Benzodiazepines, Appetite, and Taste Palatability

Transcription

1 Pergamon (94) Neuroscience and Biobehavioral Reviews, Vol. 19, No. 1, pp , 1995 Copyright 1995 Elsevier Science Ltd Printed in the USA. All rights reserved /95 $ Benzodiazepines, Appetite, and Taste Palatability KENT C. BERRIDGE I AND SUSANA PECINA Department of Psychology, University of Michigan, Ann Arbor, MI BERRIDGE, K. C. AND S. PECII~A. Benzodiazepines, appetite, and tastepalatability. NEUROSCI BIOBEHAV REV 19(1) , Benzodiazepine agonists stimulate feeding in animals. This paper reviews evidence which indicates that benzodiazepine-induced feeding is due to a specific enhancement of the perceived palatability of food and fluids, and is not a mere secondary consequence of anxiety reduction. In studies of the effect of benzodiazepines on affective reactions that are naturally elicited from rats by tastes, we have shown that (a) benzodiazepines enhance hedonic taste palatability in a receptorspecific fashion; (b) the relevant receptors and the minimal neural circuitry required to mediate benzodiazepine-induced palatability enhancement both exist complete in the decerebrate brain stem; and (c) even in normal brains, receptors in the brain stem, not forebraln, are the primary substrate for the benzodiazepine-induced enhancement of taste palatability. We conclude that a 'benzodiazepine-gaba' neural system in the brain stem constitutes an important component of the neural hierarchy responsible for taste pleasure. The reason why benzodiazepine tranquilizers have not been reported to enhance palatability for humans may be that the appropriate studies have not yet been done, that human doses are low, and that the brain stem palatability system is less responsive to commonly prescribed agonists than are anxiety/arousal benzodiazepine systems. Finally, in keeping with the purpose of the symposium in which this paper was originally presented, we discuss a number of issues regarding the measurement and interpretation of taste reactivity data. Taste Appetite Palatability Pleasure Feeding Intake Benzodiazepine Diazepam Chlordiazepoxide Brain stem Anxiolytic INTRODUCTION IF BEHAVIORAL neuroscientists were polled today on which neurotransmitter systems were "most likely to be a substrate for taste pleasure," the ber~,odiazepine system (a GABAergic neural system that incorporates benzodiazepine receptors linked to GABAA receptors) might rank among the lowest on the list. In contrast to the prominence of opioid, dopamine, and even norepinephrine and serotonin systems as candidate substrates of food reward, little attention has been given to benzodiazepine (BZD) systems. However, a growing body of evidence indicates that BZD-related systems may be important neural substrates for taste palatability. This paper will review data from studies of feeding behavior and from the "taste reactivity" measure of taste-elicited affective reactions, such as gapes and tongue protru,,;ions, that was devised for rats by Grill and Norgren (48). These data suggest that the activation of a particular BZD system by high doses of agonists produces a powerful enhancement of hedonic palatability, and that the location of this palatability-:related BZD system is in the brain stem. Benzodiazepine agonist drugs such as diazepam (Valium) or chlordiazepoxide (Librium) facilitate GABA-induced inhib- itory potentials in postsynaptic neurons that have GABAA receptors. Benzodiazepines increase the likelihood of chloride ion channel opening in response to activation of GABAA receptors, and prolong the duration of chloride channel opening (56). Both effects potentiate neuronal hyperpolarization typically produced by the neurotransmitter, GABA. These drugs are famous for their anxiety-reducing, sedative, and relaxation effects (e.g., 94). The obvious nature of those effects has overshadowed the effects of benzodiazepine agonists on eating and drinking. Most notable among these is the marked ability of the drugs at high doses to increase food and fluid intake. Eating and drinking is enhanced over the short term by BZD agonists in virtually every mammalian species that has been studied. Stimulation of Feeding by BZD is Independent of Anxiety or Sedation The original findings that feeding and drinking were stimulated by BZD drugs were generally interpreted as a mere secondary consequence of sedation or of anxiety reduction (52, 57,75,88,91). However, it has become clear over the past 20 yr that benzodiazepine-induced feeding cannot be explained 1 Requests for reprints should be addressed to Kent Berridge, Neuroscience Bldg.; University of Michigan, 1103 E. Huron St.; Ann Arbor, MI

2 122 BERRIDGE AND PECINA simply by indirect causation via effects on anxiety or arousal. For example, regarding arousal, BZD treated animals quite rapidly develop tolerance to the sedative effects of the drug but not to the hyperphagic effects (93). Recently, "partial agonist" drugs have been discovered, such as Ro , Ro , Ro , that increase intake but lack sedative effects (1,26,28,36,51,58,74,82). Further, the modulation of anxiety seems to be irrelevant to the feeding elicited in many instances since: (a) BZDs enhance feeding responses even under nonstressful conditions of complete familiarity, and when the drug itself is delivered without stress by being mixed in the animal's food; (b) Exposure to stress induced by novelty or an aversive stimulus does not enhance the feeding elicited by BZDs relative to feeding after the vehicle alone (30,84,93); and (c) Selective BZD agents called pyrazoloquinolines, such as CGS 9896 and CGS 9895, have been discovered recently to reduce anxiety by nonfeeding behavioral measures (2-4), but not to increase food intake (29,32), which suggests that the BZD-related neural systems that modulate anxiety are separable from the BZD neural systems that stimulate feeding. Do BZD Tranquilizers Stimulate Appetite in Humans? Despite the high incidence of benzodiazepine use by people for anxiolytic and sedative purposes, the modulation of human evaluations of food palatability is not numbered among the chief effects of benzodiazepines (94). It is important to note, however, that the lack of human evidence for modulation of palatability is not by itself evidence against such modulation. An adequate test of the palatability hypothesis for humans has not yet been performed. Several considerations point to this conclusion. First, people take benzodiazepines generally in situations in which they are anxious, tense, desiring of sleep, etc. These are not situations conducive to the detection of a change in food palatability. Second, since the most widely used benzodiazepines are precisely those agonists that have potent anxiolytic or sedative effects, the ability to detect an effect on palatability is likely to be overshadowed for most people by these more noticeable effects. The development of partial agonists with more specific effects, which could modulate palatability without inducing sedative or anxiolytic effects, will be especially useful in this regard. Finally, people quite possibly take benzodiazepines in doses that are simply too low to produce the palatability effects we describe in this paper. Our animal experiments on taste reactivity indicate that higher doses of benzodiazepine full agonists are required to enhance hedonic reactions to taste than to induce sedative/relaxation effects. In dose-response tests, rats appear to show reduced muscle tone and are less emotionally responsive at doses that are too low to enhance hedonic taste reactivity. This suggests that the threshold of the benzodiazepine-related neural systems responsible for palatability modulation is higher than the thresholds of benzodiazepine systems that modulate anxiety and arousal. An explanation for the difference in dose threshold between BZD anxiety/sedation vs. appetite/palatability effects may be that the two types of effects are mediated by different BZD neural systems, which are differentially responsive to full agonist drugs. However, the recent development of partial agonists, which induce fractional responses in target cells, and receptorspecific agonists, which are more highly selective to receptor subtypes, means that it may be possible eventually to induce appetite/palatability effects alone, without anti-anxiety or sedative effects, via a selective BZD agonist that more specifically activates only the relevant neural system (25). Several partial agonists, such as bretazenil and Ro , appear to produce selective feeding enhancement in animals without marked sedation effects (26,28), providing grounds for optimism in this regard. Humans who take BZD drugs as anti-anxiety agents typically take doses considerably lower than those needed in rats to produce palatability enhancement. This may be why BZD tranquilizers do not seem to be powerful appetite enhancers for human patients. For the be~zodiazepine palatability hypothesis to be properly tested in humans, it would be necessary to conduct controlled studies of human food intake, food choice, and subjective palatability ratings. This would need to be done using a wide range of doses of benzodiazepine full agonists or using partial agonists that selectively stimulate feeding (26,28,51,82). Until studies such as these have been performed, the issue of whether benzodiazepines enhance food palatability in humans must remain an open question. Benzodiazepine-Induced Feeding in Animals The possibility that BZDs stimulate feeding by activating a process directly related to appetite was first suggested decades ago (93). This hypothesis has been strengthened since the late 1970s especially by the work of Cooper and his colleagues (e.g., 21,23,25,27,30,31,33). Cooper argued as early as 1980, in what we will call the BZDpalatability hypothesis, that BZD agonists facilitate food intake by specifically potentiating taste pleasure (22,23), above and beyond anxiety or sedation effects. He and his colleagues have supported this hypothesis with several lines of evidence, which are briefly described below. Benzodiazepine-Induced Feeding Is Selective for Palatable Foods Benzodiazepines selectively enhance the consumption by animals of palatable foods and fluids (e.g., cookies, sweetened food or saccharin water) much more than of ordinary chow or water (24,30,33,63), leading to the suggestion that BZD administration 'multiplies' preexisting hedonic palatability to influence consumption. This pattern of results is produced by a wide variety of BZD full and partial agonists (32,54). The same palatability-dependent pattern of effects is produced in sham-feeding studies (in which a gastric fistula allows the escape of what is consumed, avoiding the modulation of feeding by most postingestive satiety cues) as well as in studies of normal intake (33)." Tests of the BZD "Palatability Hypothesis" by the Taste Reactivity Measure In order to test Cooper's "BZD palatability" hypothesis, Berridge and Treit (11) applied the taste reactivity measure of palatability, based on natural affective reactions of rats to taste, which was pioneered by Grill and Norgren (48). [Space does not permit us to review the evidence relevant to the assertion that the taste reactivity technique measures taste palatability. The reader may wish to consult (6,12,44,45,46,48) for evidence and perspectives on the meaning of taste reactivity data.] Berridge and Treit (11) examined the effect of a benzodiazepine agonist, chlordiazepoxide, on the hedonic and aversive patterns of taste reactivity elicited by a I min infusion of either sweet sucrose M), sour HCI (0.01 M), or bitter quinine HCI (3 10 -~ M) delivered by oral cannula 30 rain after the drug injection. In support of Cooper's hypothesis that BZD

3 BENZODIAZEPINES, AF'PETITE, AND TASTE PALATABILITY 123 agonists enhance taste pleasure, they found that systemic chlordiazepoxide (10 mg/kg, ip) selectively enhanced hedonic reactivity patterns (e.g., tongue protrusions and paw licks; Fig. 1). Aversive patterns of reactivity (e.g., gapes, headshakes, etc.) were never en]hanced, ruling out a "general enhancement in overall reactivity" interpretation. On the contrary, aversive reactions to sour HCI were slightly diminished by chlordiazepoxide reciprocally to hedonic enhancement, while aversive responses to quinine remained more robust and were not significantly altered. Berridge and Treit (11, p. 219) interpreted their results to mean that the benzodiazepine acted "to enhance the positive [(.."-> "-.L/ /~ evaluation of palatability while having little or no effect on the aversive evaluation." Drawing on a 2-dimensional (2D) model of palatability processing, which holds that evaluations of hedonic taste palatability are processed separately from evaluations of aversive taste palatability (6,9,10,45), they suggested that the BZD agonist specifically enhanced the former, and had only lesser, indirect effects on the latter (perhaps via response competition or reciprocal inhibition). Similar support for a dissociation of hedonic and aversive dimensions of palatability by BZD agonists has recently been reported by Linda Parker: chlordiazepoxide enhanced hedonic reactivity emitted to saccharin, which had previously been paired with LiCI to establish a conditioned aversion, but did not reduce aversive reactivity to the same taste (65). A follow-up study (90) examined whether the hedonic taste reactivity enhancement effect could be blocked by a BZD receptor antagonist. Such a blockade would indicate that the effect was BZD "receptor specific," and that evaluation of hedonic taste palatability was indeed likely to be mediated in part by a neural BZD-related system. This prediction was confirmed. The selective enhancement of hedonic taste reactivity patterns by systemic chlordiazepoxide was replicated (90). In this second study, however, aversive taste reactivity patterns were never significantly modulated to any taste by the BZD agonist. Regarding receptor specificity, the benzodiazepine receptor antagonist, Ro , and the "inverse agonist," CGS 8216 (which acts as an antagonist in the presence of a BZD agonist), both proved to be effective in blocking the BZD-induced enhancement of hedonic taste reactivity. These results supported the interpretation that the hedonic enhancement by chlordiazepoxide is truly mediated by BZD-GABA receptors. Neither antagonist produced a reliable effect on hedonic or aversive taste reactivity patterns by itself, although CGS 8216 did produce a slight enhancement of "neutral" taste reactivity components (see below for a discussion of taste reactivity components and their classification). Although more work needs to be done on the taste reactivity effects of antagonists and inverse agonists, the general conclusion seems solid that activation of the benzodiazepine/gaba receptor complex does indeed enhance hedonic reactions to taste in a receptor-specific fashion. Neural Substrates of Pleasure Enhancement by Benzodiazepines FIG. 1. Benzodiazepine enhancement of hedonic palatability. Taste reactivity patterns elicited from rats after either chlordiazepoxide (10 mg/kg, ip) or saline injections by three tastes: sweet sucrose, sour HC1, and bitter quinine. Only i~ngestive/hedonic reactions are markedly enhanced by the BZD agonist (dots denote statistical significance). Note that BZD enhanc(;s ingestive/hedonic reactions even to quinine: BZD appears to multiply the preexisting hedonic component of any taste [hedonic reactions to more concentrated quinine, which elicits aversion almost exclusivfly, are not enhanced by BZD (89)]. Aversive reactions, in contrast, are not enhanced by BZD for any taste. Ingestive/hedonic reactions shown here are: PL = paw lick, LTP = lateral tongue protrusion, and TP = midline tongue protrusion. Aversive actions are G =-" gape, CR = chin rub, FW = face wipe, FF = forelimb flail, HS = headshake, and LO = locomotion. Unclassified ("neutral") center actions are MM = mouth movements, and PD = passive drip. Adapted from Berridge and Treit (7). Where in the brain do benzodiazepines act to enhance hedonic reactions? The highest densities of benzodiazepine receptors are in cortex, accumbens, amygdala, and hippocampus. Moderate densities are found in striatum, thalamus, and hypothalamus, Receptor density is lower in the brain stem (77,78,92). Based on the relative distribution of receptors, it might have been expected that forebrain receptors would chiefly mediate the enhancement of positive taste reactions by benzodiazepine agents, if one assumed that structures with the highest receptor densities would make the greatest contributions to all BZD effects. However, this has turned out not to be true. A study of decerebrate taste reactivity by our laboratory, conducted in rats that were transected just above the midbrain in the now-traditionai Grill and Norgren supracollicular spatula-transection procedure (48), examined the capacity of brain stem circuits by themselves to mediate benzodiazepineinduced enhancement of hedonic reactions. This study indicated that the combined midbraln and hindbrain by itself can mediate benzodiazepine-induced enhancement of hedonic

4 124 BERRIDGE AND PECIlglA taste reactivity (5). Chlordiazepoxide (10 mg IP) enhanced bedonic taste reactivity in mesencephalic (midbrain) decerebrate rats, even though the brain stem had been isolated from input from any forebraln structure rostral to the superior colliculus (Figs. 2 and 3). The pattern of enhancement shown by Fig. 2 indicates that benzodiazepine administration doesn't simply add a constant degree of enhancement, but instead multiplies the hedonic reaction to a taste. For example, the palatability of sucrose is enhanced to a greater extent than the other tastes. This multiplicative relation between preexisting palatability and the drug could cause BZD-elicited feeding to be directed specifically towards palatable foods (23,24,33). What Does Decerebrate Competence Mean? The ability of decerebrates to show positive enhancement indicates that both the relevant benzodiazepine receptors and the minimal neural circuit needed to modulate taste reactivity exist within or below the mesencephalon. But it does not necessarily mean that the forebraln is irrelevant to BZD effects on palatability, or even that the brain stem is the primary substrate for the effect in normal brains. Decerebrate studies need to be interpreted in the context of a neural hierarchy of M Sucrose 26- (/) z w 22- i.-- m 20,- ~ ~o' 0 8- I1: O3 ~ 6- "' L 001M HCl IX 4-0 3MSucrose 2-,, I I I 0 5 I0 mg/kg CDP FIG. 2. Decerebrate enhancement of ingestive/hedonic taste reactivity by a benzodiazepine agonist. Dose response curves show the effect of chlordiazepoxide on combined ingestive/hedonic reactions emitted by mesencephalic decerebrate rats. Note that a relatively high dose (10 mg/kg) is required for the palatability enhancement, and that the effect interacts multiplicatively with taste. Decerebrates show a relatively small CDP enhancement of hedonic reactions to 0.03 M sucrose, by comparison to the enhancement for normal rats shown in Fig. 1, but show a robust enhancement to sweeter 0.3 M sucrose. Aversive and neutral reactions were not changed by the drug, and are not shown here. Adapted from Berridge (5). taste processing and behavioral control (45,46,49). Forebrain receptors might ordinarily play an equal or even greater role than brain stem receptors in mediating BZD-induced palatability enhancement. Decerebration might release brain stem systems that ordinarily are not free to function because of descending inhibitory inputs from the forebrain. As an analogy, infant reflexes commonly observed in human newborns are also observed in adult patients with cortical damage. These reflexes are inhibited ordinarily by descending connections from the mature telencephalon to brain stem structures, and are released only after cortical damage. Normally, these brain stem and spinal reflex systems are "silent" in adults. If this analogy applied to taste processing, then decerebrate competence for taste reactivity modulation in response to BZD might be misleading since it could exist only in the artificial situation created by sudden loss of the mature forebrain. How can one be sure that brain stem circuits mediating BZD-effects in a decerebrate might not be silent, or at least, normally dependent on triggers generated by the forebrain rather than by the brain stem? Role of Brain Stem BZD-Palatability Systems in the Intact Brain In order to demonstrate that activation of brain stem benzodiazepine receptors is sufficient for hedonic enhancement in an intact brain, something other than decerebration is needed. It would be necessary to show in addition, for instance, that microinjections of a benzodiazepine agonist into the brain stem (4th ventricle; Fig. 4) of an intact animal were more effective at enhancing hedonic reactions than similar microinjections into the forebrain (e.g., lateral ventricle). We have recently done this, and found that the brain stem is indeed more sensitive than the forebrain to hedonic enhancement by BZD microinjections (72 and in preparation). In this study, we compared the effects on hedonic taste responses of microinjections of diazepam, a benzodiazepine full agonist, into the lateral ventricles and into 4th ventricle of intact rats (72). Twenty-one intact rats were implanted with two intraventricular cannulae: one in a lateral ventricle (left or right) and the other in the 4th ventricle. Later, taste reactivity was assessed to sucrose infusions 10 min after microinjections of diazepam (dissolved in propylene glycol and ethyl alcohol) were made into either the fourth or the lateral ventricles. The taste stimulus used was 7% sucrose, which elicits hedonic/ingestive reactions primarily. On 16 days (spaced at least 1 day apart), rats received intraventricular microinjections of diazepam (0, 5, 15, 25, 40, 50 or 75 ug dissolved in 10 ul of the vehicle) delivered over a 2 min period. Each dose was tested on two consecutive days. The order of drug administration was random except for the first and the last injections which were always of the control vehicle. At the completion of the experiment, rats were deeply anesthetized, perfused, and given microinjections of ink into the ventricles. The brains were removed and cut midsagitauy. The presence of ink in the 4th and/or lateral ventricles verified the correct location of the ventricular cannulae. Diazepam was more effective at all doses at enhancing hedonic reactions when injected into the 4th ventricle than when injected into the lateral ventricle (/7 < 0.05). The threshold for 4th ventricle hedonic enhancement appeared to be between 40 and 50 ug (Fig. 5). The threshold for lateral ventricle hedonic enhancement was significantly higher, and was closer to 75 ug. Aversive or neutral actions were not changed significantly by diazepam at any dose. These preliminary results support the conclusion that benzodiazepines act primarily on

5 BENZODIAZEPINES, APPETITE, AND TASTE PALATABILITY 125 S 4 3 ~ 1 MESEN C EP HAL I C I I.,.,.,.,.,.,.,.,,.,,.,,.,,.,.,, w 1781,1R') 56 Fr,.---. ", ' LSV,, "--/ "', "" :," :. Z /" " ",,',,..:.~, ~::,,'~.,', "..T T ' ',... ;~,~,;..... /;/"',, /,," ", -_~.':~...- :::~ :.']' : :::.>., '-...'" -;..:,,- ~,,,,, ~:~.:;~,..':..- :?.::: -]~ ,.:.-..,' AH~,:~"~ t, ~. "'"'~ P~ Lateral 0.9 mm 1[4 113 II i t,,,o ~, ~. ;.,,~,,, ~, ~,, i I -I i i I ' i, i. t $ -I FIG. 3. Decerebration levels of transection. Drawing shows the actual level of transection for the mesencephalic decerebrates that were used for Fig. 2. Adapted from Berridge (5) ~ I 0 -! " "6-7 "l ~_ ~c fm) IrF ] ~? % \ ', I : ~PF\ Ace...~_...,~,~ \...-;;'-~:: ' vp P~ Gi M~V Lateral 1.4 mm ~4 I I II I I -I ~ -6 FIG. 4. Lateral and Fourth ventricle targets. Drawing from Paxinos and Watson (71) depicts the approximate targets for microinjections used by Pecifia and Berridge (72) aimed at the forebraln vs. brain stem ventricles (ventricles shown in black).

6 126 BERRIDGE AND PECII~A Intraventricular microinjections of Diazepam enhance hedonic reactions to taste. 40- I'P" /- \ Fourth ventricle Lateral ventricle g 0 U 1 u e- 0 '0 Q 32 3O O I 0~g I 1 I 40~g SOng 75.g Diazeoam doses FIG. 5. Fourth ventricle vs. lateral ventricle hedonic enhancement. Dose-response curves show hedonic/ingestive scores of normal rats to sucrose after microinjections of diazepam or the vehicle into either the brain stem or forebraln ventricles. Microinjections into the fourth ventricle were reliably more effective at enhancing hedonic reactions than microinjections of the same dose into the lateral ventricle. Adapted from Pecifia and Berridge (72). brain stem receptors to enhance taste pleasure even in an intact brain that has forebrain receptors and circuits available. Which Brain Stem Structures Mediate The BZD Enhancement of Palatability? Although we have no definitive answer to this question yet, we can speculate a bit on possible candidates. Several brain stem sites share the features of (a) having significant binding for benzodiazepine receptors; and (b) having been shown to be involved in taste or feeding behavior. A moderate degree of binding for benzodiazepine receptors is found within regions of the medulla oblongata that contains the dorsal nucleus of the solitary tract (77,78,92), which constitutes the second-order relay nucleus for ascending taste projections, (e.g., 60). Electrophysiological taste responses in this nucleus are localized principally around the rostral tip of the lateral division, (e.g., 59), and lesions of this nucleus disrupt normal taste reactivity, (e.g. 40,41). Whether BZD receptors occur in the gustatory solitary nucleus in particular, and if so, whether they are related to the effects of BZD agonists on hedonic reactions to taste is not known. But BZD agents might possibly act to modulate taste information here at its earliest stage of processing within the brain. A similar possibility is represented by the occurrence of BZD receptors in the region of the caudal parabrachial nuclei within the dorsal pons, which is the source of 3rd-order taste neurons for the rat (61). A column of taste-responsive cells extends from the bottom to the top of the midlateral brachium conjuctivum and above it into the dorsal parabrachial region. Lesions of the parabrachial'region disrupt normal taste reactivity patterns to a variety of stimuli (41,85,86). Opioid receptors related to feeding also appear to be contained in this region (20). The combination of taste, BZD and opioid receptors, and demonstrated modulation of feeding behavior and taste reactivity make the pontine parabrachial nuclei another excellent candidate as the substrate for BZD-enhancement of taste palatability. As an alternative to direct modulation of the ascending taste signal, it is conceivable that BZD ngonists enhance palatability by acting on brain stem structures that are completely outside of the primary sensory pathway. These structures could act either to modulate the taste signal indirectly via projections into the pathway or to modulate affect (rather than sensation per se) at a later stage of processing. Providing a candidate site for such an "extrinsic" influence, moderately dense BZD receptor binding is found in the ventral tegmental area of the midbraln. This region is well known to play a role in reward and feeding behavior, (e.g., 16). BZD-induced modulation of neurons here or in other reward-related regions

7 BENZODIAZEPINES, APPETITE, AND TASTE PALATABILITY 127 might well influence the evaluation of taste palatability. Other candidates include GABA-related neural circuits that connect the substantia nigra to the superior colliculus. These circuits modulate the responsiveness to perioral stimuli and have been shown to influence feeding behavior (34,76). Comparison to Other Neurotransmitter Candidates for Taste Pleasure We and others have collected data that allow comparison of BZD-induced enhancement of hedonic taste reactivity to the effect of other drugs (administered systemically) that act upon opioid (morphine, naloxone), dopamine (amphetamine, apomorphine, haloperidol, pimozide), norepinephrine (amphetamine), serotonin (buspirone, gepirone), and peptide (bombesin and gastrin-relea;fing peptide) neurotransmitter systems (37,39,64,67,70,73,89 and personal observations). The general pattern of results ha:~ been clear and somewhat surprising: aside from BZD, only activation of opioid neurotransmitter systems (e.g., by morphiine) has markedly and reliably enhanced hedonic reactions or suppressed aversive reactions to tastes (37,70). Agents for other neurotransmitters, even at doses that elicit feeding, fifil to enhance hedonic reactions. And agents that potently reduce feeding and that might have been regarded as substrates for palatability, most notably the dopamine antagonists, haloperidol and pimozide, fail in our hands to reduce hedonic reactions or to increase aversive reactions (89 and personal observations). Although other laboratories have occasionally found effects of dopamine manipulations under certain conditions, (cf. 55,68), we have found little to no impact on taste palatability either of dopaminergic electrical stimulation [via an electrode in the lateral hypothalamus (12)], pharmacological stimulation [via apomorphine or amphetamine (89)], pharmacological antagonism [via haloperidol or pimozide (89) and Berridge & Robinson, personal observations], or even of complete destruction of up to 99% of mesotelencephalic dopamine projections (via 6-hydroxydopamine lesions of the substantia nig~ra or of the ascending dopaminergic bundle at the level of the hypothalamus: (13) and Berridge & Robinson, personal observations). Thus we conclude that sy:;tems using benzodiazepine-gaba and opioid neurotransmitter receptors are the two chief neuropharmacological substrates for taste pleasure identified so far. These systems may be related in their operation. In fact some evidence suggests that the two systems interact. Naloxone can partially or totally reverse BZD induced hyperphagia (14,19, 50,83,87), and appears to block BZD induced enhancement of hedonic taste reactions (per;sonal observations). An hypothesis, albeit a highly speculative one, that might explain this interaction is that brain stern BZD systems form the first stage of a multi-stage system in which opioid systems, extending into the forebrain, form a later stage. In other words, opioid enhancement of hedonic reactions may be mediated by forebrain systems, in contrast to BZD enhancement which is predominantly brain stem-mediated. This hypothesis is consistent with a recent finding that hedonic reactivity to sucrose is enhanced by microinjections of morphine directly into the paraventricular nucleus of the hypothalamus (73). Note Concerning Taste Reactivity Measurement and Classification An important aspect of the symposium on taste reactivity at the 1993 Neuroscience conference was the opportunity for speakers and the audience to discuss different procedures and concepts that are currently used to measure and analyze taste reactivity. It seems appropriate therefore to reflect on these issues here. A versive and hedonic/ingestive reactions. "Aversive" and "rejection" are terms that are applied nearly interchangeably to rat taste reactions such as gapes and headshakes. "Ingestive" was the name given by Grill and Norgren (48) to taste reactions such as rhythmic and lateral tongue protrusions (44). Ingestive is still preferred by many taste reactivity investigators as a name for these components, perhaps because it carries no psychological connotations. Ingestive is certainly the most appropriate term for studies that use taste reactivity as a measure of actual ingestion, such as intra-oral intake studies. However, we now prefer the term "hedonic" for these components when applied to taste reactivity as a measure of palatability. Many studies have demonstrated that palatability, as measured by taste reactivity, can be completely dissociated from ingestion by a variety of brain manipulations. Intake can be changed without a concomitant change in hedonic/aversive taste reactivity patterns by a variety of brain lesions (e.g., 6-OHDA and amygdala lesions (13,43,81), and by electrical stimulation of the hypothalamus (12). Conversely, hedonic/ aversive taste reactivity patterns may differ to "isohedonic" tastes that typically might be equally preferred in intake measures (9). Intake and palatability can diverge because the neural and psychological controls of these two processes are not entirely identical-even though they normally overlap to a great extent (e.g., 12,15,80). In cases when "ingestive reactions" to taste fall to predict actual ingestion, the name "ingestive" applied to taste reactivity becomes misleading. When palatability and intake diverge, the name "hedonic" helps identify which process the taste reactivity measure best tracks: palatability. [One might wonder whether the emission of taste reactions by decerebrates is not an instance of taste reactivity diverging from palatability. We would suggest it is not, but it does illustrate that affective processes can exist without the consciousness of pleasure. Although a decerebrate is surely not conscious of pleasure in the normal sense, its reaction nonetheless reflects the operation of preconscious affective circuits to the limited degree that it has them.] Those who are not comfortable with subjective psychological terms for animal behavior might take comfort from the observation that "hedonic" derives etymologically from the Greek term for the taste of honey (15). In this sense, the term hedonic nicely captures the unconditioned objective (behavioral) response to a honey-like sweet taste. Neutral reactions. Is it useful to posit a third category of "neutral reactions"? Originally, only ingestive and rejection categories were used by Grill and Norgren (48), and this division is still the most appropriate for studies concerned solely with intraoral intake (since in these the question is simply whether the substance is ingested or not). The "neutral" category was first used to distinguish between components of ingestion/rejection that appeared to strongly reflect affective evaluations and other components that also influenced ingestion but were less indicative of an affective positive or negative evaluations (9,10,45). Admittedly, "neutral" is not an entirely complete name for these responses. A more accurate name might be "components which under some conditions do reflect hedonic/aversive evaluations of a taste, but which under other conditions do not, and so which are best considered separately to avoid confusion in a given case as to whether they do or do not connote affective evaluations"-but this name is less convenient than "neutral". Mouth movements and passive dripping are not entirely neutral, rather they are weakly coupled, respectively, to hedonic and aversive evaluations of pal-

8 128 BERRIDGE AND PECII~IA atability. They are often the first reactions emitted to any taste infusion: sweet, bitter, or other (9,79). An innocuous taste, such as distilled water often elicits a response composed predominantly of neutral reactions, without tongue protrusions, gapes, or other affective reactions (e.g., 35); although not always-depending upon the rat and its condition, a water infusion may sometimes elicit hedonic reactions, aversive reactions, or be incorporated into a robust grooming sequence [see below]). Rhythmic mouth movements to a continuous intraoral infusion increase with sweetness concentration up to a certain point, but then fall off as other, more affectively weighted, components begin to displace them. This rise and fall poses a paradox if mouth movements are taken as indices of hedonic assessment equal to, say, lateral tongue protrusions: why should one index rise while the other declines? But the paradox is dissolved when mouth movements are recognized as only weak indices of hedonic evaluation, which become relatively poor indicators when displaced at high levels of hedonic activation. This is related to the hypothesis that taste reactivity components within each affective category can be activated differentially as the strength of a palatability evaluation changes (17). Similarly, passive dripping can be accompanied by active rejection, and may thus in some cases reflect aversion. But passive dripping would also be "emitted" to an oral infusion by an unconscious, dead, or otherwise "affectless" subject, and is at best a weak indicator of active aversion. For these reasons, we prefer to separate responses such as rhythmic mouth movements or passive drips into a third category and away from active hedonic and aversive categories when studying palatability. The importance of response pattern for category definitions. Perhaps the most crucial point to keep in mind regarding the classification of taste reactivity components is that no component is in itself necessarily related to palatability. Tongue protrusions do not intrinsically reflect an hedonic assessment, nor do gapes intrinsically reflect aversion. Each of these, as motor events, are under the control of sensorimotor processes in addition to affective evaluation. Similar movements may be emitted as 'vacuum reactions' in the absence of taste, as after neuroleptic administration (38). Even in response to taste, a response may become entirely dissociated from affect and be dominated by these other processes under some conditions (such as particular neural manipulations). The defining features of hedonic and aversive response categories have nothing to do with the responses themselves. The defining features of affective categories instead are patterns: the pattern of relation among the responses themselves, and the pattern of the relation of responses to their eliciting stimuli. Tongue protrusions, lateral protrusions, and paw licking are all elicited together by infusions of particular stimuli such as sweet sucrose (unconditionally), salt (when sodium deprived), or tastes that have become palatable by associative conditioning (e.g., 40,42,48,53,95). Gapes, headshakes, face wash strokes, forelimb flails, etc., are not; instead these responses are elicited as a group by stimuli such as bitter quinine or tastes that have been associatively paired with visceral illness, (e.g., 17,18,47,48,62,66,69). Relationships like these define hedonic and aversive response categories. These same relationships need to be used to decide whether a brain manipulation has altered taste palatability. For example, a change in the frequency of a single component, such as tongue protrusion, without an accompanying change in other hedonic reactions, is unlikely to reflect a change in hedonic assessment. A better interpretation is that the manipulation has altered sensorimotor factors that are specific to the production of tongue protrusions (13). A related example of the importance of response pattern applies to the interpretation of paw licks and face wash strokes. Paw licks connote a highly positive assessment when they occur in the context of other hedonic actions, and typically occur as long continuous bouts. Indeed, they are so strongly positive that it is difficult to elicit such bouts with anything other than a continuous infusion of concentrated sucrose or similarly preferred substance; weaker concentrations or short pulse infusions will not suffice. Conversely, face wash strokes, made by the paw over the face, connote aversion in the context of gapes, paw shakes, etc. However, a striking feature regarding paw licks and face strokes solution has been noted by a number of laboratories: these components can dissociate from their groups and occur in rapid alternation together (e.g., 35,53). When this happens, these components function essentially as a grooming pattern, and their meaning is entirely different. In this pattern, they do not reflect a palatability evaluation of the taste, but rather are activated as part of a separate grooming system. This 'paw lick & face wash' sequential alternation occurs spontaneously during normal grooming. It can also be elicited by spraying the rat's fur with water. It can also sometimes be elicited by an oral infusion of water (or another innocuous taste), most typically when the rat has ceased to ingest the water and has begun to spread it over its body (like saliva). Because of this anomaly, several laboratories now do not score face wash strokes as aversive, nor paw licks as hedonic; they remove the components from affective categories. But the deviation from affective classification in this case is not a function of these responses as components; it is a function of their sequential pattern. In short, pattern is crucial for the interpretation of affective reactions. Our laboratory now scores face washes as aversive only when they do not occur within 2 s of a paw lick, and paw licks as hedonic only when they do not occur within 2 s of face wash strokes. We recommend that the alternating face wash/ paw lick sequential pattern be scored as an entirely separate (neutral) response. [Some readers may note that this interpretation of alternation between an hedonic and an aversive component provides analternative to the 2D palatability interpretation of alternating components described by Berridge & Grill (9). We believe this alternative interpretation to be "local". It applies specifically to alternation between face wash and pawlick components, and not to alternation among other hedonic/ aversive components. In any case, the 2D hypothesis of palatability must stand or fall by other criteria, such as the ability to manipulate one affective group of responses separately from the other. Regarding this point, it appears that although some manipulations of palatability alter hedonic and aversive reactions reciprocally, such as salt appetite or well-established conditioned taste aversions; (e.g.; 18) (either by acting on a single dimension, or by simultaneously acting on two dimensions directly, or by acting directly on only one dimension but indirectly acting on the second via reciprocal inhibition between the two), other manipulations act more selectively on only one hedonic or aversive dimension in a manner that requires a 2D explanation (9,10). These latter phenomena include caloric alliesthesia, trigeminal deafferentation, additive taste mixtures, alcohol habituation, and possibly benzodiazepine administration (e.g., 6,7,10,11,53,65,90)]. Scoring techniques. A final issue concerns the measurement of hedonic and aversive reaction patterns. One can score the simple incidence of particular taste reactivity components

9 BENZODIAZEPINES, APPETITE, AND TASTE PALATABILITY 129 (i.e., whether the component was emitted at all) without recording frequency, or score the relative frequency of each component (either in "real time" or by slow-motion videoanalysis). Obviously, these different methods vary in the amount of labor they require and information they provide. Which method is better? Among those who use videoanalysis to obtain an hedonic/ ingestive or aversive category score, some obtain a category score by adding together the unweighted response frequencies for every component in the category, while others use a "weighted bout" combination rule that assigns more weight to relatively rare events (e.g., lateral tongue protrusions) and less weight to highly frequent components (e.g., mouth movements, tongue protrusions). Again, which is better? The answer, we think, is that for some purposes all methods of scoring serve equally well. For other purposes, a particular method may be required. For example, if one wishes to detect the simple occurrence of a major shift in taste reactivity patterns (e.g., conditioned taste aversion, salt "alliesthesia" during sodium appetite, etc.) any method would work. One could choose the method that was easiest, even "mere incidence". In many situations, the degree of correlation between "incidence scores" and "frequency scores" is quite good for taste reactivity components (averaging about r = 0.80: (8)). However, if one wished to detect a more subtle shift, or to accurately compare the magnitudes of different shifts, then the increased resolution provided by a slow-motion analysis might be required. Similarly, the question of whether palatability is a continuum from hedonic to aversive vs. two separable decision processes, involves issues that require attention to the fine structure of the behavior stream. For such questions, slow-motion scoring of every component is needed. Regarding data analysis, the same results will be obtained in many cases regardless of whether taste reactivity frequency data is analyzed in actual response counts (every response counted as a unit each time it occurs) or in weighted bouts (for example, frequent responses such as rhythmic tongue protrusions or mouth movements counted in bins of 2 to 5 s) (9). During the discussion section of the Neuroscience symposium on taste reactivity, Dr. Randy Seeley described an instance (43) in which he and his colleagues at the University of Pennsylvania scored data by the individual response count method that had been scored previously in our laboratory by the weighted bout method: the result was the same. However, if a brain manipulation were to produce a change in taste reactivity that was not shared equally across all the components, then the two methods would not produce the same result. In such a case, if one were interested primarily in the effect of the manipulation on palatability, the weighted response method would be especially useful. If a single component were altered, for example, the change would either be invisible in a category score obtained by the actual count method (if the component had a low initial frequency) or would be exaggerated far beyond its potential importance (if the component had a high initial frequency). In these cases, the weighted bout measure would be a more accurate measure of general palatability, since category scores obtained by it are less likely to be dominated by a single component. By contrast, if one were interested primarily in the response change as a sensorimotor phenomenon, rather than as an index of palatability, then the "actual count" method would be essential to allow an accurate contrast of separate components. In short, the taste reactivity paradigm devised by Grill and Norgren (48) is a rich and multifaceted resource for neurobehavioral studies of the control of taste pleasure and ingestive behavior. It is useful for a variety of different purposes: to study the control of hedonic and aversive palatability, of homeostasis, of intake control, of sensorimotor function, etc. The choice of method may legitimately vary according to the purpose of a particular study. ACKNOWLEDGEMENTS We are very grateful to Professor Steven Cooper and Professor James Woods for their helpful discussion and comments on an earlier version of this manuscript. The intracranial microinjection experiment reported in this paper was supported by a Rackham faculty grant from the University of Michigan. 1. Baile, C. A.; McLaughlin, C. L. A review of the behavioral and physiological responses to elfazeparn, a chemical feed intake stimulant. J. Anim. Sci. 49: ; Bennett, D. A. Pharmacolc,gy of the pyrazolo-type compounds: agonists, antagonists and inverse agonist actions. Physiol. Behav. 41: ; Bennett, D. A.; Amrick, C. L.; Wilson, D. E.; Bernard, P. S.; Yokoyama, N.; Liebman, J. M. Behavioral pharmacological profile of C(3S 9895: A novel anxiomodulator with selective benzodiazepine agonist and antagonist properties. Drug Dev. Res. 6: ; Bernard, P. S.; Bennett, D. A.; Pastor, (3.; Yokoyama, N.; Liebman, J. M. C(3S 9896: Agonist-antagonist benzodiazepine receptor activity revealed by anxiolytic, anticonvulsant and muscle relaxation assessment in rodents. J. Pharmacol. Exp. Ther. 235:98-105; Berridge, K. C. Brain stem systems mediate the enhancement of palatability by chlordiazepo~dde. Brain Res. 447:262-8; Berridge, K. C. Modulation of taste affect by hunger, caloric satiety, and sensory-specific satiety in the rat. Appetite 16:103-20; Berridge, K. C.; Fentress, J. C. Trigeminal-taste interaction in palatability processing. Science 228:747-50; REFERENCES 8. Berridge, K. C.; Fentress, J. C. Contextual control of trigeminal sensorimotor function. J. Neurosci. 6:325-30; Berridge, K. C.; Grill, H. J. Alternating ingestive and aversive consummatory responses suggest a two-dimensional analysis of palatability in rats. Behav. Neurosci. 97:563-73; Berridge, K. C.; Grill, H. J. Isohedonic tastes support a twodimensional hypothesis of palatability. Appetite 5:221-31; Berridge, K. C.; Treit, D. Chlordiazepoxide directly enhances positive ingestive reactions in rats. Pharmacol. Biochem. Behav. 24:217-21; Berridge, K. C.; Valenstein, E. S. What psychological process mediates feeding evoked by electrical stimulation of the lateral hypothalamus? Behav. Neurosci. 105:3-14; Berridge, K. C.; Venier, I. L.; Robinson, T. E. Taste reactivity analysis of 6-hydroxydopamine-induced aphagia: Implications for arousal and anhedonia hypotheses of dopamine function. Behay. Neurosci. 103:36-45; Birk, J.; Noble, R. (3. Naloxone antagonism of diazepaminduced feeding in the Syrian hamster. Life Sci. 29: ; Booth, D. A. Learned ingestive motivation and the pleasures of the palate. In: Bolles, R. C., ed. The hedonics of taste. Hillsdale: Lawrence Erlbanm Associates; 1991: Bozarth, M. A.; Wise, R. A. Involvement of the ventral tegmen-

10 130 BERRIDGE AND PECIlqA tal dopamine system in opioid and psychomotor stimulant reinforcement. Nida Res. Monogr. 67:190-6; Breslin, P. The importance of examining individual taste reactivity components Neuroscience Taste Reactivity Symposium. Neurosci. Biobehav. Rev Breslin, P. A.; Spector, A. C.; Grill, H. J. A quantitative comparison of taste reactivity behaviors to sucrose before and after lithium chloride pairings: A unidimensional account of palatability. Behav. Neurosci. 106:820-36; Britton, D. R.; Britton, K. T.; Dalton, D.; Vale, W. Effects of naloxone on anti-conflict and hyperphagic actions of diazepam. Life Sci. 29: ; Cart, K. D. Effects of parabrachial opioid antagonism on stimulation-induced feeding. Behav. Neurosci. 545: ; Cooper, S. J. Benzodiazepines: Relations between their effects on feeding and on anxiety. It. J. Med. Sci. 1:14-8; Cooper, S. J. Benzodiazepines as appetite-enhancing compounds. Appetite 1:7-19; Cooper, S. J. Effects of chlordiazepoxide and diazepam on feeding performance in a food-preference test. Psychopharmacology 69:73-8; Cooper, S. J. Chlordiazepoxide-induced selection of saccharinflavoured food in the food-deprived rat. Physiol. Behav. 41:539-42; Cooper, S. J. Ingestional responses following benzodiazepine receptor ligands, selective 5-HTIA agonists and selective 5-HT-3 receptor antagonists. In: Rogers, R. J.; Cooper, S. J., eds. 5-HT-~A agonist, 5-HT-3 antagonists and benzodiazepines. Their comparative behavioral pharmacology. Chichester: Wiley; 1991: Cooper, S. J.; Barber, D. J. The benzodiazepine partial agonist bretazenil and the partial inverse agonist Ro : effects on salt preference and aversion in the rat. Brain Res. Bull. 612: ; Cooper, S. J.; Estall, L. B. Behavioural pharmacology of food, water and salt intake in relation to drug actions at benzodiazepine receptors. Neurosci. Biobehav. Rev. 9:5-19; Cooper, S. J.; Green, A. E. The benzodiazepine receptor partial agonists, bretazenil (Ro ) and Ro , affect saccharin preference and quinine aversion in the rat. Behav. Pharmacol. 4:81-85; Cooper, S. J.; Kirkham, T. C.; Estail, L. B. Pyrazoloquinolines: second generation benzodiazepine receptor ligands with heterogeneous effects. Trends Pharmacol. Sci. 8: ; Cooper, S. J.; McCleiland, A. Effects of chlordiazepoxide, food familiarization, and prior shock experience on food choice in rats. Pharmacol. Biochem. Behav. 12:23-8; Cooper, S. J.; Moores, W. R. Benzodiazepine-induced hyperphagia in the nondeprived rat: comparisons with CL 218,872, zopiclone, tracazolate and phenobarbital. Pharmacol. Biochem. Behav. 23: ; Cooper, S, J.; Yerbury, R. E. Benzodiazepine-induced hyperphagia: Stereospecificity and antagonism by pyrazoloquinolines, CGS 9895 and CGS Psychopharmacology 89:462-6; Cooper, S. J.; Yerbury, R. E. Clonazepam selectively increases saccharin ingestion in a two-choiee test. Brain Res. 456:173-6; Dean, P.; Redgrave, P. Dissociation of stimulation-bound feeding and apomorphine-induced gnawing by lesions of the superior colliculus. Physiol. Bchav. 32: ; Delamater, A. R.; LoLordo, V. M.; Berridge, K. C. Control of fluid palatability by exteroceptive Pavlovian signals. J. Exp. Psychol. [Anita. Behav.] 12:143-52; Della-Ferra, M. A.; Balle, C. A.; McLaughlin, C, L. Feeding elicited by benzodlazepine-like chemicals in puppies and eats: Structure-activity relationships. Pharmacol. Biochem. Behav. 12: ; Doyle, T. G.; Berridge, K. C.; Gosnell, B. A. Morphine enhances hedonic taste palatability in rats. Pharmacol. Biochem. Bchav. 46: ; Ellison, G.; See, R.; Levin, E.; Kinney, J. Tremorous mouth movements in rats administered chronic neuroleptics. Psychopharmacology 92: ; Flynn, F. W. Caudal brain stem systems mediate effects of bombesin-like peptides on intake in rats. Am. J. Physiol. 262: R37-44; Flynn, F. W.; Grill, H. J.; Schulkin, J.; Norgren, R. Central gustatory lesions: II. Effects on sodium appetite, taste aversion learning, and feeding behaviors. Behav. Neurosci. 105:944-54; Flynn, F. W.; Grill, H. J.; Schwartz, G. J.; Norgren, R. Central gustatory lesion: I. Preference and taste reactivity tests. Behav. Neurosci. 105: ; Flynn, F. W.; Webster, M.; Ksir, C. Chronic voluntary nicotine drinking enhances nicotine palatability in rats. Behav. Neurosci. 103:356-64; Galaverna, O.; Seeley, R. J.; Berridge, K. C.; Grill, H. J.; Schulkin, J.; Epstein, A. N. Lesions of the central nucleus of the amygdala: I Effects on taste reactivity, taste aversion learning, and sodium appetite. Behav. Brain Res. Bull. 59:11-17; Grill, H. J. Production and regulation of ingestive consummatory behavior in the chronic decerebrate rat. Behav. Brain Res. Bull. 5:79-87; Grill, H. J.; Berridge, K. C. Taste reactivity as a measure of the neural control of palatability. In: Sprague, J. M.; Epstein, A. N., eds. Progress in psychobiology and physiological psychology. Orlando: Academic Press; 1985: Grill, H. J.; Kaplan, J. M. Caudal brain stem participates in the distributed neural control of feeding. In: Stricker, E. M., ed. Neurobiology of food and fluid intake. New York: Plenum Press; 1990: Grill, H. J.; Norgren, R. Neurological tests and behavioral deficits in chronic thalamic and chronic decerebrate rats. Brain Res. 143: ; Grill, H. J.; Norgren, R. The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats. Brain Res. 143:263-79; Grill, H. J.; Norgren, R. The taste reactivity test. II. Mimetic responses to gustatory stimuli in chronic thalamic and chronic decerebrate rats. Brain Res. 143:281-97; Gylys, J. A.; Chamberlain, J. H.; Wright, M. N.; Doran, K. M. Interaction between diazepam and naloxone in conflict, novel food intake and antimetrazol tests. Fedn. Proc. Fedn. Am. Socs. exp. Biol. 38:863; Haefely, W. Pharmacological profile of two benzodiazepine partial agonists: Ro and Ro Clin. Neuropharmacol. 7: ; Hanson, H. M.; Stone, C. A. Animal techniques for evaluating anti-anxiety drugs. In: Nodine, J. H.; Siegier, P. E., eds. Animal and clinical pharmacological techniques for drug evaluation. Chicago: Year Book Medical Publishers; 1964: Kiefer, S. W.;.Dopp, J. M. Taste reactivity to alcohol in rats. Behav. Neurosci. 103: ; Kirkham, T. C.; Cooper, S. J. CGS 8216, a novel anorectic agent, selectively reduces saccharin solution consumption in the rat. Pharmacol. Biochem. Behav. 25:341-5; Leeb, K.; Parker, L.; Eikelboom, R. Effects of pimozide on the hedonic properties of sucrose: analysis by the taste reactivity test. Pharmacol. Biochem. Behav. 39: ; Macdonald, R. L.; Olsen, R. W. GABA^ receptor channels. Annu. Rev. Neurosci. 17: ; Margules, D. L.; Stein, L. Neuroleptics v. tranquilizers: Evidence from animal studies of mode and site of action. In: Brill, H.; Cole, J. O.; Deniker, P.; Hippius, H.; Bradley, P. B., eds. Neuropsychopharmacology Amsterdam: Excerpta Mediea Foundation; 1967: McLaughlin, C. L.; Baile, C. A. Cholecystokinin, amphetamine and diazepam and feeding in lean and obese Zucker rats. Pharrnacol. Biochem. Behav. 10:87-93; Nakamura, K.; Norgren, R. Taste response of neurons in the nucleus of the solitary tract of awake rats: an extended stimulus array. J. Neurophysiol. 70: ; 1993,

11 BENZODIAZEPINES, AFPETITE, AND TASTE PALATABILITY Norgren, R. Central neural mechanisms of taste. In: Darien- Smith, I.; ed. Handbook of physiology: The nervous system IIIsensory processes. Washington, D.C.: Am. Physiol. Soc.; 1984: Norgren, R.; Pfaffmann, C. The pontine taste area in the rat. Brain Res. 91:99-117; Ossenkopp, K. P. The chemosensitive area postrema and conditioned changes in taste reactivity neuroscience taste reactivity symposium. Neurosci. l~fiobehav. Rev Parker, L. A. Chlordiazel~oxide nonspecifically enhances consumption of saccharin solmion. Pharmacol. Biochem. Behav. 38: ; Parker, L. A. Taste reactivity responses elicited by reinforcing drugs: A dose-response analysis. Behav. Neurosei. 105:955-64; Parker, L. A. Chlordiazepoxide enhances the palatability of lithium-, amphetamine-, and saline-paired saccharin solution. Pharmacol. Biochem. Behav. in press: Parker, L. A. Taste reactivity responses elicited by flavors paired with drugs of abuse neuroseience taste reactivity symposium. Neurosci. Biobehav. Rev Parker, L. A.; Brossean, L. Apomorphine-induced flavor-drug associations: a dose-response analysis by the taste reactivity test and the conditioned taste avoidance test. Pharmacol. Biochem. Behav. 35:583-7; Parker, L. A.; Lopez, N. Jr. Pimozide enhances the aversiveness of quinine solution. Pharmacol. Biochcrn. Bchav. 36:653-9; Parker, L. A.; MacLeod, K. B. Chin rub CRs may reflect conditioned sickness elicited by a lithium- paired sucrose solution. Pharmacol. Biochem. Behav. 40:983-6; Parker, L. A.; Maier, S.; Rennie, M.; Crebolder, J. Morphineand naltrexone-induced modification of palatability: Analysis by the taste reactivity test. Behav. Neurosci. 106: ; Paxinos G.; Watson, C. The rat brain in stereotaxic coordinates. New York, Academic Press; Pecina, S.; Berridge, K. C. Fourth ventricle microinjections of diazepam enhance hedonic reactions to taste. Soc. Neurosci. Abstr. 18:1231; Pecina, S.; Bcrridge, K. C. Comparison of systemic and intracranial administration of morphine: Effects on hcdonic taste reactivity (in rats). Soc. Neurosq.'i. Abstr. 129:1820; Posadas-Andrews, A.; Nieto, J.; Burton, M. J. Chlordiazepoxide induced eating: hunger or voracity? Proc. West. Pharmacol. Soc. 26: ; Poschel, B. P. H. A simple and specific screen for benzodiazepine-like drugs. Psychopharmacologia 19:193-8; Redgrave, P.; Dean, P.; Taha, E. B. Feeding induced by injections of muscimol into the substantia nigra of rats: Unaffected by haloperidol but abolished by large lesions of the superior colliculus. Neuroscience 13:77-85; Richards, J. G.; Glinz, R.; Schoch, P.; M6hier, H. New trends in mapping benzodiazepine rl;ceptors. In: Bigglio, (3.; Costa, E., eds. Chloride channels and their modulation by ncurotransmitters and drugs. New York: Raven Press; 1988: Richards, J. G.; M6hler, H. Benzodiazepine receptors. Neuropharmacology 23: ; Schwartz, G. J.; Grill, H. J. Relationships between taste reactivity and intake in the neurologically intact rat. Chem. Senses 9: ; Sclafani, A. Nutritionally based learned flavor preferences in rats. In: Capaidi, E. D.; Powley, T. L., eds. Taste, experience, and feeding. Washington, D. C.: American Psychological Association; 1991: Seeley, R. J.; Galaverna, O.; Schulkin, J.; Epstein, A. N.; Grill, H. J. Lesions of the central nucleus of the amygdaia II: Effects on intraoral NaCl intake. Behav. Brain Res. 59:19-25; Sepinwall, J.; Sullivan, J. W.; Glinka, S.; Gold, L.; Boff, E.; Gamzu, E.; Kleim, K.; Pietrusiak, N.; Smart, T. Assessment of the anxiolytic properties of a novel benzodiazepine derivative (Ro ) with mixed agonist/antagonist profile. Soc. Neurosci. Abstr. 12:661; Sonbri~, P.; Jobert, A.; Thiebot, M. H. Differential effects on naloxone against the diazepam-induced release of behavior in rats in three aversive situations. Psychopharmacology 69:101-5; Soubri6, P.; Kulkarni, S.; Simon, P.; Boissierm, J. R. Effects of antianxiety drugs on the food intake in trained and untrained rats and mice (author's transl). Psychopharmacologia 45:203-10; Spector, A. C.; Grill, H. J.; Norgren, R. Concentration-dependent licking of sucrose and sodium chloride in rats with parabrachial gustatory lesions. Physiol. Behav. 53:277-83; Spector, A. C.; Norgren, R.; Grill, H. J. Parabrachial gustatory lesions impair taste aversion learning in rats. Behav. Neurosci. 106:147-61; Stapleton, J. M.; Lind, M. D.; Merriman, V. J.; Reid, L. D. Naloxone inhibits diazepam-induced feeding in rats. Life Sci. 24: ; Stephens, R. J. The influence of mild stress of food consumption in untrained mice and the effect of drugs. Br. J. Pharmacol. 47: 146; Treit, D.; Berridge, K. C. A comparison of benzodiazepine, serotonin, and dopamine agents in the taste-reactivity paradigm. Pharmacol. Biochem. Behav. 37:451-6; Treit, D.; Berridge, K. C.; Schultz, C. E. The direct enhancement of positive palatability by chlordiazepoxide is antagonized by Ro and CGS Pharmacol. Biochem. Behav. 26:709-14; Tye, N. C.; Nicholas, D. J.; Morgan, M. J. Chlordiazepoxide and preference for free food in rats. Pharmacol. Biochem. Behav. 3: ; Williamson, M. J.; Paul, S. M.; Skolnick, P. Labelling of benzodiazepine receptors in vivo. Nature (Lond.) 275: ; Wise, R. A.; Dawson, V. Diazepam-induced eating and lever pressing for food in sated rats. J. Comp. Physiol. Psychol. 86: ; Woods, J. H.; Katz, J. L.; Winger, (3. Benzodiazepines: use, abuse, and consequences. Pharmacol. Rev. 44: ; Zellner, D. A.; Berridge, K. C.; Grill, H. J.; Ternes, J. W. Rats learn to like the taste of morphine. Behav. Neurosci. 99: ; 1985.