Central neural regulation of heart and blood vessels in mammals.

The study of the central regulation of the circulation in the past has been directed primarily at observing reflex responses to stimulation of peripheral receptors and at producing changes in cardiovascular parameters during electrical stimulation of central sites. These studies have demonstrated that the nervous system can regulate the circulation to different vascular beds with a high degree of specificity and that it has the ability to provide a range of coordinated responses which are appropriate to the metabolic needs of a particular behavioural pattern. In addition, it has become firmly established that the nervous system is capable of coupling cardiovascular changes with other autonomic and somatic activities to produce an integrated response. In the last decade it has become apparent that although the mode of operation of central cardiovascular regulation has been described in general terms, very little is known about the accurate anatomical localization of neuronal circuits and pathways and of impulse traffic corresponding to the changes in cardiovascular parameters that have been observed. This essay reviews recent information on discrete neuronal circuits and pathways and their mode of operation in electrophysiological terms. One of the most serious difficulties in this endeavour is the problem of demonstrating specificity of pathways and circuits because patterns of firing of afferent and efferent peripheral nerves can be usually identified, but the demonstration of specificity of central structures is a conceptual and technical challenge to the most skilled investigator. Several studies have been made in the last decade in an attempt to trace anatomically and functionally pathways involved in central cardiovascular regulation. Progress has been made especially with regard to the precise sites of termination of cardiovascular afferent fibres and the pattern of discharge of efferent cardiovascular neurons; some work has also been done to trace discrete pathways between the hypothalamus and the medulla and the medulla and the spinal cord. However, in view of the difficulties of establishing the specificity of cardiovascular pathways, progress will depend on the acquisition of a wiring diagram of simple cardiovascular reflex arcs before attempts are made to study the functional interactions of regions in the brain that have been traditionally associated with central regulation of the circulation. Future experiments should concentrate less on the demonstration of cardiovascular responses to stimulation or lesions in the central nervous system and more on the connections of discrete regions.(ABSTRACT TRUNCATED AT 400 WORDS)

Autoradiographic evidence for pathways from the medial preoptic area to the midbrain involved in the drinking response to angiotensin II.

The 3H-amino acid autoradiographic method was used to localize intracerebral sites from which angiotensin II (AII) elicits drinking and to identify their efferent neural pathways. Small injections (0.02-0.1 mul) of AII and 3H-amino acid mixtures were injected together or separately into widespread regions of the forebrain of adult rats in normal food and water balance. From an analysis of 39 positive and negative injection sites it was concluded that the caudal half of the medial preoptic area and the adjacent rostral part of the anterior hypothalamic area are sensitive to AII. Two anatomically defined pathways arising from neurons within this region were identified. One descends through the medial forebrain bundle and appears to terminate in the lateral hypothalamic area, the ventromedial nucleus, the mammillary body, and the ventral tegmental area. The other descends through the periventricular region and posterior hypothalamic area to end in the midbrain central gray. Additional widespread connections with the amygdala, septum, habenula, and pons appear to arise in the lateral preoptic area (Swanson, '76). Combined AII-3H-amino acid injections centered in the subfornical organ only elicited drinking in those cases in which injected label diffuse through the third ventricle to the medial preoptic area. No efferent pathways were identified in experiments in which a small injection (0.02 mul) heavily labeled cells strictly confined to the subfornical organ and there was no ventricular spread of label.

Electrophysiological study of the effects of D1 and D2 dopamine antagonists on the interaction of converging inputs from the sensory-motor cortex and substantia nigra neurons in the rat.

The interaction of stimulation of the cerebral cortex and of the substantia nigra on the activity of neostriatal neurons was investigated in urethane-anesthetized rats. Neurons of the dorsal striatum were activated by single pulse stimulation of the sensory-motor cortex. The effects of nigral conditioning stimulation on this excitatory response of striatal neurons to cortical stimulation were studied in a series of parametric experiments in which the length of the train of pulses and the intensity of the nigral stimulation were varied. One and five pulses of nigral conditioning stimulation had little or no effect. Ten pulses of nigral conditioning stimulation reduced the excitatory response, the magnitude of the reduction being greater with higher current intensities. In another series of experiments, the effects of dopaminergic receptor antagonists on the interaction of cortical and nigral inputs to striatal neurons were studied. Sulpiride, a D2 antagonist, reversed the attenuating effects of nigral conditioning stimulation on the excitatory response of striatal neurons to cortical stimulation, whereas SCH 23390 a D1 antagonist, had no effect. The present findings support the hypothesis that the nigrostriatal dopaminergic pathway modulates the excitatory response of striatal neurons to cortical stimulation by means of dopamine D2 receptors.

Neuromodulatory action of dopamine in the nucleus accumbens: an in vivo intracellular study.

Intracellular recordings were made from neurons in the nucleus accumbens in situ to determine how dopamine produces the selective neuromodulatory action in the accumbens observed in previous studies. Electrical stimulation of the basolateral nucleus of the amygdala was found to produce monosynaptically evoked depolarizing and hyperpolarizing postsynaptic potential sequences in a large proportion of the accumbens neurons sampled. Dopamine applied iontophoretically or released endogenously by stimulation of the ventral tegmental area produced consistent membrane depolarization and an increase in membrane conductance but not an increase in spontaneous activity of the accumbens neurons. Stimulation of the ventral tegmental area with trains of 10 pulses at 10 Hz prior to stimulation of the amygdala produced 8-58% reduction in the amplitude of the depolarizing postsynaptic potential but no change in the late hyperpolarizing postsynaptic potential. Although attenuation of the depolarizing postsynaptic potential amplitude from ventral tegmental area stimulation was often accompanied by membrane depolarization, it appeared that the two responses were not causally related. The effect of ventral tegmental area stimulation on the evoked depolarizing postsynaptic potential and the membrane potential were blocked by haloperidol indicating the involvement of dopamine. Iontophoretically applied dopamine produced responses similar to ventral tegmental area stimulation with two exceptions: (i) iontophoretically applied dopamine produced consistently stronger maximal attenuation of the depolarizing postsynaptic potential than did ventral tegmental area stimulation; and (ii) iontophoretically applied dopamine always attenuated both the depolarizing postsynaptic potential and hyperpolarizing postsynaptic potential whereas ventral tegmental area stimulation produced selective attenuation of the depolarizing postsynaptic potential only. These electrophysiological results are complementary to those from pharmacological experiments and suggest that one of several physiological functions of dopamine in the nucleus accumbens is a neuromodulatory one involving presynaptic action on non-dopaminergic terminals.

Hippocampal signal transmission to the pedunculopontine nucleus and its regulation by dopamine D2 receptors in the nucleus accumbens: an electrophysiological and behavioural study.

The integrative role of the nucleus accumbens and subpallidal area in relaying hippocampal signals to the mesencephalic locomotor region in the brainstem was investigated electrophysiologically in urethan-anaesthetized rats. A behavioural study of the functional connections was also performed in freely moving rats. In the electrophysiological experiments, subpallidal output neurons to the pedunculopontine nucleus and the adjacent ventral gray were first identified by their antidromic responses to electrical stimulation of the pedunculopontine nucleus. Hippocampal stimulation was then shown to inhibit orthodromically some of these subpallidal neurons. The inhibitory response was attenuated following microinjection of a dopamine D2 agonist (LY 171555), but not a D1 agonist (SKF 38393), into the accumbens. This suggests that signal transmission from the hippocampus to the subpallidal output neurons to the pedunculopontine nucleus is modulated by a D2 receptor-mediated mechanism in the nucleus accumbens. Injections of N-methyl-D-aspartate into the ventral subiculum of the hippocampus resulted in a threefold increase in locomotor responses. Injection of a D2 agonist into the accumbens reduced the hyperkinetic response dose-dependently and suggests that D2 receptors regulate locomotor responses initiated by the hippocampal-accumbens pathway. Injection of nipecotic acid, a GABA uptake inhibitor, into the subpallidal area or of procaine, a neural transmission blocker, into the region of the pedunculopontine nucleus, also reduced significantly the hippocampal-induced hyperkinetic response. These results provide evidence of limbic (e.g. hippocampus) influences on locomotor activity by way of nucleus accumbens-subpallidal-pedunculopontine nucleus connections which may contribute to adaptive behaviour. Signal transmission from the hippocampus may be regulated by a dopamine D2 receptor mechanism in the accumbens, presumably mediated by the converging mesolimbic dopaminergic input from the ventral tegmental area.

An electrophysiological study of the neural projections from the hippocampus to the ventral pallidum and the subpallidal areas by way of the nucleus accumbens.

The integrative role of the ventral striatum in transmitting signals from the hippocampus to the ventral pallidal and subpallidal areas was investigated in urethane-anaesthetized rats using an extracellular single-unit recording technique. Neurones of the nucleus accumbens were first activated by single-pulse stimulation of the ventral subiculum of the hippocampus. Further tests were made to investigate whether these accumbens neurones could be activated antidromically by stimulation of either the ventral pallidal or subpallidal areas. More than 4 times as many accumbens neurones, activated by hippocampal stimulation, responded antidromically to stimulation of subcommissural ventral pallidum than to stimulation of the sublenticular subpallidal area. This observation suggests that the hippocampus has preferential inputs to accumbens efferent neurones which project monosynaptically to the ventral pallidum. Spontaneously active neurones in the ventral pallidum and subpallidal area were inhibited by stimulation of the ventral subiculum of the hippocampus. These inhibitory responses were reduced when glutamic acid diethyl ester, a glutamate antagonist, was microinjected into the medial accumbens, apparently blocking the hippocampal-accumbens glutamatergic synapses to both the ventral pallidal-directed and the subpallidal-directed accumbens efferents. This evidence suggests that signals from the hippocampus reach ventral pallidal and subpallidal regions by way of the nucleus accumbens. The presence of a projection from ventral pallidal and subpallidal regions to the brainstem mesencephalic locomotor region further supports the hypothesis that limbic (e.g. hippocampus) can influence somatomotor activities by way of the nucleus accumbens and its efferent projection to ventral pallidal and subpallidal regions.

Facilitation of self-stimulation of the prefrontal cortex in rats following chronic administration of spiroperidol or amphetamine.

The effect of chronic administration of spiroperidol, a dopaminergic antagonist, on self-stimulation of the prefrontal cortex was investigated. When spiroperidol was administered either before or after daily self-stimulation tests for 9 days, self-stimulation rates were significantly elevated for several weeks following withdrawal of the drug. Self-stimulation of the nucleus accumbens, supracallosal bundle, and other forebrain sites was not altered, suggesting that the increased self-stimulation of the prefrontal cortex was not due to increased motor activity. Self-stimulation of the prefrontal cortex was also facilitated by chronic administration of d-amphetamine whereas self-stimulation of the supracallosal bundle was suppressed and self stimulation of the nucleus accumbens was unchanged. The results suggest that dopamine modulates self-stimulation of the prefrontal cortex. Additionally, the effects of chronic spiroperidol on self-stimulation of this structure may model the therapeutic effects of neuroleptics in humans.

Electrophysiological evidence of modulatory interaction between dopamine and cholecystokinin in the nucleus accumbens.

Dopamine has been shown to modulate responses of accumbens neurones to excitatory inputs from the amygdala. The demonstration that cholecystokinin (CCK) co-exists and appears to be co-released with dopamine in the accumbens suggests that the modulatory action of dopamine in the accumbens may in turn be modified by CCK. This possibility was investigated in the present study. Single unit recordings were obtained in the medial and caudal accumbens of urethane-anaesthetized rats. These neurones were strongly excited by amygdala stimulation, and concurrent stimulation of the ventral tegmental area (VTA) at 10 Hz attenuated the responses, presumably due to dopamine release. Iontophoretic application of proglumide (PRG) at 30 nA enhanced the attenuating effect of VTA stimulation on the excitatory response to amygdala stimulation. Exogenous dopamine produced a similar attenuation in response and the attenuation was in turn suppressed by concurrent iontophoresis of sulphated CCK fragments applied at a current titrated not to produce significant effect on the spontaneous activity of the neurone nor its response to amygdala stimulation. These results demonstrate that exogenous and endogenous CCK can modify the postsynaptic action of dopamine in the nucleus accumbens in addition to modulating its release shown in other studies, and further suggests that CCK is likely an endogenous functional antagonist of dopamine, serving a comodulatory role in regulating synaptic transmission in the ventral striatum.

Electrical and chemical activation of the mesencephalic and subthalamic locomotor regions in freely moving rats.

The locomotor activity of freely moving rats was increased by electrical stimulation of brainstem sites, including the pedunculopontine nucleus, a major component of the mesencephalic locomotor region (MLR), and sites located in the subthalamic locomotor region (SLR), which is in the area of the zona incerta (ZI) dorsomedial to the subthalamic nucleus. Injections to the MLR of glycine, an inhibitory transmitter of the spinal cord and brainstem, had no effect on locomotion, nor did strychnine sulfate, a glycine antagonist. Unilateral injections of the excitatory amino acid, N-methyl-D-aspartic acid (NMDA), and kainic acid, a glutamate analogue, into the MLR produced an increase in locomotion not seen with glutamate, an excitatory amino acid, into the same area. A still greater response, having a later onset than NMDA but also a longer duration, was produced by administration of picrotoxin and bicuculline methiodide, GABA antagonists, to the MLR. Carbachol injections into the MLR produced two types of responses: either increased or decreased locomotion. Hypermotility resulted from microinjections of glutamate, and picrotoxin and bicuculline, into the ZI. The short latency, short duration response to glutamate resulted in a greater increase in locomotion than with picrotoxin or bicuculline when each was administered into the SLR. These results provide further evidence for the functional role of the MLR and SLR in the initiation of locomotor activity in the intact, freely behaving rat.

Inhibition of amphetamine-induced locomotor activity by injection of carbachol into the anterior hypothalamic/preoptic area: pharmacological and electrophysiological studies in the rat.

The effects of carbachol injected into the anterior hypothalamic/preoptic area on locomotion initiated by intra-accumbens injections of amphetamine were investigated. Changes of locomotion following intracerebral injections were measured in an automated activity box and the mean firing rate (m.f.r.) from neurons in the mesencephalic locomotor region (MLR) recorded in parallel acute electrophysiological experiments. Amphetamine (20.0 micrograms) injected to the nucleus accumbens caused a 2.5-fold increase in locomotion of rats. Subsequently, injections of carbachol (0.5 or 1.0 microgram) into the hypothalamic/preoptic area reduced the amphetamine-induced locomotion. These effects were stronger with ipsilateral than with contralateral injections and were reversed by pretreating the hypothalamic/preoptic area with 1.5 micrograms of atropine before carbachol injection. In electrophysiological experiments, injecting carbachol into the hypothalamic/preoptic area reduced the m.f.r. of MLR neurons from 8.3 +/- 0.7 to 4.1 +/- 0.5 per s and reduced the m.f.r. of 13 of 17 MLR neurons recorded continuously before and after injection. In contrast, injecting amphetamine into the nucleus accumbens increased the m.f.r. of units from 8.3 +/- 0.7 to 12.8 +/- 1.0 per s and increased the m.f.r. of 11 of 12 MLR neurons recorded continuously before and after injection. These results suggest that the hypothalamic/preoptic area contains muscarinic cholinoceptive areas which reduce locomotor activity by direct or indirect effects on the MLR.

Decrease of locomotor activity by injections of carbachol into the anterior hypothalamic/preoptic area of the rat.

Cholinergic elements in forebrain structures are implicated in locomotion but their role is still unclear. In the present study, the effects of intracerebrally injected carbachol or atropine on spontaneous locomotion and rearing activity were investigated. Effective injection sites were found in the area between frontal planes 5.3 and 6.3 mm from interaural plane and between the ventricle wall and lateral plane 1.1 mm from the midline which corresponds to the medial anterior hypothalamic/preoptic area. Injections of 1.0 micrograms of carbachol into this area decreased locomotor activity and rearing to one-third of the control level during the first 5 min of recording. These reductions of locomotion and rearing were dose-dependent and reversed by 1.5 microgram of atropine. Atropine alone, at this dose, had no effect on locomotion but higher doses (20.0-60.0 micrograms) of atropine produced a dose-dependent increase of locomotion. A comparison of the injection sites with recent maps of the cholinergic system indicates that muscarinic cholinoceptive, presumably non-cholinergic, cells throughout the medial AH/POA might be associated with a decrease of locomotor activity caused by intracerebral injections of carbachol.

Convergence of signals in the zona incerta for angiotensin-mediated and osmotic thirst.

Extracellular single-unit activity was recorded from 109 neurons in the diencephalon of urethane-anesthetized rats. Injections of angiotensin II (ANG II) into the subfornical organ (SFO) increased the activity of 15 zona incerta (ZI) neurons and decreased the activity of 9. Injections of ANG II into the SFO increased the activity of 8 lateral hypothalamic neurons and decreased the activity of 7. Of the units which responded to the injection of ANG II into the SFO, 9 neurons in the ZI and 5 in the lateral hypothalamus (LH) also responded to injections of hyperosmotic saline into the medial preoptic area. The SFO and preoptic area are possible sites of receptors for ANG II-mediated and osmotic thirst, respectively, and the present results suggest that signals important for the initiation of these thirst mechanisms converge on neurons in the ZI and LH. These findings are discussed in relation to other neural structures that have been implicated in the regulation of water intake.

Electrophysiological responses of neurones in the nucleus accumbens to hippocampal stimulation and the attenuation of the excitatory responses by the mesolimbic dopaminergic system.

Extracellular single unit recordings were obtained from neurones in the nucleus accumbens of urethane anaesthetized rats. Single pulse stimulation (300-800 microA, 0.15 ms, 0.5-1.5 Hz) of the ventral subiculum of the hippocampus strongly excited silent and spontaneously active (3-6 spikes/s) medial accumbens neurones. The majority of neurones excited by hippocampal stimulation were quiescent and identified only by the elicited action potentials. Neurones on the dorso-medial border of the nucleus accumbens and adjacent lateral septum, with a faster spontaneous discharge rate (8-12 spikes/s), were inhibited by hippocampal stimulation. In the ventral border of the accumbens and the olfactory tubercle, hippocampal stimulation also inhibited the fast-firing (greater than 20 spikes/s) neurones. When trains of 10 conditioning pulses (300-800 microA, 0.15 ms, 10 Hz) were delivered to the ventral tegmental area (VTA) 100 ms before each single-pulse stimulation of the hippocampus, the excitatory responses of the silent and spontaneously active accumbens neurones were attenuated. The possibility of this relatively prolonged attenuation effect being dopamine-mediated was supported by several lines of evidence. Dopamine, applied iontophoretically, reduced markedly the excitatory response of accumbens neurones to hippocampal stimulation. Iontophoretically applied dopamine mimicked the attenuating effect produced by VTA conditioning stimulation in the same neurone. The attenuating effects of VTA conditioning stimulation on the activation of accumbens neurones by hippocampal stimulation was reduced by: (1) administration of 6-hydroxydopamine to the VTA 2 days and 7-9 days prior to the recording session, (2) the intraperitoneal injection of haloperidol 1 h before the recording session, and (3) the iontophoretic application of trifluoperazine to accumbens neurones. These observations support the hypothesis that the attenuating effects of the mesolimbic dopamine system on limbic inputs to the nucleus accumbens may have a role in limbic-motor integration.

Inhibitory response of pallidal neurons to cortical stimulation and the influence of conditioning stimulation of substantia nigra.

Single pulse stimulation of the sensory motor cortex of rats anesthetized with urethane was observed to inhibit the activity of neurons in the globus pallidus. When a train of 10 pulses delivered to the substantia nigra, preceded the cortical stimulation, the inhibitory response was significantly reduced in 46 of 66 globus pallidus neurons tested. A single pulse stimulus to the substantia nigra had no effect on the inhibitory response of globus pallidus neurons to cortical stimulation. Similar interaction experiments were performed in rats treated with haloperidol (HPL), a dopamine antagonist, or with 6-hydroxydopamine. In such experiments a train of stimulus pulses delivered to the substantia nigra did not attenuate the inhibitory response of globus pallidus neurons to cortical stimulation, suggesting that the observed interactions are dopamine-mediated.

Reversible hyperphagia and obesity following intracerebral microinjections of colchicine into the ventromedial hypothalamus of the rat.

Colchicine, a drug which produces a reversible inhibition of intraaxonal transport and synaptic transmission, was used as a reversible neural blocker to investigate the role of the ventromedial hypothalamus (VMH) in the control of ingestive behavior and body weight regulation. Male Sprague-Dawley rats received intracranial microinjections of colchicine into the VMH. Volume and concentration of the colchicine solution were varied to assess specificity of action and dose-response relationship. When colchicine (2 and 4 microgram) was microinjected bilaterally into the VMH, there was a dose-dependent increase in food and water intakes and body weight gain which lasted several days. The acute period of hyperphagia was followed by a marked depression in feeding which persisted until body weight was lowered to control levels. This suppression of feeding appeared to be a consequence of the preceding period of hyperphagia and obesity, since colchicine-treated rats which were pair-fed with controls to prevent obesity continued to maintain normal food intake and body weight gain when later fed ad libitum. The results of this study confirm the importance of the VMH in the long term regulation of feeding, and indicate that reversible neuronal blocking with colchicine is a useful technique for investigating the neural substrates of feeding and other behaviors.

An electrophysiological study of inputs to neurons of the ventral tegmental area from the nucleus accumbens and medial preoptic-anterior hypothalamic areas.

Extracellular recordings were obtained from neurons in the ventral tegmental area (VTA) of urethane-anesthetized rats. Neurons were divided into two types based on the latencies of antidromic activation following electrical stimulation of the nucleus accumbens (NAcc), and on the durations of action potentials. Type A neurons had longer latencies for antidromic activation (mean 15.9 msec) and longer durations of action potentials (> 2.6 msec), while type B neurons had shorter latencies (mean 4.5 msec) and shorter duration of action potentials (< 2.6 msec). Electrical stimulation of the medial preoptic-anterior hypothalamic areas (mPOA-AHA) and NAcc produced the following effects on the two types of VTA neurons: (i) the majority of both type A and B neurons were suppressed by mPOA-AHA stimulation with onset latencies of less than 10 msec; (ii) 42% of type B neurons were also suppressed by NAcc stimulation, with onset latencies of less than 10 msec; (iii) type A neurons were suppressed (33%) or activated (43% by NAcc stimulation, the onset latencies usually being longer than 10 msec; (iv) 71% of type A neurons tested had convergent inputs from the mPOA-AHA and NAcc, usually suppressed-suppressed or suppressed-activated, while 45% of type B neurons had convergent inputs from these two areas, usually suppressed-suppressed.

Effect of picrotoxin and nipecotic acid on inhibitory response of dopaminergic neurons in the ventral tegmental area to stimulation of the nucleus accumbens.

Electrical stimulation of nucleus accumbens inhibited the activity of neurons in the ventral tegmental area (VTA). Inhibition was potentiated by nipecotic acid, a GABA uptake inhibitor, and was attenuated by picrotoxin, a GABA antagonist. Four units inhibited by nucleus accumbens stimulation were also antidromically activated. These observations suggest that neurons in the VTA, including specifically those projecting to the nucleus accumbens, receive a descending GABAergic input from that area.

Association of the mesencephalic locomotor region with locomotor activity induced by injections of amphetamine into the nucleus accumbens.

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.

An electrophysiological study of convergence of entopeduncular and lateral preoptic inputs on lateral habenular neurons projecting to the midbrain.

Extracellular recordings were made from single neurons in the lateral habenular nucleus of urethane-anesthetized rats. Single pulse stimulation of the entopeduncular nucleus influenced the spontaneous activity of 200 out of 293 (68%) lateral habenular neurons tested, with the most frequent response being suppression of activity and initial activation followed by suppression. Single pulse stimulation of the lateral preoptic area influenced the activity of 140 out of 165 (85%) lateral habenular neurons tested. Response were similar to those for entopeduncular stimulation. In a series of 137 lateral habenular units, 85 (62%) were influenced by stimulation of both sites indicating convergence of inputs from these two forebrain areas. Approximately half of the lateral habenular neurons which received converging inputs from entopeduncular nucleus and lateral preoptic area were activated antidromically by stimulation of the fasciculus retroflexus, indicating that they were output neurons. These electrophysiological findings support the suggestion from recent neuroanatomical studies that the lateral habenular nucleus is a site of integration for entopeduncular and limbic inputs and in turn sends signals to the midbrain.

Neuropharmacological and electrophysiological evidence implicating the mesolimbic dopamine system in feeding responses elicited by electrical stimulation of the medial forebrain bundle.

The contribution of the mesolimbic dopamine pathway to feeding behavior was investigated in rats in which feeding responses were elicited by electrical stimulation of the medial forebrain bundle at the level of the lateral hypothalamus. Injections of spiroperidol, a dopamine antagonist, into the nucleus accumbens ipsilateral to the stimulating electrode significantly attenuated the elicited feeding responses whereas injecting spiroperidol into the contralateral nucleus accumbens had no effect. The spontaneous discharge rates of neurons of the ventral tegmental area, identified by their electrophysiological characteristics as dopaminergic, were both increased and decreased in response to single pulse stimulation of sites in the medial forebrain bundle from which feeding responses had been elicited. These observations suggest that mesolimbic dopaminergic neurons may have a role in feeding behavior and indicate the need for chronic electrophysiological recording experiments to see whether or not the activity of these neurons is correlated with the initiation of elicited and spontaneous feeding responses.