induced by injection of kainic acid (KA, 0.1; 0.2 pg[ into the midbrain periaqueductal grey region (PAG) and antero-medial hypothalamus (AMH) in the cat were examined and compared with EDR and accompanied neurotoxic and EEG effects induced by injection of cholinergic agent, carbachol (CCH[, into the same sites. The injections of KA (0.2 hg) into the PAG induced EDR which closely resembled the defense behavior typically observed after administration of CCH. However, in contrast to CCH-induced EDR, the defensive response induced by KA was found to be accompanied by EEG symptoms of epileptiform activity in the limbic cortex and a massive cell loss in the site of injection. It is proposed that KA-induced EDR and seizure activity may have resulted from the activation of different cell populations localized either in the vicinity of the injection (i.e. PAG region) and in the area remote from the injection loci, the limbic cortex. KA induced activation of PAG neuronal network would trigger the ‘local response’ (emotional-defensive response) and produce a remote effect — epileptiform activity.
It has been proposed that the positive reinforcing and motor stimulating effects of drugs involve the activation of a common neural substrate. Reinforcing effects of food, drugs and brain stimulation are blocked by lesions of the pedunculopontine tegmental nucleus (PPTg), which is a component of the mesencephalic locomotor region. This has suggested that the PPTg may be involved in both positive reinforcement and forward locomotion. In four separate experiments, rats were prepared with NMDA (0.5 μ1 of 0.1 M solution) or sham lesions of the PPTg. Animals in the first two experiments were tested for the development of a conditioned place preference (CPP) to morphine (2 mg/kg × 3 pairings) or amphetamine (1.5 mg/kg × 3 pairings). Ten days later, spontaneous motor activity (SMA) was assessed in these animals following a subcutaneous injection of saline or amphetamine (1.5 mg/kg). In two further experiments, drug-naive lesioned and control animals were tested for SMA only (saline or 1.5 mg/kg amphetamine in Experiment 3, and saline, 0.5 mg/kg, or 3 mg/kg amphetamine in Experiment 4). Lesions of the PPTg blocked the development of a CPP to both morphine and amphetamine. In contrast, lesions had no effect on saline or amphetamine-stimulated SMA. The PPTg, therefore, appears to be involved in the reinforcing effects of amphetamine and morphine, but is not necessary for the expression of amphetamine-induced activity.
The purpose of this study was to evaluate changes in brain activity during voluntary walking in normal subjects using technetium-99m-hexamethyl-propyleneamine oxime single photon emission computed tomography. This study included 14 normal subjects. Statistical parametric mapping analysis revealed that the supplementary motor area, medial primary sensorimotor area, the striatum, the cerebellar vermis and the visual cortex were activated. These results suggested that the cerebral cortices controlling motor functions, visual cortex, basal ganglia and the cerebellum might be involved in the bipedal locomotor activities in humans.
In vivo dialysis was performed in the ventral pallidum of the conscious rat, and extracellular levels of γ-aminobutyric acid (GABA) measured. Forty minutes following peripheral administration of amphetamine (2.0 mg/kg, s.c.) the extracellular concentration of GABA was significantly reduced, in parallel with a significant elevation in motor activity. These data indicate that a decline in GABA transmission in the ventral pallidum may be important in the initiation of amphetamine-induced motor activity.
The aim of the present work was to study the effects of three different types of bilateral lesions performed on the nucleus accumbens, upon the behaviors elicited in adult cats by parenteral administration of amphetamine and apomorphine, and to obtain an understanding of the functional role played by the cited structure. To this end, 10 cats received bilateral injections of 6-OHDA, 18 microg in each accumbens; 8 cats received a similar treatment with ibotenic acid (20 microg), and 11 cats were submitted to bilateral electrolytic damage. Before and after performing these lesions, in separate sessions, amphetamine (2.5 mg/kg SC) and apomorphine (2.0 mg/kg SC) were administered and their respective behaviors were compared. Besides, in a group of 10 cats, 6 of them were bilaterally injected with the above cited dose of 6-OHDA into the accumbens to determine dopamine concentration and the other four served as control. In three cats, ibotenic acid (20 microg) was unilaterally injected into the accumbens for histological analysis. The contralateral structure served as control. Finally, four cats were sham operated. The results obtained show that the accumbens in cats participates in locomotion, in stereotyped motor behaviors, and in emotional fear-like behavior. Its role in the production of motor behaviors apparently is not as important as has been reported in rodents.
Ultrasonic vocalizations (USV) are emitted by rats in a number of social situations such as aggressive encounters, during sexual behavior, and during play in young rats, situations which are predominantly associated with strong emotional responses. These USV typically involve two distinct types of calls: 22 kHz calls, which are emitted in aversive situations and 50 kHz calls, which are emitted in non-aversive, appetitive situation. The 50 kHz calls are the focus of the present study and to date both the glutamatergic and the dopaminergic systems have been independently implicated in the production of these 50 kHz calls. The present study was conducted to examine a possible relationship between glutamate (GLU) and dopamine (DA) in mediating 50 kHz calls. It was hypothesized that the dopaminergic system plays a mediating role in 50 kHz calls induced by injections ofGLU into the anterior hypothalamic/preoptic area (AHPOA) in adult rats. A total of 68 adult male rats were used in this study. Rats' USV were recorded and analyzed in five experiments that were designed to test the hypothesis: in experiment 1, rats were treated with systemic amphetamine (AMPH) alone; in experiment 2, intra- AHPOA GLU was pretreated with systemic AMPH; in experiment 3, intra-AHPOA GLU was pretreated with intra-AHPOA AMPH; in experiment 4, rats were treated with high and low doses of intra-AHPOA AMPH only; in experiment 5, rats were treated with systemic haloperidol (HAL) as a pretreatment for intra-AHPOA GLU. Analysis of the results indicated that AMPH has a facilitatory effect on 50 kHz USV and that a relationship between DA and GLU in inducing 50 kHz calls does exist. The effect, however, was only observed when DA receptors were antagonized with HAL and was not seen with systemic AMPH pretreatments of intra-AHPOA GLU. The DAGLU relationship at the AHPOA was unclear.
We previously have reported that nondopamine (non-DA) neurons in substantia nigra (SN) and ventral tegmental area (VTA) of the rat show increased discharge rates during amphetamine (AMPH) and apomorphine (APO)-induced motor activity. The present study represents an attempt to determine the contribution of nucleus accumbens (ACC) dopaminergic activity to these effects, and to ascertain whether the effects in VTA differ from those seen in SN when dopaminergic activity is enhanced locally in ACC. The experiments were carried out in male albino rats (300-400 g) chronically implanted with multiple fine wire electrodes (62 microns) aimed at the pars reticulata of SN (SNR) and VTA. Unit activity was recorded extracellularly in the behaving rat, from neurons identified on the basis of the properties of their action potentials as representing the output of the non-DA neurons in these two structures. In each drug session, unit activity was recorded in parallel from several probes, while motor activity was measured with the open-ended wire technique. But with the recording technique used, a unit represented in most instances the output of a small family of neurons (3-10). Each animal underwent a series of tests given on consecutive days. During these tests, motor and unit activity were measured for 90 min before the drug was administered, and for 135 min after. The first test was of the effects of AMPH, 5 mg/kg, given by the systemic route. The second was of the effects of saline containing 0.1% ascorbic acid (the vehicle) injected bilaterally in ACC, in a volume of 2 microliters per side. The third and all subsequent tests were of the effects of a mixture containing 40 micrograms AMPH, 20 micrograms DA, and 20 micrograms pargyline (P) dissolved in 2 microliters of the vehicle, injected bilaterally in ACC. The results showed that systemic AMPH made the animal hyperactive and at the same time, increased the discharge rate of the non-DA neurons. The bilateral injections of the vehicle in ACC, increased motor activity for about 7 min, an effect interpreted as a rebound from the restraint of the animal during the intracerebral injections, and then depressed motor throughout the 135 min of the postinjection recording period. The effect of the vehicle was to depress unit activity. The effects of injecting the mixture in ACC was to increase motor activity, but with the magnitude and duration of the increase depending on the number of treatments received.(ABSTRACT TRUNCATED AT 400 WORDS)
The effect of 6,7-dinitroquinoxaline-2,3-dione (DNQX), an alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainic acid glutamate receptor antagonist, injected into the zona incerta (ZI) was investigated to determine whether the behavioral responses to systemic amphetamine involve AMPA/kainic acid receptors in this brain region. Rats were injected bilaterally in the ZI with either vehicle or DNQX (1 microgram/0.5 microliter) and immediately given a systemic injection of D-amphetamine (0.5, 1.0 or 10.0 mg/kg, s.c.). Locomotor activity was recorded for 1 h. DNQX did not significantly affect hypermotility stimulated with 0.5 and 1.0 mg/kg amphetamine, but markedly increased the level of locomotor activity elicited by the higher dose, 10 mg/kg. To test the hypothesis that the enhanced locomotor response to high dose amphetamine was due to an inhibition of stereotyped behavior, the effect of DNQX in the ZI on amphetamine and apomorphine-induced stereotypy was investigated. DNQX significantly inhibited stereotypy induced by amphetamine (10 mg/kg) and apomorphine (1 mg/kg), with the onset of inhibition of amphetamine-induced stereotypy corresponding to the onset of enhanced locomotor activity. Ibotenic acid lesions of the ZI produced similar results, having an insignificant effect on locomotor activity stimulated by low dose amphetamine (1 mg/kg) and an attenuation of apomorphine-induced stereotypy which was of a magnitude comparable to that produced by DNQX. Thus, the AMPA/kainic acid subtypes of glutamate receptors in the ZI may be involved in the regulation of motor function mediated via striatal output but not mesolimbically generated locomotor activity.
Previous studies have indicated that the basal forebrain at the level of the preoptic area contains neurons which participate in the initiation of locomotion. This study attempted to localize those neurons by mapping sites at which 25- and 50-microA stimulation (50 Hz, 0.5 ms cathodal pulses, 10-s trains) initiated hindlimb stepping. Anesthetized rats were held in a stereotaxic apparatus supported by a sling so that stepping movements rotated a wheel. Anesthesia was maintained by periodic injections of Nembutal (7 mg/kg) supplemented by lidocaine injections. Stimulation was applied through 50-70-microns diameter pipettes filled with 2 M NaCl at approximately 1600 sites in the basal forebrain, adjacent thalamus, and striatum. A circumscribed grouping of 25-microA locomotor sites, centered in the lateral preoptic area, defined the preoptic locomotor region. It extended into the ventral bed nucleus of the stria terminalis, the lateral part of the medial preoptic area, the anterior hypothalamic area, the medial and rostral parts of the ventral pallidum, medial substantia innominata, and the horizontal limb of the diagonal band. This general region is known to project to the midbrain locomotor region and the ventral tegmental area; it is proposed to initiate locomotion in service of primary motivational systems. Among the structures generally negative for locomotor sites were the dorsal and ventral striata, septal complex, bed nucleus of stria terminalis, and lateral ventral pallidum and substantia innominata. These findings indicate that low current stimulation applied to a circumscribed area centered in the lateral preoptic area produces locomotor stepping in the anesthetized rat. Whether the activated elements in this preoptic locomotor region are cells or fibers is not yet known. The degree of localization afforded by these findings indicates that the areas that are most likely to contain the mediating elements are quite limited in extent.
Nerve growth factor (NGF) infusion into normal Fischer 344 x Brown Norway (F344/BN) hybrid male rats for 2 weeks resulted in a dose-dependent stimulation of choline acetyltransferase (ChAT) enzyme activity to 70% above control values in both the basal forebrain and striatum, and a statistically significant 10% loss in animal weight. There was a significant correlation between weight gain and stimulation of striatal ChAT activity, but not with stimulation of basal forebrain ChAT. Thus, unlike some other rat strains, the normal F344/BN rat is sensitive to exogenous NGF, and can be used to study the efficacy of NGF on normal central cholinergic neurons. The NGF effect on weight gain may be mediated by cholinergic stimulation of the nucleus accumbens.
Injections of the dopamine D2 agonist quinpirole (LY 171555) into the nucleus accumbens reduced exploratory locomotion in a dose-dependent manner. Injections of the dopamine D1 agonist SKF 38393 had no effect on exploratory locomotion. The results are consistent with observations from recent electrophysiological and behavioral experiments which suggest a presynaptic action of the D2 agonist. It is proposed that quinpirole activates D2 receptors on the axon terminals of glutamatergic hippocampal-accumbens neurons that are associated with exploratory locomotion.
Locomotor activity measured in an open-field apparatus was increased by adding partitions to enhance exploratory locomotion and by injecting amphetamine into the nucleus accumbens. Administration of the dopamine D2 agonist, quinpirole, into the nucleus accumbens reduced significantly both exploratory and amphetamine-elicited locomotion. It is suggested that these effects of quinpirole are mediated by different presynaptic mechanisms.
It is well established that the mesolimbic dopamine projection from the AlO dopamine region in the ventromedial mesencephalon to the nucleus accumbens is important in mediating spontaneous and psychostimulant — induced locomotion (Fink and Smith, 1980; Koob et al., 1981; Clarke et al., 1988). The nucleus accumbens has a dense projection to the ventral pallidum (Nauta et al., 1978; Mogenson et al., 1983; Heimer et al., 1987; Churchill et al., 1990) which utilizes both GABA and enkephalin as neurotransmitters (Walaas and Fonnum, 1979; Zahm et al., 1985). Modulation of this projection to the ventral pallidum by dopamine in the nucleus accumbens mediates dopamine-dependent locomotion. Thus, locomotion elicited by stimulation of dopamine receptors in the nucleus accumbens is abolished following a lesion of the ventral pallidum (Swerdlow et al., 1984a). A role for GABA transmission in the accumbens-ventral pallidal pathway has been shown by the observation that stimulation of GABAa receptors in the ventral pallidum blocks motor activity produced by dopamine agonist injection into the nucleus accumbens (Jones and Mogenson, 1980; Mogenson and Nielsen, 1983; Swerdlow et al., 1984b; Austin and Kalivas, 1988). More recently, it was found that locomotion elicited by microinjection of other neurotransmitter agonists or antagonists into the nucleus accumbens, including a mu opioid agonist, GABAa antagonist, nicotinic agonist and glutamate agonist, is also blocked by muscimol injection into the ventral pallidum (Austin and Kalivas, 1989; Shreve and Uretsky, 1988). Therefore, it appears that locomotion elicited pharmacologically from the nucleus accumbens involves modulation of a GABAergic projection to the ventral pallidum, regardless of the neurochemical stimulus.
The basal forebrain is composed of many important components, one of which is the ventral striatum including the nucleus accumbens and olfactory tubercle. Both neuroanatomical and behavioral studies have provided important evidence implicating the ventral striatum as an interface between the limbic system and the extrapyramidal motor system (Kelley and Stinus, 1984; Heimer and Wilson, 1975; Mogenson and Nielson, 1984a). The ventral striatum receives allocortical projections from the hippocampus and amygdala (Kelley and Domesick, 1982), and a major dopaminergic projection from the ventral midbrain, especially the region of the ventral tegmental area. The availability of reliable behavioral measures and powerful neuropharmacological probes has allowed substantial progress to be made in the understanding of the functional significance of the ventral striatum and its circuitry.
The contribution of hippocampal glutamatergic and VTA dopaminergic inputs to the nucleus accumbens and the role of accumbens--ventral and subpallidal GABAergic pathway in integrating the limbic signals into motor responses via pedunculopontine nucleus were examined with electrophysiological and behavioural techniques. Stimulation of hippocampal input to the accumbens activates GABAergic output to the subpallidal area which leads to suppression of spontaneous firing of subpallidal neurons, while activation of dopamine receptors in the accumbens suppresses GABAergic output to subpallidal area and thus increases the firing of picrotoxin-sensitive ventral pallidal neurons. However, both treatments induced hypermotility suggesting the functional heterogeneity of the ventral and subpallidal areas in "limbic-motor integration". Furthermore, both hippocampal output signals and dopaminergic input to the accumbens descend via ventral and subpallidal areas serially to the pedunculopontine nucleus, the region of the mesencephalic locomotor region. In addition, a parallel ascending pathway from the subpallidal area to the mediodorsal nucleus, and subsequently to the medial prefrontal cortex, probably mediates behaviour, e.g. food hoarding, that requires higher cognitive processing.
New opto-electronic camera systems permit easy quantification of the motor performance during natural acts in freely moving humans. We used a simple test movement (PLM test) to quantify the disturbance in the postural (P), locomotor (L) and manual (M) part of the body movement and the coordination of the different movement phases into a smooth motor act. The test movement time was used to quantify the overall performance. With this technique we have measured the effects of selegiline on the degree of parkinsonism in a double-blind, placebo-controlled pilot study of 5 de novo patients with Parkinson's disease. There was a clear trend that selegiline was superior to placebo in reducing the test movement time.
The acute effects of increasing doses of the antidepressant drugs amineptine (5-40 mg/kg, IP) and desipramine (5-20 mg/kg IP) were studied in mice on three parameters of the activity (the horizontal activity, the vertical activity and the number of small movements without displacement) measured in a computerized Digiscan actimeter. The horizontal and vertical activities were dose dependently and similarly increased by acute amineptine, whereas the number of movements without displacement was increased up to 10 mg/kg with no further significant modification up to 40 mg/kg; in contrast, all three parameters were reduced in an identical manner by desipramine. The changes in the responses to the selective D-1 dopamine (DA) receptor agonist SK&F 38393 (1.87-30 mg/kg, SC), to the selective D-2 DA receptor agonist LY 171555 (0.1-1.6 mg/kg, SC) and to the selective DA uptake inhibitor GBR 12783 (1.25-20 mg/kg, IP) were measured on the three parameters of activity in mice chronically treated with amineptine (20 mg/kg, IP twice daily during 15 days) or by desipramine (10 mg/kg, IP, twice daily during 15 days). The chronic treatments with amineptine or desipramine did not modify the motor stimulant effects GBR 12783 and of SK&F 38393 on the three parameters (excepted for a slight modification of the horizontal activity for 7.5 mg/kg SK&F 38393 in mice chronically treated with amineptine). In contrast, the motor inhibitory effects of the lowest doses of LY 171555 (0.1-0.4 mg/kg) were strongly reduced in mice chronically treated with amineptine or desipramine but only on the horizontal activity with no change on the vertical activity and on the number of small movements without displacement.(ABSTRACT TRUNCATED AT 250 WORDS)
Locomotor stepping in the Nembutal-anesthetized rat was elicited by electrical stimulation of either of two sites in the right or left posterolateral hypothalamus. Essential midbrain loci were identified by reversibly blocking the elicited locomotion through local injections of the anesthetic procaine (15%, 0.5 microliter). Two types of critical midbrain sites were found. At ipsilateral block sites (n = 21), procaine blocked only that locomotion elicited by ipsilateral stimulation. These sites could be along the course of a direct descending ipsilateral pathway although a possible bidirectional pathway is not to be excluded. At bilateral block sites (n = 21), procaine blocked locomotion elicited by both ipsilateral and contralateral stimulation. These sites could be involved in functions prerequisite for the initiation of locomotion or in the generation of the stepping pattern. Procaine injections in 35 sites had no effect on locomotion. Ipsilateral and bilateral block sites were intermixed and generally located in regions ventral to the midbrain central gray: chiefly the anterior ventromedial midbrain, the pontis oralis nucleus and the pedunculopontine nucleus. Negative sites were located in both the dorsal and ventral midbrain. Ipsilateral block sites were relatively prevalent in the anterior midbrain, indicating that the locomotor initiation signals are lateralized at this level. Bilateral block sites were more prevalent in the posterior levels, suggesting that the initiation signals are proximal to, or interact with, circuits that have a bilateral influence on locomotion.
This study was undertaken to investigate the effects of activating dopamine receptors in accumbens and prefrontal cortex on self-stimulation behavior in the medial forebrain bundle. The experiments were carried out in rats chronically implanted with one stimulating electrode in medial forebrain bundle and two bilaterally-placed cannulas for giving injections into accumbens or prefrontal cortex. After completion of training, animals classified as responders and non-responders were given drug tests. The non-responders were tested to determine the effects of the treatment on motor activity. The self-stimulation task involved the depression of a lever to obtain a stimulus of 0.25 s duration, 60 Hz sine waves applied to the medial forebrain bundle. Dopamine receptor activation in accumbens or prefrontal cortex was induced with bilateral injections in these structures of a mixture containing 5 mg dopamine, 10 mg d-amphetamine sulfate and 5 mg pargyline mixed in 0.5 ml saline containing 0.1% ascorbic acid (dopamine + d-amphetamine sulfate + pargyline, the cocktail). Each injection was of 2 microliters/side, yielding a concentration of 20 micrograms of dopamine, 40 micrograms of d-amphetamine sulfate and 20 micrograms of pargyline/injection. The bilateral injections were given immediately before the self-stimulation session which lasted 12 h, starting in late afternoon. The effects of saline containing the ascorbate were determined in control sessions. Saline injected bilaterally in accumbens or prefrontal cortex of self-stimulators or non-self-stimulators had no effects on the response-rate of self-stimulators or on the gross motor activity of non-responders. In contrast, the cocktail of dopamine + d-amphetamine sulfate + pargyline injected in accumbens of self-stimulators induced a complex response which included first a facilitation, then a prolonged suppression and then again one or two episodes of facilitation interspersed with periods of suppression of self-stimulation and then a return to baseline rats. The same cocktail of dopamine + d-amphetamine sulfate + pargyline injected bilaterally in accumbens of non-self-stimulators resulted also in a complex response including as a first component a facilitation of responding, but the complex effect was of shorter duration and lower magnitude, never raising the rate of lever-pressing to levels meeting self-stimulation criteria. The same cocktail of dopamine + d-amphetamine sulfate + pargyline injected in prefrontal cortex of self-stimulators simply attenuated or suppressed responding, and the effect lasted for most of the session. The same effect was seen in non-self-stimulators indicating a decrease in gross motor activity.(ABSTRACT TRUNCATED AT 400 WORDS)
The behavioral stimulant effect of peripheral cocaine injection into rats is augmented following daily administration. In vivo dialysis in the nucleus accumbens of conscious rats was used to determine if the increased behavioral response following daily cocaine administration is associated with an increase in extracellular dopamine concentration. Acute injection of cocaine (15 mg/kg, ip) produced an elevation in extracellular dopamine concentration in the nucleus accumbens. Following daily pretreatment with cocaine (15 mg/kg, ip X 4 days), a subsequent acute injection of cocaine (15 mg/kg, ip) significantly elevated the extracellular dopamine levels compared to that produced by a single acute injection. Although the levels of extracellular dopamine metabolites was significantly lowered by both acute cocaine and daily cocaine, no difference between these two groups of animals was measured. The increase in extracellular dopamine following a single acute injection of cocaine was not correlated to the motor stimulant response. However, after daily pretreatment with cocaine the motor stimulant response to acute cocaine was positively correlated with the increased extracellular concentration of dopamine in the nucleus accumbens. These data demonstrate that enhanced dopamine release into the nucleus accumbens may mediate the behavioral sensitization produced by daily injections of cocaine, but that other neural systems are influential in mediating the acute motor stimulant effect of cocaine.
Perinatal exposure to diazepam has been shown to lead to alterations in motor activity and exploratory behavior in neonatal animals. Exploratory and locomotor behavior have been associated with changes in mesotelencephalic dopamine function. We have therefore examined the effects of perinatal diazepam administration on both exploratory behavior and mesotelencephalic dopamine turnover in the adult rat. Animals exposed to the benzodiazepine during the perinatal period engaged in significantly less exploratory behavior than did control subjects. The diazepam-induced alterations in behavior were developmentally specific: decreased exploratory behavior was observed at 90, but not 60, days of age. At 90 days of age, specific changes in dopamine turnover in diazepam-treated animals were restricted to mesolimbic (nucleus accumbens and ventral tegmental area) sites; alterations in dopamine turnover were not seen in other mesotelencephalic sites examined. The findings indicate that perinatal exposure to benzodiazepines leads to behavioral changes that are present in adulthood. These changes in exploratory behavior may be associated with alterations in mesolimbic dopamine function.
Different evidence is presented showing that the detailed pattern of locomotion is generated centrally by spinal α-γ-linked circuits. Data concerning rhythmic interneuronal activity related to the spinal generator for locomotion will be discussed.
The anatomical organization and electrophysiological characteristics of a projection from the nucleus accumbens to anteroventral parts of the globus pallidus and to a subpallidal region that includes the substantia innominata (SI), the lateral preoptic area (LPO), and anterior parts of the lateral hypothalamic area (LHA) were investigated in the rat. Autoradiographic experiments, with injections of 3H-proline into different sites in the nucleus accumbens and adjacent caudoputamen, indicate that the descending fibers are organized topographically along both mediolateral and dorsoventral gradients, although labeled fibers from adjacent regions of the nucleus accumbens overlap considerably in the ventral globus pallidus and subpallidal region. Injections confined to the caudoputaman only labeled fibers in the globus pallidus. Retrograde transport experiments with the marker true blue confirmed that only the nucleus accumbens projects to the subpallidal region and that the caudoputamen projects upon the glubus pallidus in a topographically organized manner. In electrophysiological recording experiments single pulse stimulation (0.1 to 0.7 mA; 0.15 msec duration) of the nucleus accumbens changed the discharge rate of single neurons in the ventral globus pallidus and in the SI, LPO, and LHA. Typically, the responses were inhibition of neuronal discharge with latencies of 6 to 18 msec. Single pulse stimulation of the dorsolateral caudoputamen altered the discharge rate of single neurons in dorsal regions of the globus pallidus, with inhibition being the most frequently observed response. The results of these anatomical and electrophysiological experiments are complementary and indicate that fibers from the nucleus accumbens innervate the anteroventral region of the globus pallidus as well as the subpallidal region, while most fibers of the caudoputamen innervate the globus pallidus but not the subpallidal region. It appears, therefore, that these two components of the striatum have different output connections. The possible functional significance of these findings is discussed in relation to the projections of the subpallidal region, which may include an output to the mesencephalic locomotor region, and in relation to the nucleus accumbens afferents from the amygdala and hippocampal formation.
The present experiments investigated the hypothesis of a projection relating to the release of gamma-aminobutyric acid (GABA) from the nucleus accumbens to the globus pallidus subserving ambulatory activity in the rat. The GABA antagonist picrotoxin, microinjected into the globus pallidus, elicited dose-dependent increases in ambulatory activity. The administration of dopamine into the nucleus accumbens had a synergistic effect and further stimulated ambulatory activity. GABA injected into the ventral posterior globus pallidus significantly attenuated the ambulatory activity stimulated by injecting dopamine into the nucleus accumbens. These observations provide evidence of a GABAergic projection from the nucleus accumbens to the globus pallidus and implicate it in the initiation of ambulatory activity.
The neural organization of the vertebrate locomotor system is compared to the current picture of the corresponding invertebrate networks. The descending control is given particular attention and the experimental data available is reviewed.
Intra-accumbens d-amphetamine caused a dose-dependent hyperactivity which was shown to involve the release of newly synthesized dopamine. The amphetamine response was antagonised by apomorphine in a narrow dose range. This antagonistic effect of apomorphine was specifically inhibited by the neuroleptic agents pimozide and haloperidol in doses too low to inhibit the amphetamine response per se. Also, apomorphine exerted its antagonistic effect only when administered directly into the nucleus accumbens, not when injected into the caudateputamen or tuberculum olfactorium. Further, doses of intra-accumbens apomorphine which antagonised the amphetamine response reduced the homovanillic acid content of the nucleus accumbens but not that of the caudateputamen or tuberculum olfactorium. The apomorphine induced change in accumbens homovanillic acid was antagonised by haloperidol at doses effective in the behavioural experiments. Finally, the ability of apomorphine to antagonise amphetamine hyperactivity was abolished following the intra-accumbens injection of 6-OHDA (the amphetamine response being maintained after lesion) which specifically destroyed dopamine nerve terminals in the nucleus accumbens. This data is forwarded to support a general conclusion that intra-accumbens apomorphine antagonises the hyperactivity induced by intra-accumbens amphetamine by an action at neuroleptic sensitive sites within the nucleus accumbens and which may be located on nerve terminals, i.e. presynaptic receptors. The ability of neuroleptic agents to antagonise at postsynaptic dopamine receptors (antagonise the amphetamine response per se) was compared with an ability to reverse the apomorphine antagonism of the amphetamine response at a hypothesised ‘presynaptic receptor’. A differential dose could not be determined for clozapine of thioridazine. For pimozide and haloperidol the ratio of pre- to postsynaptic activity was small, whilst (−)-sulpiride was 5 fold more effective to inhibit pre- than postsynaptic receptors. This data provides support for the hypothesis that there may exist more than one neuroleptic mechanism in the nucleus accumbens which contribute to an overall control of motor function via the mesolimbic system.
Locomotor activity was elicited by injecting dopamine into the nucleus accumbens of the chronically cannulated rat. Dopamine was also injected together with cholinergic, serotoninergic and GABAergic agonists and antagonists to investigate the possible contribution to locomotor activity of these putative neurotransmitters. Carbachol elicited a transient enhancement of dopamine-stimulated activity. Atropine attenuated carbachol-stimulated enhancement but did not attenuate dopamine-stimulated activity. Serotonin attenuated dopamine-stimulated activity. The peripheral serotonin antagonist, methysergide, also attenuated locomotion. The administration of GABA elicited a bimodal response in locomotion, the lower dose eliciting a small increase in locomotion and the larger dose eliciting a reduction. The GABA antagonist, picrotoxin, elicited only increases in locomotion at all doses. These results suggest that there is not a cholinergic interneuron on the dopamine-stimulated pathway subserving locomotion but that both cholinergic and serotoninergic projections may modulate locomotor activity. Further they suggest that such modulation must be at least one inhibitory interneuron away from the dopamine synapse on the locomotor pathway. In addition, these results suggest a direct influence of GABAergic interneurons on the pathway subserving locomotor activity within the nucleus accumbens.
Whereas large lesions of the superior colliculus in rats increase locomotor activity in the open field, bilateral collicular microinjections of muscimol (an agonist of the inhibitory neurotransmitter GABA) have been reported to reduce open-field activity. This difference might be due to muscimol's acting on a subpopulation of collicular neurones, or to some feature of the microinjection technique. The issue was investigated by observing open-field behaviour after reversible lesions produced by bilateral microinjections of the local anaesthetic procaine (10–300 μg in 0.5 μl) into midbrain sites. Injections of procaine into the superior colliculus produced effects similar to those reported after muscimol injections: both locomotor activity and other exploratory responses were suppressed, with the rats spending much of their time motionless in an alert posture. In contrast, animals with injections of procaine into the mesencephalic reticular formation (MRF) ventral to the superior colliculus resembled rats given large collicular lesions: they showed very striking increases in locomotor activity, while their rearing and exploratory head movements were reduced. It is suggested that in some experiments large collicular lesions may have increased locomotor activity in the open field because they invaded underlying MRF. However, it is also possible that in rodents the acute effects of collicular inactivation, as assessed by microinjection of muscimol or procaine, are different from the chronic effects that are observed in experiments with electrolytic or radiofrequency lesions.
The effects of local injections of drugs into terminal areas of the mesolimbic dopamine system were investigated. Bilateral administration of dopamine, but not of noradrenaline and serotonin, into the nucleus accumbens of non-pretreated rats resulted in stimulation of locomotor activity. No clear or only minor effects were seen after injections of the dopamine metabolites 3-methoxytyramine, DOPAC and HVA and after injections of media with different pH and osmolality. d-Amphetamine proved more effective than dopamine in producing locomotor stimulation, whereas both stimulant and depressant effects were observed following injection of apomorphine into the nucleus accumbens. ET 495 and the noradrenaline agonists clonidine, phenylephrine and isoprenaline did not enhance locomotor activity, but theophylline was effective. Pretreatment with haloperidol, but not with clozapine, significantly reduced the effects of dopamine and theophylline. Locomotor stimulation was also found following bilateral administration of dopamine, d-amphetamine and apomorphine into the tuberculum olfactorium, whereas noradrenaline, serotonin and ET 495 produced no, or rather depressant effects. These results provide further evidence for an important role of the mesolimbic dopamine system with respect to locomotor activity.
The authors investigated the possible role of the nucleus accumbens in the hypothesized dopaminergic/serotoninergic control of motor function. 5 HT injections into the nucleus accumbens were shown to reduce the hyperactivity response to prior injections of dopamine in a dose dependent manner, and, at larger doses, to completely abolish the dopamine effect. Further, when forebrain concentrations of 5 HT were specifically reduced following lesions of the medial raphe nucleus the hyperactivity responses to dopamine injections were markedly increased.
The central stimulant actions of d-amphetamine are not altered in animals in which brain stores of catecholamines have been depleted with reserpine, but they are blocked by alpha-methyltyrosine, which inhibits catecholamine synthesis. The results of a variety of experiments suggest that the central actions of amphetamine result primarily from the ability of the drug to facilitate the release of newly synthesized dopamine from nerve terminals in the forebrain. The results of experiments in animals in which dopaminergic nerve terminals in various brain regions have been selectively destroyed by intracranial microinjection of 6-hydroxydopamine reveal that the locomotor stimulant actions of relatively low doses of amphetamine are dependent upon mesolimbic dopaminergic neurons, whereas the stereotyped behaviors induced by relatively larger doses of amphetamine are dependent upon nigrostriatal dopaminergic neurons. The central actions of amphetamine appear to be the primary result of interactions with dopamine neurons, but secondarily the drug also alters the dynamics of other putative neurotransmitters (e.g. acetylcholine, 5-hydroxytryptamine) in the brain.
The efferent connections of the hippocampal formation of the rat have been re-examined autoradiographically following the injection of small quantities of 3H-amino acids (usually 3H-proline) into different parts of Ammon's horn and the adjoining structures. The findings indicate quite clearly that each component of the hippocampal formation has a distinctive pattern of efferent connections and that each component of the fornix system arises from a specific subdivision of the hippocampus or the adjoining cortical fields. Thus, the precommissural fornix has been found to originate solely in fields CA1-3 of the hippocampus proper and from the subiculum; the projection to the anterior nuclear complex of the thalamus arises more posteriorly in the pre- and/or parasubiculum and the postsubicular area; the projection to the mammillary complex which comprises a major part of the descending columns of the fornix has its origin in the dorsal subiculum and the pre- and/or parasubiculum; and finally, the medial cortico-hypothalamic tract arises from the ventral subiculum. The lateral septal nuclei (and the adjoining parts of the posterior septal complex) constitute the only subcortical projection field of the pyramidal cells in fields CA1-3 of Ammon's horn. There is a rostral extension of the pre-commissural fornix to the bed nucleus of the stria terminalis, the nucleus accumbens, the medial and posterior parts of the anterior olfactory nucleus, the taenia tecta, and the infralimbic area, which appears to arise from the temporal part of field CA1 or the adjacent part of the ventral subiculum. The projection of Ammon's horn upon the lateral septal complex shows a high degree of topographic organization (such that different parts of fields CA1 and CA3 project in an ordered manner to different zones within the lateral septal nucleus). The septal projection of "CA2" and field CA3 is bilateral, while that of field CA1 is strictly unilateral. In addition to its subcortical projections, the hippocampus has been found to give rise to a surprisingly extensive series of intracortical association connections. For example, all parts of fields CA1, CA2 and CA3 project to the subiculum, and at least some parts of these fields send fibers to the pre- and parasubiculum, and to the entorhinal perirhinal, retrosplenial and cingulate areas. From the region of the pre- and parasubiculum there is a projection to the entorhinal cortex and the parasubiculum of both sides. That part of the postsubiculum (= dorsal part of the presubiculum) which we have examined has been found to project to the cingulate and retrosplenial areas ipsilaterally, and to the entorhinal cortex and parasubiculum bilaterally.
In a search for behavioural tests where certain behaviours related to dopamine and noradrenaline transmission can be recorded automatically we have developed and tested an automatic version of the hole board. The test measures two behaviour variables: the open field variable defined as the number of interruptions of photocell beams symmetrically covering an open field area and the 'hole' variable, defined as the number of head-dips into holes recorded by photocell beams positioned underneath the floor of the cage. The method was evaluated by observations of the rats concomitant with the automatic registrations. The animals were tested on dopamine agonistic drugs, which were found to decrease the 'hole' counts and cause an increase in the open field counts as compared to saline injected controls. d-Amphetamine which is known to increase the release of dopamine as well as of noradrenaline caused an increase in both the open field counts and the 'hole' counts. The increase in 'hole' counts caused by d-amphetamine was reduced when the animals were pretreated with a dopamine-beta-hydroxylase inhibitor (FLA 63) or a noradrenaline receptor blocker (phenoxybenzamine). These results suggests that the increase in the 'hole' variable was related to an increased noradrenaline transmission while the increase in the open field variable was related to an increased dopamine transmission. The lowest dose of apomorphine caused a behavioural inhibition which may be explained by a preferential stimulation of dopamine autoreceptors.
The increased motor activity of reserpine-nialamide pretreated rats given dopamine into the nucleus accumbens was potentiated in a dose-dependent manner by systemically administered caffeine. Similarly, the increase in motor activity seen when the endogenous dopamine was released by intraperitoneally administered amphetamine was potentiated by systemically given caffeine. These effects might be due to an increase in the dopamine-induced accumulation of cyclic AMP in the nucleus accumbens after inhibition of the phosphodiesterase by caffeine.
The efferent fiber connections of the nuclei of the amygdaloid complex with subcortical structures in the basal telencephalon, hypothalamus, midbrain, and pons have been studied in the rat and cat, using the autoradiographic method for tracing axonal connections. The cortical and thalamic projections of these nuclei have been described in previous papers (Krettek and Price, ′77b,c). Although the subcortical connections of the amygdaloid nuclei are widespread within the basal forebrain and brain stem, the projections of each nucleus have been found to be well defined, and distinct from those of the other amygdaloid nuclei.
The basolateral amygdaloid nucleus projects heavily to the lateral division of the bed nucleus of the stria terminalis (BNST), to the caudal part of the substantia innominata, and to the ventral part of the corpus striatum (nucleus accumbens and ventral putamen) and the olfactory tubercle; it projects more lightly to the lateral hypothalamus. The central nucleus also projects to the lateral division of the BNST and the lateral hypothalamus, but in addition it sends fibers to the lateral part of the substantia nigra and the marginal nucleus of the brachium conjunctivum. The basomedial nucleus has projections to the ventral striatum and olfactory tubercle which are similar to those of the basolateral nucleus, but it also projects to the core of the ventromedial hypothalamic nucleus and the premammillary nucleus, and to a central zone of the BNST which overlaps the medial and lateral divisions. The medial nucleus also projects to the core of the ventromedial nucleus and the premammillary nucleus, but sends fibers to the medial division of the BNST and does not project to the ventral striatum. The posterior cortical nucleus projects to the premammillary nucleus and to the medial division of the BNST, but a projection from this nucleus to the ventromedial nucleus has not been demonstrated. Projections to the “shell” of the ventromedial nucleus have been found only from the ventral part of the subiculum and from a structure at the junction of the amygdala and the hippocampal formation, which has been termed the amygdalo‐hippocampal area (AHA). The AHA also sends fibers to the medial part of the BNST and the premammillary nucleus.
Virtually no subcortical projections outside the amygdala itself have been demonstrated from the lateral nucleus, or from the olfactory cortical areas around the amygdala (the anterior cortical nucleus, the periamygdaloid cortex, and the posterior prepiriform cortex). However, portions of the endopiriform nucleus deep to the prepiriform cortex project to the ventral putamen, and to the lateral hypothalamus.
Reports from previous works has given different classifications for the nucleus accumbens. There also appears to be a general lack of information regarding the fiber connections of the nucleus. The present investigation was undertaken to clarify the connections of this structure. Silver impregnation methods were used to discern some of the afferent fibers of the nucleus, and autoradiographic techniques were used to locate target areas of efferent projections. Afferents were found to be predominately from the septum. Other sources of possible afferents were the mid cingulate gyrus and the ventral nucleus of the diagonal band. No argyrophilia was observed in the nucleus accumbens following transection of the fornix body, lesions of the anterior orbital frontal cortex or anterior cingulate gyrus. On the basis of grain counts made from autoradiographic studies, the nucleus accumbens projects predominately to the lateral hypothalamus. Counts above background were found in the cingulate gyrus, septum, ventral nucleus of the diagonal band, midline thalamic nuclei, habenula, caudate and substantia nigra. Thus, efferent projections appear to distribute to both limbic and extrapyramidal structures. Considering these connections and the functions reported by various workers the nucleus accumbens may serve as bridge between limbic and extrapyramidal motor systems effecting limbic influence in some movements.
The effect of local application of dopamine into the nucleus accumbens on locomotor activity was studied in rats during and after withdrawal of long-term ethanol treatment. The bilateral application of dopamine into the nucleus accumbens of both the ethanol and withdrawal rats produced a pronounced increase in coordinated locomotor activity, which was 8-10 times higher than that of untreated water control rats. This effect of dopamine was antagonized by intraperitoneally administered haloperidol indicating a specific effect on dopamine receptors. It is concluded that prolonged ethanol administration may produce an increased sensitivity of the dopamine receptors in the nucleus accumbens and further support the contention that central catecholamine mechanisms are involved in the mediation of the withdrawal syndrome observed after long-term treatment with ethanol.
The effect of intracerebral administration of antagonists of dopamine and noradrenaline upon the locomotor stimulation induced by intraperitoneal injection of d-amphetamine sulfate in rats was investigated. Injection of low doses of the dopamine antagonist haloperidol (2.5 Μg and 5 Μg) bilaterally into the nucleus accumbens antagonized the locomotor stimulation following d-amphetamine. No significant inhibition was observed following administration of the alpha-adrenergic antagonist phentolamine or the beta-adrenergic antagonist propranolol into the nucleus accumbens. Injection of the same doses of haloperidol into the caudate nucleus did not inhibit the d-amphetamine induced locomotor activity, in contrast to the effects seen following injection into the nucleus accumbens.
The results confirm the significance of dopaminergic mechanisms for the locomotor stimulant effect of d-amphetamine and indicate that the mesolimbic dopamine system plays an important role in this respect.
The effects of injections of monoamines, alone and in combination with different antagonists, bilaterally into the nucleus accumbens of nialamide-pretreated rats were investigated.
Dopamine was found to produce a stronger stimulation of locomotor activity than noradrenaline, whereas serotonin was effective only in a small number of animals, in which the duration of locomotor stimulation was shorter than after dopamine or noradrenaline. The effects of both dopamine and noradrenaline were completely antagonized by administration of a small dose of the dopamine antagonist haloperidol, administered bilaterally 15 min after the catecholamines. The α-adrenergic antagonist phentolamine did not inhibit the effect of noradrenaline but, on the contrary, potentiated and considerably prolonged the duration of locomotor stimulation. Also, the effect of dopamine was potentiated and prolonged by phentolamine. Bilateral injection of phentolamine alone had no influence upon locomotor activity. The effect of noradrenaline was not clearly inhibited nor potentiated by the Β-adrenergic antagonist propranolol. It is suggested that the stimulation of locomotor activity induced by injection of noradrenaline into the nucleus accumbens of nialamide-pretreated rats is brought about via dopaminergic mechanisms.
The intracerebral injection technique was used to apply dopamine directly into dopamine-containing areas of the mesolimbic system, the nucleus accumbens septi, tuberculum olfactorium and nucleus amygdaloideus centralis. 200 mug dopamine injected bilaterally into the nucleus accumbens septi caused a stereotyped sniffing behaviour and hyperactivity but only a periodic hyperactivity developed after similar injections into the tuberculum olfactorium and no change in behaviour was observed following injections into the nucleus amygdaloideus centralis. After pretreatment with nialamide, the effects of intracerebral dopamine were enhanced, doses of 1-50 mug dopamine causing consistent stereotyped sniffing and a dose-dependent hyperactivity on injection into the nucleus accumbens septi or tuberculum olfactorium. The effects initiated from the nucleus accumbens septi were most marked. In addition, 50-100 mug dopamine injected into the tuberculum olfactorium caused a periodic biting behaviour. Biting was not observed after injections into the nucleus accumbens septi and, even in the presence of nialamide, injections of dopamine into the nucleus amygdaloideus centralis failed to cause any change in motor behaviour.
Eight mug of 6-hydroxydopamine (6-OHDA) injected bilaterally into the nucleus accumbens septi (NAS) or the caudate nucleus of the rat resulted in 79% and 50% depletion of endogenous dopamine (DA) at these respective sites. Fourteen days after the injection a low dose of amphetamine failed to induce the characteristic locomotor response in the NAS-lesioned rats but did so in the caudate-lesioned animals. By contrast the caudate lesion, but not the NAS lesions, abolished intense forms of stereotyped behaviour induced by higher doses of amphetamine. Both lesioned groups exhibited supersensitivity to the dopamine agonist, apomorphine; the NAS group showed enhanced locomotor activity and the caudate group enhanced stereotyped behaviour. The block of amphetamine locomotion and the enhanced response to apomorphine were maximal around 14 days after the operation and gradually attenuated up to 90 days. Theer is evidence that remaining DA levels in the NAS are greater at 90 than at 14 days postoperatively. Thus recovery of behavioural effects correlated with an increase in the remaining levels of DA in the NAS.
The effect of local application of dopamine to the nucleus accumbens or corpus striatum on locomotor activity was studied in rats 4 days after withdrawal from a 6 weeks term of penfluridol medication. The bilateral application of dopamine into the nucleus accumbens of penfluridol-treated rats produced a very marked increase in coordinated locomotor activity which was 3-5 times higher than that of rats not treated with penfluridol. This effect of dopamine in both penfluridol-treated and control rats was antagonized by intraperitoneally administered haloperidol. The bilateral application of dopamine into the corpus striatum of penfluridol-treated animals produced a marked stereotyped behavioural syndrome in all rats studied, whereas no signs of stereotyped behaviour were observed in any of the rats not treated with penfluridol. The results indicate that long-term treatment of rats with the dopamine receptor blocking agent penfluridol produces an increase in the sensitivity of the dopamine receptors in the nucleus accumbens and corpus striatum and that the nucleus accumbens may play a role in locomotor activity.
A series of anatomical, electrophysiological and behavioral experiments was carried out in the rat to investigate the possible functional significance of a recently demonstrated neural pathway from the substantia innominata of the subpallidal forebrain to the mesencephalic locomotor region. Following injections of the anterogradely transported lectin PHA into the substantia innominata labeled fibers with terminal boutons were observed in the zona incerta, dorsal to the medial part of the subthalamic nucleus, and some appeared to continue on to the pedunculopontine nucleus. Electrophysiological recordings of action potentials were made from neurons in the substantia innominata and some of these neurons were activated antidromically by single-pulse stimulation of the zona incerta and/or by single-pulse stimulation of the pedunculopontine nucleus as well. Neurons in the zona incerta responded orthodromically to stimulation of the substantia innominata. Locomotor activity was initiated by injecting picrotoxin, a GABA antagonist, unilaterally into the substantia innominata through chronic cannulae, as reported previously. This picrotoxin-initiated locomotor activity was reduced significantly when procaine (a neuronal blocker) was injected into the ipsilateral zona incerta. Injecting procaine into the contralateral zona incerta had little or no effect on the picrotoxin-initiated locomotor activity. Taken together these observations suggest the tentative working hypothesis that projections from the substantia innominata to the zona incerta as well as the pedunculopontine nucleus may contribute to the locomotor component of adaptive behaviors resulting from limbic forebrain integrative activities, an hypothesis that can now be investigated further.
Stimulation of dopamine receptors in the nucleus accumbens results in enhanced locomotor activity. The behavioural pattern showed the same characteristics as seen after injection of ergometrine, i.e. continuous exploring activity, except that the time for the appearance of locomotor stimulation was shorter. This finding favours the assumption that ergometrine has dopamine stimulating properties in the rat brain. The experiment provided evidence that the mesolimbic dopamine system with cell bodies in the A 10 group and nerve terminals in the nucleus accumbens and tuberculum olfactorium is functionally different from the nitrostriatal dopamine system.
This chapter discusses the pharmacology and physiology of stereotyped behavior. Amphetamines apparently produce stereotyped behavior in all mammals, including man and therefore, it seems reasonable to assume that the stereotypy also in man is mediated by the dopamine in the brain. The excitatory or stimulant effect of amphetamines, including apomorphine, is not a general one affecting all kinds of behavior alike, but it is selective; certain items of behavior are quantitatively increased while others are concurrently decreased or abolished. This selectivity of effect is seen already after small doses of amphetamine but becomes more pronounced after larger doses. Many, probably all kinds of behavior are affected, resulting in a profound change in the whole behavioral pattern. Stereotypy, that is, lack of variation and apparent aimlessness, is a characteristic feature of the pattern that emerges; in the extreme, the behavior consists in the continuous repetition of one or a few acts. With the higher doses, the extremely stereotyped behavior does not appear immediately after a subcutaneous injection but develops gradually through a pre-phase with selective stimulation and inhibition comparable to that seen with the smaller doses; after the period of maximal stereotypy, there is again a post-phase which is similar to the pre-phase.
Continuous stimulation (60 c/s) of a region below the inferior coliculus can induce locomotion on the treadmill of precollicular, postmammilar cats. This study aims at revealing what changes occur in the spinal cord, when the “locomotor region” is stimulated. This stimulation enables the cat to walk if the treadmill is moved. After controlling the threshold for evoking good locomotion, the cats were curarized. Stimulation at a strength that evoked walking prior to curarization induced a depression of inhibitory short-latency reflex effects to α-motoneurones from cutaneous, and high threshold muscular afferents without changing the direct excitability of α-motoneurones. The threshold for evoking longlasting reciprocally organized discharges was lowered. The results suggest that the effects are induced by a slow fiber system, that releases the activity of the spinal stepping generating neurones. The results would be explained if the noradrenergic reticulospinal system was activated from the mesencephalic locomotor region.
A series of anatomical and electrophysiological experiments have been carried out to examine the organization of a direct projection from the substantia innominata and the lateral preoptic area of the hypothalamus, referred to collectively as the subpallidal region, to the pedunculopontine nucleus and adjacent parts of the dorsal midbrain in the adult rat. In the first series of experiments, the retrogradely transported fluorescent tracer SITS, which does not appear to be taken up by fibers-of-passage, was injected into the pedunculopontine nucleus, and the distribution of labeled neurons was plotted in the substantia innominata and lateral preoptic area, as well as in adjacent regions including the medial preoptic area, the bed nucleus of the stria terminalis and parvocellular parts of the paraventricular nucleus. Then, the anterogradely transported lectin PHA-L, which also does not appear to be taken up in effective amounts by fibers-of-passage, was injected into parts of the substantia innominata and lateral preoptic area that project directly to the pedunculopontine nucleus. These experiments demonstrated that fibers from both regions descend through the medial forebrain bundle and give rise in the pedunculopontine nucleus to a terminal field that contains many structures with the appearance of terminal boutons. They also indicated that individual fibers from the subpallidal region innervate both the pedunculopontine nucleus and adjacent parts of the central gray, and that the pathway innervates areas along the length of the medial forebrain bundle on its way to the dorsal midbrain. In a third series of experiments the retrogradely transported fluorescent tracer True Blue was injected into upper thoracic levels of the spinal cord, and it was found that the region of the pedunculopontine nucleus that receives the densest input from the subpallidal region contained many retrogradely labeled neurons on both sides of the brain. And finally, a series of electrophysiological experiments demonstrated that single-pulse stimulation of the substantia innominata and the lateral preoptic area altered the firing rate of a majority of the neurons in and around the pedunculopontine nucleus, and that excitatory and inhibitory responses occurred about equally. These results clearly suggest that the subpallidal region projects directly to the pedunculopontine nucleus and adjacent regions including the central gray and the superior colliculus.(ABSTRACT TRUNCATED AT 400 WORDS)
The projection from the superior and inferior colliculi to the basilar pons in the rat was studied with the technique of orthograde transport of labeled amino acids and autoradiography. Injections restricted to the medial or lateral regions of the superior colliculus gave rise to grain labeling representing terminal fields over the ipsilateral peduncular, dorsolateral, and ventrolateral regions of the caudal basilar pons and over the dorsomedial area of the contralateral nucleus reticularis tegmenti pontis (NRTP). The pontine projection from the superior colliculus to the lateral basilar pons is topographically organized; the medial superior colliculus projects primarily to the peduncular region, wheras the lateral superior colliculus terminates chiefly in ventrolateral pontine areas. A projection from the superior colliculus to the contralateral dorsomedial pontine and medial peduncular pontine regions, a previously undescribed finding, has also been shown. Descending fibers from the inferior colliculus do not appear to terminate extensively within the basilar pons but rather course adjacent to pontine cells of the dorsolateral region in the caudal pons. Pretectal nuclei project ipsilaterally to medial and lateral nuclei in the rostral and middle basilar pons, respectively. A rostrocaudal topography exists in the tectopontine projection; the pretectum projects to rostromiddle basilar pons, the superior colliculus to more caudal pontine regions, and the inferior colliculus (although sparsely) to further caudal areas.
It has been suggested that the depression of excitatory synaptic potentials produced by general anaesthetics can be attributed to a partial blockade of impulse conduction in the terminal branches of axons. This hypothesis has been tested by comparing the actions of pentobarbitone, procaine and tetrodotoxin (TTX) on synaptic transmission in the guinea‐pig olfactory cortex.
Pentobarbitone (0.1–0.3 m m ) depressed the evoked synaptic potentials without any significant depression of impulse conduction in the afferent fibres of the lateral olfactory tract (l.o.t.). It had no effect on the electrical excitability of either the l.o.t. axons or the postsynaptic neurones.
Tetrodotoxin (TTX; 1–5 × 10 ⁻⁸ m ) slowed conduction of impulses in the l.o.t. and decreased the amplitude of the l.o.t. compound action potential in proportion to the concentration applied. All concentrations of TTX elevated the electrical threshold of the l.o.t. axons and there was evidence to suggest that the threshold of the postsynaptic neurones was also elevated. The synaptic potentials were depressed in direct proportion to the depression of the l.o.t. compound action potential.
Procaine (0.1–0.5 m m ) exhibited a pattern of activity intermediate between pentobarbitone and TTX. The most marked effect, seen at all concentrations tested, was a slowing of impulse conduction and a decrease in the electrical excitability of the l.o.t. axons.
It is concluded that general anaesthetics (exemplified by pentobarbitone) depress synaptic transmission by interfering with the processes involved in chemical transmission and not by blocking impulse conduction in the terminal branches of afferent nerves.
The neurotoxic properties of ibotenate and kainate after intracerebral application were compared in several regions of the rat brain. Ibotenate, being 5-10 times less toxic than kainate, caused lesions which were generally found to extend spherically from the tip of the injection cannula. In contrast, kainate injections often resulted in neuronal degeneration distant from the site of infusion, thus severely limiting its use as a tool for causing lesions in neurobiological studies. In some of the brain regions examined (hippocampus, septum), neurons appeared differentially susceptible to kainate but uniformly vulnerable to ibotenate. Some cell groups, such as those in the medial septum and the locus coeruleus, proved highly resistant to kainate but could be selectively ablated by ibotenate. These findings, together with differences between the two toxins in the evolution of neuronal degeneration (exemplified here in the hippocampal formation), appear to support previous suggestions that ibotenate and kainate exert their excitotoxic actions via different mechanisms. On the other hand, neuropathological changes caused in the cerebellum did not differ, since both ibotenate and kainate preferentially destroyed granule cells. Two nuclei, the arcuate nucleus of the hypothalamus and the nucleus of the fifth nerve, were found to be extremely resistant to either neurotoxin.
Bilateral anodal and cathodal electrolytic lesions of the nucleus reticularis tegmenti pontis (NRTP) increased forward locomotion in rats. The correlation between the magnitude of locomotion and percent of NRTP damage demonstrated that the more complete the NRTP destruction the greater the increase of locomotion. The lesioned rats exhibited at the same time low level rearing and running wheel activity as well as some lack of motor coordination during body balance tests. Taking into consideration the neural connections of the NRTP we suggest that disruption of NRTP-cerebellar pathways, rather than connection with forebrain structures is associated with the lesion-induced increase of forward locomotion.
The 'supersensitive' locomotor response to apomorphine resulting from 6-hydroxydopamine (6-OHDA)-induced denervation of the nucleus accumbens (N.Acc.) was studied in animals following selective damage to cell bodies within the substantia innominata (SI) and lateral preoptic region (LPO). Ibotenic acid-induced lesions of the SI and LPO dramatically attenuated the locomotor response to apomorphine in 6-OHDA-infused animals. Thus, the locomotor response that follows dopaminergic stimulation within the N.Acc. depends to a great degree on the integrity of cells within the SI and LPO region.
These studies demonstrate the presence of the MLR in the rat brain. Controlled locomotion on a treadmill could be induced by low level stimulation (less than 50 microA) of an area in the posterior midbrain following a precollicular-prenigral brainstem transection. This area included the lateral part of the cuneiform nucleus and anterior as well as posterior portions of the pedunculopontine nucleus. In addition, the presence of a subthalamic locomotor region in the fields of Forel was determined in rats after prethalamic transections.
Neural projections from nucleus accumbens to subpallidal region, which contains a major GABAergic component, have been demonstrated with anatomical and electrophysiological techniques. The possible contribution of this GABA projection to the initiation of locomotor activity was investigated using neuropharmacological techniques. Injecting picrotoxin, a GABA antagonist, into the ventral globus pallidus increased locomotor activity measured in an open-field test, confirming findings. Locomotor activity was also increased when picrotoxin was injected into the lateral preoptic area, the sublenticular part of the substantia innominata and bed nucleus of the stria terminalis. In another series of experiments locomotor activity initiated by injecting dopamine into the nucleus accumbens was attenuated by pretreating the lateral preoptic area, the substantia innominata and ventral globus pallidus with GABA. These observations provide evidence that GABAergic projections from accumbens to subpallidal region contribute to locomotor activity and raise the possibility that they have a role in exploratory locomotion and in certain goal-directed behaviors.
It has been shown that the nucleus accumbens receives input from the amygdala and that mesolimbic dopaminergic projection from the ventral tegmental area (VTA) modulates the response of accumbens neurons to amygdala input. Since the nucleus accumbens projects to the ventral pallidum, the purpose of this study was to investigate, using electrophysiological techniques, whether or not the nucleus accumbens relays the projection from the amygdala to the ventral pallidum and whether or not the mesolimbic dopamine projection interacts with this pathway. Extracellular single-unit recordings were obtained from the ventral pallidum of urethan-anesthetized rats, and the responses of these neurons to electrical stimulation of the amygdala were investigated. Of 392 neurons tested, 36% were inhibited and 11% were excited following amygdala stimulation. Latency of onset of inhibitory responses showed a bimodal distribution with peaks in the ranges of 4-6 ms and 16-18 ms, respectively. Fifty-four percent of inhibitory responses with latencies greater than 12 ms were attenuated by 1) injection of procaine hydrochloride into the nucleus accumbens, or 2) injection of d-amphetamine into the nucleus accumbens, or 3) stimulation of VTA with a train of 10 pulses (10 Hz) prior to stimulation of amygdala. Acute administration of haloperidol intraperitoneally or injection of 6-hydroxydopamine into the ipsilateral VTA, 2 days prior to the recording experiment, reduced the attenuating effects of intra-accumbens injection of d-amphetamine and VTA conditioning stimulations on the inhibitory response of ventral pallidal neurons to amygdala stimulation. These results support the hypothesis that the nucleus accumbens provides a link between the amygdala and the ventral pallidum. Since the amygdala is a limbic structure and the ventral pallidum has possible connections with the extrapyramidal motor system, it is suggested that the amygdala to nucleus accumbens to ventral pallidum projection may be a bridge between the limbic and motor systems. We also suggest that this relay of output from the amygdala to the ventral pallidum via the nucleus accumbens is under the modulating influence of the mesolimbic dopamine projection from the ventral tegmental area.
Procaine (0.025–0.1%; pH 7.9) caused a reduction in the amount and rate of development of the early transient (sodium) and late steady state (potassium) currents which occur during a depolarizing voltage step applied to the excised, voltage clamped squid axon. Consistent results were obtained by holding the membrane potential at a hyperpolarized value prior to the applied step. No effect was seen on the resting potential, on the sodium equilibrium potential, or on the proportion of the sodium carrying system which was ‘inactive’ at any membrane potential. The blocking action of procaine is a result of the inhibition by the drug of the sodium carrying system. The effect of procaine on the potassium conductance is such as to oppose the blocking action.
Neurotoxic action of kainic acid
- Coyle
Covle. J. "1".. Neurotoxic action of kainic acid. J. Neurochem., 41 11983) 1-11.
Amphetamine and apomorphine responses in the rat following 6. ()HDA lesions of thc nucleus accumbcns septi and corpu, striatum
- P Kelly
- It
- P W Seviour
- S D Iverscn
Kelly, P. It., Seviour, P. W. and Iverscn. S. D., Amphetamine and apomorphine responses in the rat following 6.
()HDA lesions of thc nucleus accumbcns septi and corpu,
striatum, Brain Res'earch. 94 ( 19751 5117 522.
Automatic registration of behaviour related to dopamme and noradrenalme transmission, l:urop
- T Jungberg
- U Ungerstedt
[,jungberg, T. and Ungerstedt, U., Automatic registration
of behaviour related to dopamme and noradrenalme transmission, l:urop. J. Pharmmvd.. 36 11976) IN1-INN.
11 1,. I.ocomotor activity elicited by injections of pictrotoxin into thc ventral tegmcntal area is attenuated b., injections of (_;AB:\ intt~ the globus pallidus. Brain Re.search. lt)l (ltJgO)
- G J Mogenson
- . M Wu
- Jonc
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tegmcntal area is attenuated b.,, injections of (_;AB:\ intt~
the globus pallidus. Brain Re.search. lt)l (ltJgO) 569-571.
Electroph,vsiological and neuropharmacological-beha~ioral studies ol the re, titus accumbens: implications for it, role as a limbic-motor intcuface
- G J Mogcnson
- Yim
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2 Ill --22~, +.
Stimulation of locomotor activity following rejection of dopamine into the nucleus accumbens
- A J J Pijvlenburg
- J M Van T,R, Ossum
Pijvlenburg. A. J. J. and Van t,r, ossum, J. M.. Stimulation of
locomotor activity following rejection of dopamine into the
nucleus accumbens,.1 Pharm Pharma~ol.. 25 (1973)
1003-10115.
Connections of tile nucleus accumbens
- E W Pmvcll
- R B Lcman
Pmvcll, E. W. and Lcman, R. B., Connections of tile nucleus accumbens, Bruin Re.search. 105 (1976) 389-403.