Download - The role of GABA in the ventromedial hypothalamic regulation of food intake

Brrrin Resrarch Bulkrin, Vol. 5, Suppl. 2, pp. 453-460. Printed in the U.S.A

The Role of GABA in the Ventromedial Hypothalamic Regulation of Food Intake’

JAAK PANKSEPP

Department of Psychology, Bowling Green State Utriversiry, Bowling Green, OH 43403

AND

R. B. MEEKER

Department of Phar~ucol#gy and Psychiatry, university of North Carolina, Chapel Hill, NC 27514

PANKSEPP, J, AND R. B. MEEKER. The role of GABA in rhe v~~tfr(~~edj~l ~~!~~~t~ul~r~i~ re~M~~~~~~~ oJ:fbod inttrke. BRAIN RES. BULL. 5: Suppl. 2, 453-460, 1980.-The rat hypothalamus was mapped for sites in which metabolic substrates (D-glucose, beta-hydroxybutyrate), amino acids (GABA. glutamate, glutamine, gamma-hydroxybutyric acid) and pharmacological GABA manipulations (amino-oxyacetic acid (AOAA). bicuculline) altered feeding behavior in ad lib fed male Long-Evans rats. In a region along the base of the brain lateral to the ventromedial nucleus in which D-glucose injections decreased daily food intake, both GABA and AOAA produced immediate decreases in food intake, which after AOAA continued for 24 hr. Blockade of GABA receptors with bicuculline increased 24 hr intakes. Food consumption was relatively unaffected following 1SSmM saline, L-glucose, beta-hydroxybuty~te, and glutamine injections into this area. GABA manipulations also affected feeding following administration into the ventromedial nucleus proper and into the perifornicai area in the anterior hypothalamus, but the effects were not as consistent as injections into the basolateral Ventromedial hypothalamus (BVMH). The data support the existence of cells within the BVMH which are sensitive to glucose metabolism and which may encode metabolic i~ormation through the formation of glutamate and GABA via substrate entry into the GABA shunt. Since flow through GABA shunt parallels the flow of energy through the tricarboxylic acid cycle, a direct link between energy metabolism and functional neural activity could be maintained.

Ventromedial hypothalamus GABA Glucose Bicuculline Feeding -I__-.____--

THE relative stability of energy intake and expenditure in mammals should ultimately be mediated through a linkage between the energy yielding processes of intermedi~y metabolism and the firing patterns of neural circuits which control food-seeking behaviors 127,301. Since glucose is almost the exclusive metabolic substrate for brain activity in well-fed animals, as weII as a common denominator for peripheral energy metabolism, much research during the past 25 years has been devoted to determining whether availability of glucose controls feeding behaviors. Although there is a subs~ntial amount of indirect evidence indicating that both medial and lateral areas of the hypothalamus could control feeding in response to glucose availability [S, 8,9,23, 24, 28, 301, except for the existence of glucoreceptors [24], the manner in which this control might be exerted remains unknown. However, the existence of glucoreceptors in the hy~~~arnus has yet to be rigorously linked to feeding behavior, and most investigators have encountered difficulties in decreasing feeding by direct application of glucose into the hypothalamus. Accordingly, it is possible that these receptors participate more in brain control of blood glucose and liver carbohydrate homeostasis than directly in the control of feeding.

More direct evidence for glucose sensitive elements which may be important to the regulation of feeding is provided by studies in which gold-thioglucose (GTG), injected either systemically or directly into the ventromedial

hypothalamus (VMH), produces a syndrome of overeating and obesity similar to the classic ventromedial hypothalamic syndrome [S, 9, 451. Although the precise reason for the selective damage of the VMH by GTG remains unclear [6,7, 1 I], it seems likely that something unique about the giucose utilization of this part of the brain exerts regulatory controi over food intake. Indeed, the present work was premised on the specific hypothesis that glucose catabolism in the area may be functionally linked to the control of feeding circuits by the capacity of some VMH neurons to synthesize neuroactive amino acids from intermedi~y carbohydrate metabolism which can subsequently provide inhibitory control over long-term food intake [313.

Our thinking about this possibility evolved from a recog- nition that the traditional notion of the medial hypothalamus mediating short-term satiety is incorrect 1251, the evidence being substantially more consistent with the possibility that the VMH elaborates a neuro-metabolic process which is es- sential for the long-term stability of body energy 126,301, Our studies of medial hypothalamic nutrient disposition and metabolism suggested that this area processed glucose differently than adjacent hypothalamic areas 128, 31, 36,371, and this led us to evaluate the long-term feeding effects of glucose injections into this area. Indeed, glucose administered directly into the basal VMH decreased daily food intake while having little effect on immediate post-injection feeding behavior [28, 34, 361. Since the behavioral effects

Copyright 8 1980 ANKHO rnte~ationa1 Inc ,-0361-9230/80/08~53-08$01.30/O

454 PANKSEPPANDMEEKER

TABLE 1 SUBSTANCES~NJECT~NTOTHE HY~THALAMuS

Compound Concentration pH Desired CNS action

D-Glucose solid - Normal energy substrate B-hydroxybutyrate solid - Alternative energy substrate L-Glucose solid - Contro~nonmeta~lizable hexose

GABA 100 nMol/pl 7.1 Putative transmitter

Glutamate 100 nMoVp1 7.2 Intermediate of GABA shunt Glutamine 100 nMoU$ 6.8 Intermediate of GABA shunt 155 mM NaCl 7.0 Control

AOAA 20 nMoU,uI 7.4* Long-term elevation of GABA levels Bicuculline 10 nMol&l 7.0t GABA receptor antagonism ~-hydroxybuty~te 100 nMol&l 7.8 Inhibition of amino acid synthesis

from glucose

155 mM NaCl 7.0 Control

*pH of aminooxyacetic acid adjusted with NaOH. tlnfused as a fine saline suspension.

occurred long after the glucose should have been metabolically disposed of, it appeared that the reduced feedings was dependent on some aspect of hypothalamic carbohydrate metabolism rather than the structure of the glucose molecule itself.

Concurrently it was observed that feeding decreased following injections of amino acids into the hypothalamus [33], especially by neuroactive amino acids which could be de- rived from glucose metabolism, for instance glycine and alanine, The effects were largest following injections into the VMH, but smaller reductions were also seen in animals with bilateral placements in the lateral hypothalamus [28,31]. Contrary to glucose administration, however, amino acids suppressed feeding during the first meal following treatment. Taken together, these results suggested the existence of a hypothalamic feeding regulatory mechanism whereby metabolic i~o~a~on could be directly transformed into long-term functional information at the synapse.

Although a vast number of neurochemical manipulations can affect feeding [19,38], as can a vast number of internal and external stimuli [321, the linkage between energy metabolism and the generation of amino acids provides a rather simple mechanism whereby energy production, not only from present energy stores but from past food ingestion, could be (or have been) encoded into regulatory control of feeding. Although all the neuroactive amino acids which emanate from intermediary metabolism of carbohydrates [ 12,401 could provide such regulatory input, the unique pres- ence of the GABA shunt situated in parallel with brain Krebs cycle energy tlux [2,42] is in an ideal position to monitor and integrate cardinal energy transactions of the brain and body 118,313. To determine whether such a regulatory system exists, we measured feeding changes in the rat following microinjection of metabolic substrates, GABA shunt intermediates, and related pharmacological compounds into lo- calized areas throughout the hypothabunus. Special atten- tion was devoted to the basal VMH where long-term feeding in~bito~ effects of glucose injections had been previously detected.

METHOD

Subjects

A total of 151 male Long-Evans rats were used in these experiments. Individual animals were housed in stainless steel wire mesh cages with continuous ad lib access to food and water. Each rat was adapted to feeding from a food jar which was refilled with powdered Wayne lab chow every fourth day. This insured a stable feeding baseline at the out- set of each experimental manipulation. The colony room was maintained at 23 * 1°C on a I2:12 hr 1ight:dark cycle.

Surgery

Bilaterally symmetrical 23 ga stainless steel cannulae were stereotaxicahy positioned above hypothalamic target sites ranging from the preoptic area to the premammilIary region while animrds were under ~nto~bi~ anesthesia (40 m&kg). These guides were sect&y anchored to the skull with dental cement and were kept patent with solid stainless steel inserts which extended the length of the guide tubes. At least one week was allowed for recovery from surgery before testing.

A summary of the compounds infused into the hypothalamus is provided in Table 1. The first group received endogenous metabolic substrates in order to test the sensitivity of each region to energy availability. The second group received three primary intermediates associated with the GABA shunt-aunt, glutamine and GABA. The third group was infused with compounds which either phar- macologicaIly or metabolically interfere with the function of neuronal systems which might use GABA as a transmitter. Aminooxyacetic acid (AOAA) exerts a long-lasting inhibitory action on GABA-transaminase, the enzyme which metabolizes GABA to succinyl CoA. A gradual long-term elevation of brain GABA levels consequently results 1391. Bicuculline, on the other hand, blocks the action of GABA at

GABA, VMH AND FEEDING

the synapse. Gamma-hydroxybutyrate has been reported to interfere with glucose metabolism and the related synthesis of amino acids [ 13,481.

Each infusion was made bilaterally in volumes of 1.0 ~1 with the aid of a 28 ga stainless steel injection needle con- nected to a 10 ~1 Hamilton syringe. In an effort to provide long-term exposure to the substrate materials, a sterile hol- low stainless steel injector filled with solid substrate was lowered to the appropriate depth and left in place for a period of 24 hours. A quantity of 32 ? 5 pg diffused from the tip over that time period.

Behavioral Measures

In order to assess the effects of each manipulation on normal ongoing regulation, all infusions were made in ad lib fed rats. Food intake, fluid intake and body weight measurements were recorded at 1, 2,4, 24,48 and 72 hr intervals. Injections were always made 24 hr after a food cup refill and approximately two hours prior to the onset of the dark cycle (20:00 hr). This procedure maximized the stability of food intake over the following three day period and, in addition, allowed the assessment of the short-term behavioral effects during the rat’s most vigorous feeding period. Both increases and decreases in food intake resulting from each compound were analyzed by comparison with their respective control infusions.

Histological Analysis

After the termination of testing, each rat was perfused through the left ventricle of the heart with 10% Formalin. The brain was removed and stored in 10% Formalin. Sec- tions 40 Jo thick were cut from each brain according to De Groot [lo] orientation through the extent of tissue damage. Based on histological analysis, animals were divided into anatomical subgroups so that group comparisons could be performed in addition to maps of individual animal re- sponses.

RESULTS

Diagrams of the neuroanatomical distribution of sites within the hypothalamus sensitive to D-glucose, GABA, bicuculline, aminooxyacetic acid, and gamma-hydroxybutyrate are provided in Figs. 1 and 2. Each solid symbol in the left of each section represents the approx- imate area from which a significant short-term (1-4 hr) or long-term (24 hr) effect on food intake was noted following a single microinjection. Open symbols on the right represent injection sites which did not yield results larger than 2 standard deviations from baseline conditions.

As Fig. 1 illustrates, there is a clustering of glucose- sensitive sites within three regions: the perifomical area (at A 5.8), the ventral premamillary area (at A 5.0) and near the ventrolateral tip of the ventromedial nucleus (at A 5.8-6.2). Of these, only the basolateral VMH injections produced long-term effects on food intake.

Sites sensitive to GABA (decreased food intake) and bicuculline (increased food intake) (Fig. 1) exhibited a clustering pattern similar to that for glucose. The highest density of clustering in both cases was in the basolateral VMH and throughout the perifomical region. A high density overlap of sites sensitive to glucose, GABA and bicuculline is most notable at AP 5.8-6.2 [lo] in the basolateral VMH. There were a number of relatively ineffective sites at these anatom-

1

5.8 1

FIG. 1. Hypothalamic sites at which glucose decreased (O), GABA decreased (V) and bicuculline increased (m) food intake. Solid symbols on the left represent intakes greater than 2 standard deviations from baseline at 1, 2, 4, or 24 hr measurements. Open symbols on right indicate that intakes were less than 2 standard deviations from

baseline values.

FIG. 2. Hypothalamic sites at which AOAA decreased (V) and y-hydroxybutyrated increased (W) food intakes. Solid and open symbols depict changes which were more or less than 2 standard

deviations from baseline values, respectively.

ical groupings suggesting either that certain animals are more sensitive to these manipulations, that differential diffusions occurred at different injection sites, or that the sensitive systems are geometrically organized so that small changes in placement have large effect on how well relevant synapses are perfused.

AOAA and gamma-hydroxybutyrate decreased and increased food intake respectively when infused into the sites summarized in Fig. 2. Again, the basolateral VMH proved to be highly sensitive to both compounds. A large number of infusions into the perifomical region were also effective in altering food consumption. Four sites in the preoptic-

456 PANKSEPP AND MEEKER

TABLE 2

FOOD INTAKE DEVIATIONS FROM CONTROL BASELINES (g) FOLLOWING MICROINJECTIONS INTO TEN REGIONS OF ‘THE HYPOTHALAMUS

Group I

Mean control intakes (g) D-Glucose ,&HB GABA

Group II Group III

Glutamate Glutamine AOAA Bicuculline y-HB

CA-ACB 1 hr +0.9 ( 9)

24 hr 17.6

AHA-T’GA 1 hr 1.2 (11)

24 hr 19.0

PVH-AHA I hr 1.2 (14)

24 hr 25.8

LHA I hr 2.1 ( 6)

24 hr 21.0

ZI 1 hr 1.4 (14)

24 hr 25.0

VMN 1 hr 1.6 (10)

24 hr 26.6

Basolateral VMH I hr 2.1 (20)

24 hr 26.7

PMV I hr 3.0( 7)

24 hr 29.3

PH 1 hr 1.3 (17)

24 hr 23.6

3rd ventricle 1 hr 1.1 (12)

24 hr 24.3

- -

- -

+1.2 ( 3) +2.5 ( 3)

+o.f? ( 3) +7.1

+1.1 ( 3) +3.2

+0.4 ( 6) +1.2 ( 6) -1.9 -0.6

+0.6 ( 6) 0.0

-0.2 ( 4) +2.4

-0.5 ( 4) -0.6

0.0 ( 7) +I.3

- - - -

-0.3 ( 5) +0.8

-0.1 ( 5)

-2.0 -0.4 ( 5) -0.8

-0.9 ( 5) -5.3*

+0.6 ( 4) +0.7 ( 4) +1.5 +3.6

+0.2 ( 4) -0.4

.+0.1 ( 3) +8.5

-0.9( 3) +6.6

-1.6( 3) i-o.9

O.O( 3) i-1.6( 3) -10.0 -5.2

+0.4 ( 3) -4.6 -

- -

-0.2 ( 8} -1.9

-0.2 ( 8) -0.2

+0.6 ( 6) +1.4

+0.3 ( 6) -1.8

0.0 ( 6) i-1.5

- -

-0.8 ( 4)* 12.9

+1.3 ( 4) -4.5*

-0.7 ( 4) +1.9

-0.4 ( 6) -0.5 ( 6) +0.1 +6.5*

-0.7 ( 6) -3.2 -

- -

-0.4 ( 8) -4.1*

+0.2 ( 8) -0.6

+0.2 ( 5) i4.1

-2.5 ( 7)* +0.4 ( 7) - 10.0* +4.4*

-I.O( 5)*

-1.6 -0.4 ( 5) -0.1

+0.2 ( 7) +4.9*

-1.8( 7)* -2.4

-1.6 ( 7)* -0.8

- - - -

+os (10)

+2.4 -0.1 (IO)

+1,7 -1.3 ( 4)* +0.8

-l.O( 4) +1.2

-l.Z( 4) -3.0

+o.i ( 3) 0.0 ( 3) +1.4 +1.2

+0.4 ( 3) +0.4

co.3 ( 4) -0.7

+0.9 ( 4) -0.3 f 4) +_5.1 +1.7

+0.3 ( 4) +1.4

+0.2 ( 4) -4.4

to.2 ( 4) i-2.7

+0.6 ( 4) i2.5

+1.5 ( 4) -2.3

*1>‘s<O.05, n’s indicated in parentheses.

the ventral premammillary region, both D-glucose and P_hydroxybutyrate suppressed one hour food intake (down 53-60%) but had no effect in subsequent intervals. Infusions of GABA and glutamate into the ventromedial nucleus (VMN) decreased one hour food intake (down 50%) and 24 hr (down 17%) intakes respectively. Bicucu~ne, on the other hand, increased (up 24%) 24 hr intakes when infused into the VMN. Finally, the basolateral VMH was the only area in which both D-glucose and manipulations of GABAminergic function altered food intake. A significant decrease of intake was noted after four hours of exposure to D-glucose which continued to a maximum after 24 hr (intake down 15%). Within this same region, GABA suppressed one hour food intakes (down 48%), while AOAA produced a profound decrease in food intake at all intervals, reaching a maximum at 24 hr (down 37%). The GABA antagonist, bicuculliue, pro- moted elevated food intakes which were maximal after 24 hr (up 16%). G~ma-hydroxybut~te similarly produced an

suprachiasmatic region and five sites in the region bordered by the posterior hypothalamus and zona incerta resulted in elevated food intakes when gamma-hydroxybutyrate was infused.

It is clear from Figs. 1 and 2 that there is extensive overlap of glucose, GABA, bicu~u~~e~ AOAA and gamma- hy~xybutyrate within the basolateral VMH. Twenty-three of 27 infusions within this region affected food intake. In almost every case, glucose, GABA and AUAA suppressed feeding while bicuculline and gamma hydroxybutyrate enhanced feeding. In the perifornical region, 20 of 31 infusions resulted in altered food intake.

A summary of the actual magnitude of changes in food intake for 10 different hypothalamic areas is provided in Table 2. Changes in food intake after one hour reflect the immediate effects of each compound whereas the 24 hour intakes reflect the long-term effects. Of all the areas, only three were associated with consistent changes in feeding. In

GABA, VMH AND FEEDING 457

PVH - AHA

1 2 4 24

HOURS AFTER INJECTION

FIG. 3. Cumulative changes in feeding (experimental-control) following administration of indicated substances into the paraventricular-anterior hypothalamic area. Reliable (pcO.05 and

greater) changes are indicated by asterisks.

elevation in 24 hr intakes (up 18%). In addition to the a- bove areas, GABA suppressed food intake in the paraventricular-anterior hypothalamic region (PVH-AHA) and in the posterior hypothalamus, but no other compounds were effective. The far lateral hypothalamus also appeared to be sensitive to GABA and related compounds, but high variability and a small number of subjects prevented any conclusions from being reached.

A comparison of the temporal patterns of feeding elicited by microinjection of the eight compounds into the PVH- AHA is provided in Fig. 3. All compounds were within t2 g of the control baseline except GABA and bicuculline which diverged markedly at 24 hr. This pattern of results can be contrasted with the pattern in Fig. 4 which summarizes the effects of infusions into the ventromedial nucleus. Bicucul- line and glutamate produced a differential long-term shift in food intake similar to that of bicuculline and GABA in the PVH-AHA. GABA was only effective in altering the 1 hr food intake.

Again, the only hypothalamic region which was associated with strong and consistent alterations in feeding across all drug conditions was the basolateral VMH. The 1, 2, 4 and 24 hr intakes are summarized in Fig. 5. With the exception of the transient depression of food intake after an infusion of GABA, all the significant effects on feeding were expressed as gradual decreases (D-glucose and AOAA) or increases (bicuculhne and gamma-hydroxybutyrate) in feeding which reached a maximum somewhere between 4 and 24 hr after injection.

GENERAL DISCUSSION

The results are compatible with the existence of cells in the basal ventromedial hypothalamus (BVMH) which monitor and integrate metabolic flux through the Krebs cycle by synthesis of GABA. The infusion of GABA and AOAA into the VBMH reduced food intake while blockade of GABA receptors with bicuculline increased feeding, as one would expect if GABA is functioning as an inhibitory transmitter in feeding control circuits. Manipulations which altered substrate availability (D-glucose) or utilization

+6 c VMN I

1 2 4 24

HOURS AFTER INJECTION

FIG. 4. Cumulative changes in feeding (experimental-control) following administration of indicated substances into the ventromedial nucleus of the hypothalamus. Reliable (p<O.O5 and greater) changes

are indicated by asterisks.

(gamma-hydroxybutyrate) or pharmacologically protected GABA (AOAA) all produced graded changes in feeding which reached a maximum 4-24 hr after infusion. The observation of such gradual changes is important for two reasons. First, the behavior mimics the regulatory adjustments seen after intragastrically delivered glucose, that is, there is a feeding inhibition which accumulates across the span of several meals [4,27]. Second, feeding was never totally inhibited indicating that the BVMH system probably serves as a buffer or regulator of feeding by shifting the satiating capacity of individual meals up or down [29]

The glucose induced reduction in daily food intake in the BVMH is congruent with a metabolic interpretation. If one assumes that most of the substrate was restricted to one cubic millimeter of tissue, then the disappearance of 32 pg of glucose over a 24 hr period represents an average rate of 0.123 nMol/mg/min glucose lost to the site. Under normal conditions the glucose utilization of the hypothalamus has been reported to be approximately 0.61 nMol/mg/min [46]. Thus the exogenous glucose we administered represents only 20% of the total daily glucose metabolized at the site. This figure compares favorably with the 15% suppression of feeding which resulted from the infusion. Sufficient data is not yet available for a precise assessment of this relationship, but the correspondence seems sufficiently accurate that a dose-response analysis might demonstrate close to a 1: 1 relationship between exogenous glucose added to the site and the resulting suppression of food intake. Beside the immediate formation of synaptically active amino acids, this part of the brain could further integrate metabolic information by local lipid and glycogen synthesis. Gradual with- drawals from these metabolic buffers (in GABA currency) could further help balance total body energy intakes and expenditures across the time span of several meals, or days.

It is worth noting that even though the in vivo utilization of glucose (or at least of 2-deoxyglucose) is low in the hypothalamus as compared to other brain areas [44,46], the relative conversion of (U-14C)-d-glucose to 14-C-GABA is unusually high [2 I]. In addition, regional analyses of GAB A

+I D-Glucose n -8

PANKSEPP AND MEEKER

BASOLATERAL VMH

I Bicuculline n.7 I

r- Hydroxybutyrate

z +3L Alnlnooxyecetlc ACM n=7 0 Glutamate n = 5 0 Glutamine n I 5

4 0 ._______________________________---

2 3

-3. ?‘f *l _.

.

HOUR AFTER INJECTION

FIG. 5. Cumulative changes in feeding (experimental-control k SEM) following administration of indicated substances into hypothalamic tissue just basolateral to the ventromedial nucleus. Reliable

CpCO.05 and greater) changes are indicated by asterisks.

content support the idea that the VMH has greater than average GABA activity [20]. The neuroanatomical localization of the glucose-GABA sensitivity corresponds highly with the region where gold thioglucose [8, 9, 451 and electrolytic lesions [IS] produce a profound regulatory dyns~~tion char- acterized by hyperphagia and obesity. Also, electrical stimulation of the medial hypothalamic region suppresses food intake, with the region of highest sensitivity located near the basolateral border of the VMN [3). It seems unlikely to be a coincidence that the primary effects of so many different manipulations have converged on a rather discrete region in the BVMH.

The cytoarchitecture. of the BVMH region is organized such that a lateral to medial and ventral to dorsal flow of information might be expected. Following gold thioglucose treatment, the anterogmde degeneration follows a path from

the ventrobasal hypothalamus into the perifomical and anterior hypothalamic regions [ 1 J. Millhouse has demonstrated the existence of a dense network of dendrites which extend from the outer portions of the VMN in a ventrolateral direc- tion 1221. A knife cut in the saggital plane would presumably disrupt these fibers, and result in overeating and the development of obesity [43]. It is possible that synapses impinging on these fibers in the basolateral VMH may utilize GABA as a primary transmitter.

Although glucose and GABA manipulations in the BVMH yielded an internally coherent pattern of results, GABA manipulations at several other sites yielded internal inconsisten- cies. For instance, while injections of bicuculhne into the VMN increased feeding and GABA reduced feeding, AOAA (which had a robust inhibitory elect ventrolateral to the nucleus) produced a slight increase in feed&g. A similar pattern

GABA, VMH AND FEEDING

of results was observed from PVH-AHA injection sites. Al- though this suggests that GABAminergic feeding control synapses (perhaps from BVMH axons) may reside in various parts of the hypothalamus, the pattern of results is confus- ing. However, these effects may be explicable if GABAminergic synapses in the VMH and perifomical areas both inhibit and disinhibit feeding (e.g. by inhibition of excitatory intemeurons in feeding circuits, as depicted in Fig. 9 of [26]).

In a similar manner, our results might be brought in line with the feeding induction observed by Kelly and colleagues [17] following GABA administration into the VMN and by Grandison and Guidotti [ 141 following muscimol injections into this area. Perhaps our observation of a small increase in feeding from these sites following AOAA indicates that our VMN cannulae are in a functionally heterogenous zone which contains both excitatory and inhibitory feeding control circuits [26].

In any case, the results with BVMH placements are the most noteworthy of the present work: The anticipated effects were obtained from cannulae placements in brain tissue thought to contain body energy detectors [30]. Thus, our working hypothesis is that GABA is the transmitter for metabolic detector cells of the BVMH, but there is one piece of data incompatible with that possibility. Katoka and colleagues [16] have reported that electrolytic lesions of the VMH reduce glutamic acid decarboxylase (GAD) levels in distant areas (e.g. septum) while goldthioglucose lesions do not reduce septal GAD nor medial hypothalamic GAD. Those results suggest that, if anything, GABA neurons must be situated postsynaptically to the GTG sensitive metabolic detectors of the VMH.

Whether BVMH GABA cells are small intemeurons or have long axons is not yet known. However, if GABA-coded metabolic information detection is restricted to the BVMH, then other feeding control circuits which rely on GABA synapses must also exist-namely those which are confluent with the perifomical hypothalamus and substantia nigra [ 171.

459

Indeed, in addition to a BVMH long-term regulatory system, amino acid based feeding control systems may be a common feature throughout the neuroaxis of brain feeding circuitry, perhaps as a segment of a relatively non-specific brain mod- ulator process. Since some amino acids (glutamine, aspartic and cystic acids) can depolarize neurons in widespread parts of the brain, while others (GABA, glycine, alanine) hyper- polarize neurons of diverse systems, these substances could change feeding by a general modulation of central nervous system tone.

Still, the present results are compatible with the idea that a very specific body energy regulatory function may be mediated by hypothalamic GABA systems. The parallel relationship between GABA levels and glucose metabolism provides a logical linkage between the metabolic utilization of nutrient materials and compensatory adjustments in feeding behavior. However, before this logical linkage can be accepted as physiological reality, it needs to be determined whether the feeding inhibitory effect of glucose infusions into the BVMH can be inhibited by either GABA receptor blockade or by inhibition of glucose entry into GABA shunt intermediates. If such experiments can affirm the existence of a GABA mediated body energy regulatory system, subsequent work might be able to elucidate the interaction of these systems with other nearby neurochemical systems in the VMH [ 14, 19, 471 which are likely to be important for the overall regulatory process to operate.

ACKNOWLEDGEMENTS

This research was supported by National Institute of Health grant AM 17157 and NIMH Research Scientist Development Award MH-00086 to J. P. This paper is partially based on a dissertation submitted by R. M. in partial fultillment of a Ph.D. degree at B.G.S.U. in 1976. A summary of the work was presented at the Sixth International Conference on the Physiology of Food and Fluid Intake, July 25-28, 1977, Pairs-Jouy en Josas, France.

REFERENCES

1. Arees, E. A. and J. Mayer. Anatomical connections between medial and lateral regions of the hypothalamus concerned with food intake. Science 157: 1574-1575, 1967.

2. Balazs, R., Y. Machivama. B. J. Hammond. T. Julian and D.

3.

4.

5.

6.

7.

8.

Richter. The operation of ‘the y-aminobutyrate bypath of the tricarboxylic acid cycle in brain tissue in vitro. B&hem. J. 116: 445-461, 1970. Belt& B. M. and R. E. Keesey. Hypothalamic map of stimulation current thresholds for inhibition of feeding in rats. Am. J. Physiol. 229: 1124-l 133, 1975. Booth, D. A. Satiety and behavioral caloric compensation following intragastric glucose loads in the rat. J. camp. physiol. Psychol. 78: 412-432, 1972. Booth, D. A. Neurochemistry of appetite mechanisms. Proc,. Nutr. Sot. 37: 181-191, 1978. Caffyn, Z. E. Early vascular changes in the brain of the mouse after injections of gold thioglucose and pipiperidyl mustard. J. Path. 106: 49-56, 1972. Caffyn, Z. E. The inhibition of gold thioglucose and pipiperidyl mustard-induced hypothalamic lesions by anti-inflammatory agents. J. Path. 106: 57-63, 1972.

10. De Groot, J. The rat forebrain in stereotaxic coordinates. Vet-h. K. ned. Akad. Wet. 52: l-40, 1959.

11. Epstein, A. N., S. Nicolaidis and R. Miselis. The glucoprivic control of food intake and the glucostatic theory of feeding behavior. In: Neural Integration of Physiological Mechanisms and Behavior, J. A. F. Stevenson Memorial Volume, edited by G. J. Mogenson and F. R. Carlaresu. Toronto: Univ. ofToronto Press, 1975.

12. Gaitonde, M. K., D. R. Dahl and K. A. C. Elliott. Entry of glucose carbon into amino acids of rat brain and liver in vivo after injections of uniformly 14C-1abelled glucose. Biochem. J. 94: 345-352, 1%5.

13. Godin, Y., J. Mark and P. Mandel. The effects of 4-hydroxybutytic acid on the biosynthesis of amino acids in the central nervous system. J. Neurochem. 15: 1085, 1091, 1977.

14. Grandison, L. and A. Guidotti. Stimulation of food intake by muscimol and beta endorphin. Neuropharmucology 16: 53% 536, 1977.

Debons, A. F., I. Krimsky, A. From and R. J. Cloutier. Gold thioglucose induction of obesity: significance of focal gold de-

15. Hetherington, A. W. and S. W. Ranson. The spontaneous ac-

posits in hypothalamus. Am. J. Physiol. 219: 1403-1408, 1970. tivity and food intake of rats with hypothalamic lesions. Am. J. Phvsiol. 136: 609-617, 1942.

9. Debons, A. F., I. Krinksy, H. J. Likuski, A. From and R. J. Cloutier. Gold thioglucose damage to the satiety center: inhibition in diabetes. Am. J. Physiol. 214: 652-6581 1968.

460 PANKSEPPANDMEEKER

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

Katoka, K., H. Danbara, K. Sunayashiki, S. Okuno, M. Sorimachi and M. Tanaka. Accumulation of gold in the ventromedial hypothalamus of the brains of gold thioglucose-obese mice, and the level of transmitter enzymes. In: Foodfntu~e am/ C‘hrmicul Senses, edited by Y. Katsuki, M. Sato, S. F. Takagi and Y. Oomura. Tokyo: Univ. of Tokyo Press, 1977. Kelly, J., G. F. Alheid, A. Newberg and S. P. Grossman. GABA stimulation and blockade in the hypothalamus and mid- brain: effects on feeding and locomotor activity. Phurmcrr. Biochem. Behav. 7: 537-541, 1977. Kimura, H. and K. Kuryama. Distribution of gamma- aminobutyric acid (GABA) in the rat hypothalamus: functional correlates with activities of appetite-controlling mechanisms. J. Nrurochem. 24: 903-907, 1975. Leibowitz, S. F. Neurochemical systems of the hypothalamus in control of feeding and drinking behavior and water- electrolyte excretion. In: Handbook ofthe Hypothalamus, Vol. 3A. Behuvioral Studies of rhe Hypothalamus, edited by P. J. Morgane and J. Panksepp. New York: Marcel Dekker, Inc., 1980, (In Press). Makar, G. B., Gy. Rappay and E. Stark. Autoradiographic localization of “H gamma-aminobutyric acid in medial hypothalamus. Expl Brain. Res. 22: 44W.55, 1975. Meeker, R. and R. D. Myers. In vivo i4C amino acid profiles in discrete hypothalamic regions during push-pull perfusion in the unanesthetized rat. Neuroscience 4: 495506, 1979. E. 0. Millhouse. A golgi anatomy of the rodent hypothalamus. In: Handbook of the Hypothalamus, Vol. I: Anutomy of the Hypothalamus. edited by P. J. Morgane and J. Panksepp. New York: Marcel Dekker, Inc., 1979, (In Press). Novin, D., M. F. Gonzalez and J. D. Sanderson. Paradoxical increased feeding following glucose infusions in recovered lateral rats. Am. J. Physiol. 230: 1084-1089, 1976. Oomura, Y. Input-output organization in the hypothalamus re- lating to food intake behavior. In: Handbook of the Hypothalamus, Vol. 2, Physiology of the Hypothalamus, edited by P. J. Morgane and J. Panksepp. New York: Marcel Dekker, Inc., 1980, (In Press). Panksepp, J. Is satiety mediated by the ventromedial hvnothalamus? Phvsiol. Behav. 7: 381-384. 1971. P&sepp, J. A re:examination of the role of the ventromedial hypothalamus in feeding behavior. Physiol. Behav. 7: 385-394, 1971. Panksepp, J. Effects of fats, proteins and carbohydrates on food intake in rats. Psychon. Monogr. Suppl. 4: (5) (Whole No. 53), 1971. Panksepp, J. Hypothalamic radioactivity after intragastric glucose-ilC in rats. Am. J. Physiol. 223: 396-401, 1972. Panksepp, J. A reanalysis of feeding patterns in the rat. J. camp. physiol. Psychol. 82: 78-94, 1973. Panksepp, J. Hypothalamic regulation of energy balance and feedine behavior. Fedn. Proc. 33: 115&1165. 1974. PanksLpp, J. Central metabolic and humoral factors involved in the neural regulation of feeding. Pharmac. Biochem. Behav. Suppl. I. 3: 107-l 19, 1975. Panksepp, J. On the nature of feeding patternsprimarily in rats. In: Hunger: Basic Mechanisms and Clinical Implications, edited by D. Novin, G. Bray and W. Wyrwicka. New York: Raven Press. 1976.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

Panksepp, J. and D. A. Booth. Decreased feeding after injections of amino acids into the hypothalamus. ,Yarrrre 233: 341- 342, 1971. Panksepp, J. and R. Meeker. Suppression of food intake in diabetic rats by voluntary consumption and intrahypothalamic injection of glucose. Physiol. Behar. 16: 763-770, 1976. Panksepp, J. and D. M. Nance. Insulin, glucose and hypothalamic regulation of feeding. Phvsiol. Behal,. 9: 447-451. 1972. Panksepp, J. and D. M. Nance. The hypothalamic “C differential and feeding behavior. Bull. Psychon. Sec. 3: 325-327, 1974. Panksepp, J. and P. Reilly. Medial and lateral hypothalamic oxygen consumption as a function of age, starvation and glucose administration in rats. Bruin Res. 94: 133-140, 1975. Panksepp, J., P. Bishop and J. Rossi III. Neurohumoral and endocrine control of feeding. Ps~~choneuroendocrirzolo~~ 4: 89-106, 1979. Perry, T. L. and S. Hansen. Sustained drug-induced elevation of brain GABA in the rat. J. Neurochem. 21: 1167-1175, 1973. Potashner, S. J. Evoked release from guineal pig cerebral cortex slices of endogenous i*C labelled amino acids, IabelIed via D-(U-i4C) glucose. Can. J. Physiol. Pharmac. 54: 949-952, 1976. Powley, T. L., C. A. Opsahl, J. E. Cox and H. P. Weingarten. The role of the hypothalamus in energy homeostasis. In: Hand- book of the Hypothalamus, Vol. 3A, Behavioral Studies of the Hypothalamus, edited by P. J. Morgane and J. Panksepp. New York: Marcel Dekker, Inc., 1980, (In Press). Roberts, E. y-aminobutyric acid and nervous system function-a perspective. Biochem. Pharmac. 23: 2637-2649, 1974. Sclafani, A., C. N. Bemer and G. Maul. Feeding and drinking pathways between medial and lateral hypothalamus in the rat. J. camp. physiol. Psychol. 85: 29-51, 1973.

44. Schwartz, W. J. and F. R. Sharp. Autoradiographic maps of regional brain glucose consumption in resting, awake rats using (‘“C) 2-deoxyglucose. J. camp. Neural. 177: 335-360, 1978.

45. Smith, C. J. V. Hypothalamic glucoreceptors-the influence of gold thioglucose implants in the ventromedial and lateral hypothalamic areas of normal and diabetic rats. Physiol. Behav. 9: 391-396, 1972.

46. Sokoloff, L., M. Reivich, C. Kennedy, M. H. Des Rosiers, C. S. Patlak, K. D. Pettigrew, 0. Sakurada and M. J. Shinohara. The (i4C) deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the consious and anesthetized albino rat. J. Neurochem. 28: 879916, 1977.

47. Watson, S. J. C. W. Richard III and J. D. Barchas. Adrenocor- ticotropin in rat brain: immunocytochemical localization in cells and axons. Science 200: 118&1182, 1978.

48. Wolfson, L. I., 0. Sakurada and L. Sokoloff. Effects of y-butyrolacetone on local cerebral glucose utilization in the rat. J. Neurochem. 29: 777-783, 1977.

49. Wood, J. D., W. J. Watson and A. J. Ducker. The effect of hypoxia on brain y-aminobutyric acid levels. J. Neurochem. 15: 603-608, 1%8.

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