The human behavioral pharmacology of the common core heptapeptides

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Specialist Subject Editors: D. DE W I E D , W. H. (;ISI'EN and TJ. B. VAN WIMERSMA GREIDANUS

THE

HUMAN BEHAVIORAL COMMON CORE

PHARMACOLOGY HEPTAPEPTIDES

OF

THE

ROLAND J. BRANCONNIER

Geriatric P,~ychopharmacolo.qv. In,~titute Jbr P,~ychophurmacologic Reseurch. 1842 Beacon Street. Brookline. M u,~sttchu,setts I)2146. U.S.A.

1. INTRODUCTION The employment of pharmacologic agents to enhance human performance is not a recent phenomenon. The Incas were aware of the effects of erythroxylon coca and exploited its stimulant properties to augment working capacity. Indeed, this property was so prominent that an ergometric unit of measurement the 'cocada" was adopted by them to express the energizing effects of a single chew of coca (Carroll, 1977). Similarly, the Chinese have recognized the Central Nervous System (CNS) analeptic activity of ephedrine and have employed it as part of their medicinal armamentarium for over 5000 yr (Chen et al., 1930). With the advent of modern pharmacology, an increasingly broad spectrum of both natural and synthetic compounds with putative performance enhancing capabilities have been investigated. Such studies have focused on the effects of these agents on an array of human performance variables ranging from elementary motor activities to the complex cognitive processes of learning and memory. The principal drugs that are employed as augmentors of physical capacity and endurance are the anabolic steroids such as methandrostenolone (Dianabol) (Bowers et al., 1972). Evidence suggests that these agents increase physical capacity by stimulating the growth of muscular mass via retention of nitrogen and promotion of protein synthesis (Papanicolaou et all, 1938). While these steroids are utilized widely in sports medicine, the large number of untoward effects as well as questionable efficacy in this respect make the use of such compounds inadvisable (Johnson et al., 1972). Bridging the gap between agents whose action is primarily on physical capacity to those that may effect cognitive processes are the stimulants. Caffeine and the sympathomimetic amines such as the amphetamines are the most thoroughly studied performance enhancing drugs (Latz, 1967). Since the early study of Rivers and Webber (1907), the preponderance of evidence has indicated that the stimulants are capable of augmenting human performance. However, until recently, the question of whether the quality of the enhancement was supranormal or a restoration of an optimal performance state was in dispute. In 1962, a definitive review by Weiss and Laties concluded that, in man, the stimulants primarily restore both physical and mental activity degraded by fatigue and that there was considerable evidence to suggest supranormal performance. Indeed, a large number of studies (Blum et al., 1964; Evans et al., 1964; Hurst et al., 1967; Kornetsky, 1969; Hartmann et al., 1977) published subsequent to this review, support their former but not their latter conclusion regarding the nature of the response to stimulants. In recent years, the interest in performance enhancing drugs has centered on agents that might be capable of improving learning and memory rather than ameliorating fatigue or improving working capacity. Agents that can be grouped under this rubric fall into three broad categories: (1) the cholinergics, (2) the nootropics, and (3) the neuropeptides. It has long been recognized that the administration of antimuscarinic agents such as scopolamine and atropine impair storage and retrieval from secondary memory (SMt 161

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ROLAND J. BRANCONNIER

while sparing primary memory (PM) and that this negative effect can be antagonized by physostigmine (Safer et al., 1971 ; Deutsch and Lutzky, 1967). More recently, studies by Davis et al. (1976) and Sitaram (1978) have shown that supranormal enhancement of retrieval from SM can be obtained with both physostigmine and the cholinomimetic, arecoline, in normal subjects. These findings have generated considerable interest in the cholinergics not only as possible performance augmentors but also as therapeutic agents for the treatment of Senile Dementia-Alzheimer's type (SDAT), a disease in which a possible cholinergic deficit occurs (Perry et al., 1978: White et al., 1977: Spillane et al., 1977: Bowen et al., 1979). For a review of this area, readers are referred to Growden and Corkin (1980). Giurgea (1972) has coined the term "nootropic" to describe a class of drugs that selectively activate telencephalic integrative mechanisms and therefore augment higher cortical functions. Piracetam, the prototypical agent, is a GABA derivative that has been shown in at least one study to enhance verbal learning in normals (Dimond and Brouwers, 1976). While enticing, at present, these findings have not been replicated. Other compounds in this class such as PRL-8-53 (Hansl and Mead, 1978) are so new, very little data is available concerning their efficacy. With the exception of the stimulants, the pro-opiocortin (Eipper and Mains, 1978: Roberts et al., 1978) derived neuropeptide hormones of the hypophysis are the most thoroughly investigated of the agents of putative value in the enhancement of human performance. Therefore, the remainder of this paper will be devoted to a review of the literature regarding the physiology and behavioral effects of these agents. 2. PHYSIOLOGY AND BIOCHEMISTRY OF PRO-OPIOCORTIN HORMONES The established physiological role of ACTH is to promote the synthesis of the adrenocortical steroid hormones in the adrenal cortex via activation of cyclic AMP (Haynes et a/., 1959). The adrenocorticotropic activity of ACTH is destroyed by cleavage of the N-terminal serine but serial cleavage from the C-terminal phenylalanine does not result in a reduction of activity until removal of the 20th amino acid. valine (Hofmann et al., 1961). Since both :t- and fl-MSH are peptides shorter than 19 amino acids, neither possesses significant ACTH-Iike properties. However, ACTH, zt- and fl-MSH as well as fl- and 7-LPH are capable of stimulating melanin production in chromophores (Turner and Bagnara, 1978). This similar biological activity may be due to the presence of an homologous heptapeptide sequence common to all of these neuropeptide hormones (see Fig. 1). ACTH4_~o (01-63) is the common core heptapeptide (CCH) of the pro-opiocortin derived hormones. It was first used by Ferrari et al. (1963) and de Wied (1966) in behavioral studies. This compound is devoid of ACTH activity, is a weak melanocyte stimulating agent and like ACTH is capable of ameliorating a number of behavioral deficits as a result of hypophysectomy (de Wied. 1969). However, ACTH4.x0 has two pharmacokinetic characteristics that limit its usefulness, a rapid enzymatic degradation in plasma resulting in a half-life of only 90 sec and a lack of enteral absorption (Witter et a/., 1975). Therefore, Greven and de Wied (1973) synthesized a congener of ACTH4.10 by substituting the methionine at position 4 with a methionine sulphoxide and replacing the position 8 arginine with d-lysine and the position 9 tryptophan with a phenylalanine. The resulting compound ACTH4_9 (ORG-2766) had an increased resistance to proteolytic cleavage with a t l , equal to 5-10 min could be absorbed orally, and in animal tests had behavioral potency thousand times greater than ACTH4_~o (Greven et al.. 1973: Rigter and Van Riezen. 1975). 3. INTRODUCTION TO HUMAN STUDIES To preface the discussion of the CCH on human performance, it is necessary to define the nomenclature and concepts as well as outline the format that will be employed in the remainder of this review.

Behavioral pharmacology of the common core heptapeptides

163

Pro-opiocortin derived neurohormones with homologous heptapeptide core

Abbr.:

ACTH:

ser 1

try . . . m e t -glu--his 2 4 5 6

gly.., gly 10 38

phe 39

~-MSH:

ser 1

try...met 2 4

gly...pro 10 12

val 13

fl-LPH:

glu----leu.., met - g l u - - h i s - - p h e 1 2 47 48 49 50

t r y - - g l y . . , gly 52 53 89

gh 90

7-LPH:

glu - l e u . . . m e t 1 2 47

try 52

gly.., lys 53 57

asp 58

]~-MSH: a s p ~ g l u ... m e t - - g l u - - h i s - - p h e - - a r g - - t r y - g l y . . . lys 1 2 7 8 9 10 11 12 13 17

asp 18

glu 5

phe 7

arg--try 8 9

his--phe---arg 6 7 8 arg 51

glu--his--phe--arg 48 49 50 51

try 9

ACTH = Adrenocorticotropic Hormone -MSH = Melanocyte Stimulating Hormone -LPH = Lipotropin

FIG. 1. The five neuropeptides illustrated represent the Common Core Heptapeptides (CCH) derived from the pro-hormone, pro-opiocortin. The homologous amino acid sequence is presented in boldface along with the corresponding numerical position in the respective hormone.

The topic of human performance concerns performance of specific types of tasks and since the studies to be reviewed below have utilized a wide spectrum of tests paradigms, an ~arm chair' factor analysis was performed to group tests that presumably assess similar functions. This resulted in the condensation of the initially large number of tests into five categories: (1) Electroencephalographic Measurements; (2) Peripheral Electrophysiological Measures; (3) Tests of Psychomotor Performance and Attention; (4) Affective Ratings; and (5) Tests of Learning and Memory (see Table 1). While the first four groups are self-explanatory, as can be seen from Fig. 2, the structure of human memory is a complex topic. Therefore, a discussion of the structure and assessment of human memory is necessary in order to provide a conceptual framework for analysis of the studies to be reviewed. The current concept of the structure of human memory is that it consists of four distinct stores each with characteristic storage capacity, facility with which items are retrieved and resistance to forgetting. They are Sensory Memory, Primary Memory, Secondary Memory and Semantic Memory (Crowder, 1976). Sensory memory is a high capacity, ultra-short trace duration system that is modality specific (Sperling, 1967). In the visual system, sensory memory is called iconic memory and has the properties of extracting visual characters at the rate of 100 items per second and holding them in storage for approximately 250 msec (Averbach and Coriell, 1961: Sperling; 1967). Performance on iconic memory tasks has been shown to be correlated with clinical measures of memory such as the Weschler Memory Scale and the BrownPeterson Paradigm (Branconnier and Cole, 1977; Branconnier et al., 1978). The analog of iconic memory in the auditory system is echoic memory or the precategorical acoustical store (Neisser, 1967; Crowder, 1969). While little is known regarding the capacity of this system, masking experiments have shown that trace duration is on the order of 2 sec (Massaro, 1972). The Primary Memory (PM) system or operating memory is a limited capacity, short duration store that is phonemic as well as visual (Waugh and Norman, 1965: Posner. 1973: Kintsch and Buschke, 1969; Shepard and Meltzer, 1971). Items in PM are highly accessible and subject to rapid forgetting due to displacement by subsequently processed information or previously learned material (Peterson and Peterson, 1959; Estes, 1972). PM capacity has been estimated to be 2.2 items and is unaffected by aging, intelligence, general anesthetics or anticholinergic drugs (Glanzer and Razel, 1974: Thurm and Glanzer, 1971): Craik. 1968; Adam. 1973: Drachman, 1977).

164

ROLAND J. BRANCONNIER TABLE 1. "Armchair' Factor Analysis q/Tests Employed in Studies o[ Common Core Heptapeptides Electroencephalographic Measures 1. Spontaneous EEG 2. Contingent Negative Variation 3. Visual Evoked Potential 4. Somato-sensory Evoked Potential 5. Alpha Blocking Response

11. Peripheral Electrophysiological Measures I. Heart Rate/Heart Rate Variability 2. Forearm Blood Flow 3. Tendon Reflex Activity 4. Electromyographic Action Potential II1. Affective Ratings 1. Spielberg State Trait Anxiety 2. Norris Analog Rating Scale 3. Profile of Mood States 4. Mood Scale Elderly 5. Beck Depression Inventory IV. Tests of Psychomotor Performance and Attention 1. Simple/Disjunctive Reaction Time (Short) 2. Serial Reaction Time (Long) 3. Continuous Performance Test 4. Digit Symbol Substitution Test 5. Rod and Frame 6. Embedded Figures/Closure Flexibility 7. Hidden Word 8. Dot Discrimination 9. Cross-outs 10. Stroop Color Word I 1. Finger Tapping Speed 12. Perdue Pegboard V. Tests of Learning and Memory A. Sensory Memory 1. Sperling's Perceptual Trace B. Primary Memory 1. Digit Span 2. Brown-Peterson Paradigm 3. Running Memory Span 4. Sternberg Item Recognition C. Secondary Memory 1. Paired Associate Learning 2. Paragraph Recall 3. Squire Remote Memory 4. Kim Object Recall 5. Buschke Selective Reminding 6. Benton Visual Retention 7. Design Recall 8. Face Recognition 9. Non-Verbal Incidental Learning 10. Extra-Dimensional Shift Learning D. Semantic Memory 1. Willner Instance Similarities Test E. Active Conditioned Avoidance F. Reversal of ECS Induced Amnesia

S e c o n d a r y M e m o r y (SM) is a m a s s s t o r a g e s y s t e m t h a t has n o k n o w n limits to its c a p a c i t y ( S h e p a r d , 1967 S t a n d i n g et al., 1970). F u r t h e r , it is b o t h t e m p o r o - v e r b a l as well as v i s u a l - s p a t i a l a n d c a n r e t a i n i n f o r m a t i o n in e i t h e r o r b o t h m o d e s p e r m a n e n t l y ( P a v i o a n d C s a p a , 1969' S m i t h , 1963; Hill, 1957). S e m a n t i c m e m o r y is the e q u i v a l e n t of a m e n t a l t h e s a u r u s t h a t stores the c a t e g o r i z a t i o n s a n d s e m a n t i c r e l a t i o n s h i p s of v e r b a l m a t e r i a l ( T u l v i n g , 1972). It has the c h a r a c t e r istics of SM, with the e x c e p t i o n t h a t the m a t e r i a l is c o n t e x t - f l e e (see below).

Behavioral pharmacology of the c o m m o n core heptapeptides

165

Schematic of human memory

Semantic memory

I

~[Echoie memory Sensory memory

I

2 ~ Iconic memory "4"--~ Scannalnrg t i me ~IL------~SVcioS!~:~Pd!~ 1or y l ~ .

I 2 3 4 5 6 7 8 9

Auditory inpu? Visual input Phonemic encoding Visual image Semantic encoding Rehersal Categorization Dual trace TO.T (Test- Operate- Test}

9

: I

Recognition

11

Output

FIG. 2. This figure illustrates the stages and control processes of h u m a n memory. The model is based on current concepts of the structure and information processing characteristics of h u m a n memory derived from a large body of experimental evidence.

Sensory, primary and secondary memory are believed to be episodic while semantic memory is not. Episodic memory is described as memory that is associated with a specific spatial or temporal context. For example, in the laboratory, a subject is asked to learn the word 'cat' as part of a list. If the subject fails to remember "cat' as part of the list; it is only because he failed to incorporate it into a specific context. He knows the word 'cat' and has a number of semantic associations as part of his knowledge of animals. Therefore, the failure to remember is associated with episodic memory while the general knowledge is associated with semantic memory. The transfer of items from one store to the next is modulated by a number of control processes (Atkinson and Shiffrin, 1968). Among those control processes that have been identified are encoding, rehearsal, scanning, search and recognition (Craik 1972: Atkinson and Shiffrin, 1968; Sternberg, 1966; Anderson and Bower, 1972). In the laboratory, the assessment of memory is concerned with a quantitative analysis of the temporal retention of verbal or non-verbal information. Basically, there are three methods of assessing retention; two are direct, recognition and recall and the third, relearning is indirect (Deese and Hulse, 1967). All three methods can be used with a variable time interval intervening between learning and the test of retention. Thus, a memory test can be described in terms of time. A memory test can be described in terms of time. A memory test that has a retention interval greater than sensory memory but less than secondary memory is a test of 'immediate' memory and is approximately equivalent to PM. Tests of Short-Term Memory (STM), Long-Term Memory (LTM) and Remote Memory are to varying degrees dependent on SM (Crowder, 1976). In the literature, recal! performance is assessed most frequently, recognition less frequently and relearning infrequently. Tulving and Pearlstone (1966) have drawn a distinction between what is in memory and what can be retrieved--i.e, availability vs accessibility. It has been demonstrated repeatedly that recall is both highly correlated with degree of initial storage as well as being an insensitive indicator of what is available in memory (Hulicka and Weiss, 1965; Slamecka, 1967). In contrast, recognition performance is very sensitive and can often detect availability of previously learned material when recall (accessibility) fails to do so (Schonfield and Robertson, 1966; Harwood and Naylor, 1969).

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ROLAND J. BRANCONNIER

Anderson and Bower (1972) have proposed a search recognition hypothesis to explain why recognition is a more sensitive indicator of retention than recall. Recall is a two-step process requiring both the implicit search for an available target item in memory followed by the recognition that the item is correct. In recognition, only one-step is required. The target item is presented and must only be identified as an available item in storage. The apparent superiority of recognition over recall results from retrieval (accessibility) failure due to ineffective search. Therefore, when evaluating the effects of any pharmacologic agent on memory, it is necessary to be aware of which memory store or control processes are being assessed as well as how sensitive the test measurements are. 4. BEHAVIORAL P H A R M A C O L O G Y O F CCH IN H U M A N S 4.1.

ELECTROENCI!PHALOGRAPHIC

MtiASURES

Endroczi and coworkers (1970) were the first investigators to report an effect of CCH on the human EEG. In this single-blind study, young, normal subjects were treated with single doses o f 0 . 5 m g ACTHl_24, 1 and 2 m g ACTHI_~o, I and 2rag ACTHll.24 or saline by i.v. injection. EEG was recorded during a go/no-go task and habituation of the alpha blocking was the dependent variable. Their findings indicated the ACTH fragments containing CCH were capable of reinstating the alpha blocking response of the EEG after habituation. Since alpha blocking is considered an EEG index of central attention (Hughes, 1968), the authors concluded that these agents were affecting attentional processes.

Miller et al. (1974) studied the effects ACTH~_~,~ (0.5 rag, i.v.) and ACTH,~_~o (10rag, i.v.) on spontaneous EEG, contingent negative variation (CNV) and EEG alpha blocking. In contrast to the findings of Endroczi et aL (1970), ACTHI_ failed to alter any of the electrophysiological measures assessed. However, in the spontaneous EEG, ACTH4.~o induced a significant reduction in 3-7 Hz activity with a concomitant increase in frequencies greater than 7 Hz. Moreover, they also observed a disinhibition of the alpha blocking response. More recently, Miller et al. (1976) investigated the activity of ACTH,,.10 administered s.c. in an acute, placebo controlled, double-blind, cross-over experiment. Again. spontaneous EEG was evaluated as well as Visual Evoked Potential (VEP) recorded during the Continuous Performance Test (CPT). Results indicated that ACTH,~_t0 increased the latency and decreased the amplitude of the late components of the VEP while a trend toward faster frequencies in the resting EEG was noted. In contrast, Sannita et al. (1976) have reported that 60 mg ACTH4_~o i.v. was ineffective in altering the resting EEG when analyzed by computerized power spectral methods. Kastin et aL (1971) studied the effects of single dose of l0 mg synthetic MSH. i.v. on the Somatosensory Evoked Potential (SEP) obtained from four normals, three patients who had been hypophysectomized and two with Sheehan's syndrome. The data obtained revealed that MSH induced a marked enhancement of the amplitude of the SEP. In fact, the increase was so robust that the usual averaging methods were not required to visualize it, A more recent study by Ashton et al. (19771 failed to show any effect of either synthetic ~-MSH (10 mg, i.v.) or fl-MSHI.z2 (10 mg. i.v.) on CNV. The effects of ACTH4_~o on the EEG activity of patients with senile dementia has been evaluated in three published studies. Ferris et al. (1976) in a double-blind, placebo controlled trial of 15 and 30rag ACTH4,~o injected s.c. for three consecutive days, failed to obtain any evidence of an effect on EEG with either dose in these patients. In a subsequent study, Ferris et al. (1980) administered ACTH4.9 at 10 and 20 mg p.o. for up to two weeks. Again. this agent failed to alter EEG activity. In contrast, a single dose, double-blind, controlled study of 30 mg of ACTHa_lo given s.c. to patients with mild to moderate senile dementia indicated that this agent induced a statistically significant reduction in the abundance of alpha band activity with a con-

Behavioral pharmacology of lhe common core heptapeptides

167

comitant increase in theta activity in the spontaneous EEG when analyzed by computerized zero-cross analysis (Branconnier et al., 1979). Of the nine studies cited above, six evaluated spontaneous EEG. Two reported statistically significant alterations in frequency, one a trend and three were negative. The conclusion is that the present evidence is equivocal regarding the effects of CCH on human spontaneous EEG. With respect to the event related EEG, five studies measured some type of task related EEG and four of these were positive. While this is not significant by Binomial Test, p = 0.188, there is a trend. Therefore, despite the small number of studies, the evidence suggests that these compounds can affect EEG activity when recorded during stimulation or information processing. 4.2. PERIPHERAL ELECTROPHYSIOLOGICAL MEASURES

Several parameters of peripheral electropbysiology have been employed in studies of the neuropeptides with the aim of assessing the effects of these compounds on arousal. The most frequently used measurements reported in the literature are heart rate (HR) or heart rate variability (HRV). Miller et al. (1974) were the first to report that ACTH,.24 and ACTH4.10 had no detectable effect on HR. In a subsequent study, Miller et al. (1977), in a placebo controlled cross over study, were able to replicate their earlier findings, demonstrating that 30 mg ACTH4.~o produced no change in HR. These data are substantially in agreement with those of Sandman et al. (1975) who also failed to show HR differences attributable to peptide treatment. In contrast to the above, Sandman et al. (1976; 1977) has observed that ACTH4_~o (15 mg, i.v.) reduced HRV significantly in mentally retarded men as well as young norreals. The authors concluded that the observed reduction in HRV was due to a CCH induced increase in the orienting response. Likewise, in more recent studies, Brunia and van Boxtel (1978) using 15 and 30 mg ACTH4,~o, i.m., Gaillard and Varey (1979) using 5, 10 or 20 mg ACTH4.9, p.o. and Breier et al. (1979) using 30 mg ACTH4_~o, s.c. have all reported that HRV was significantly reduced by neuropeptides. Thus, three studies are negative and five positive regarding CCH effects on HR and HRV. This distribution has a p = 0.36, indicating that the data weakly support a peptide effect on arousal as measured by changes in HR especially if recorded during task performance. Several studies also report significant effects of CCH on a variety of other electrophysiological parameters. Thus, Breier et al. (1979) have reported that ACTH4_lo increased forearm blood flow; Brunia and van Boxtel (1978) that tendon reflexes were enhanced by ACTH4_~o and Strand et al. (1977) that 3, 6 and 15 mg of ACTH4.1o administered i.v. prevent the normal decline in electromyographic action potential resulting from nerve evoked muscle stimulation in patients with muscle atrophy. None of the above findings have been replicated therefore they must be considered tenuous at this time. 4.3. AFFECTIVE RATINGS Eight published studies have evaluated the acute effects of CCH on affect in normals. Miller et al. (1974j in the study cited above, evaluated the anxiety level of his subjects by employing the Spielberg State-Trait Anxiety Scale. While ACTHl_24 produced no significant effect on state or trait anxiety, ACTH4.1o reduced state anxiety significantly. This is in agreement with the observation of Sandman et al. (1975) who demonstrated that anxiety was significantly reduced by 15 mg of ACTH4_lo given by i.v. administration. However, Miller et al. (1976) failed to replicate the anti-anxiety effect using a higher dose of ACTH4.1o. Gaillard and Sanders (1975) studied ACTH4_~o (30 mg, s.c.) in a double blind, parallel groups study. Their findings with respect to affect, showed that the ACTH4_~o group reported being significantly more 'quick-witted' on the Norris analog rating scale. However, in a more recent study by Gaillard and Varey (1979) the Profile of Mood States (POMS~ was unable to discriminate 5, 10 or 20 mg of ACTH4_9 from placebo.

16~

ROLAND J. BRANCONNIER

In the study by Ashton et al. (1977), they report that the subjects complained of fatigue upon questioning. Yet, this elicited information was not reflected in the subject's own self-rated evaluation. Likewise, Veith et al. (1978) studied 30 mg ACTH4_to given s.c. in menstrual and midcycle women. Their findings with respect to anxiety indicated that there was a statistically significant interaction between peptide and menstruation. However, no main effect for drug occurred and the authors concluded that the peptide had no significant effect on anxiety. Ward et al. (1979) also failed to demonstrate an anti-anxiety effect of 30 mg ACTH4_a0 given s.c. in a controlled, double-blind cross-over study. Results obtained from studies of the acute effects of ACTH4_lo on mood in pathological groups has been uniformly negative. Three studies failed to show effects in senile dementia at doses of 15 or 30 mg, s.c, or in hyperkinetic children at 30 mg, s.c. (Ferris et al., 1976; Will et al., 1978; Branconnier et al., 1979; Rapoport et al., 1976). Combining all the published studies of the effects of acute administration of neuropeptides on affect, three are positive and nine are negative. Analysis of this distribution reveals that p = 0.073 and therefore it can be concluded that acute administration of these drugs does not alter affective status. Studies assessing the effects of CCH when given subchronically to pathological groups are scarce. Ferris et al, (1980) have reported that ACTH,,_9 given in a dose range of 10-20 mg per day, p.o. for two weeks to patient with mild cognitive impairments resulted in a reduction of self-rated depression and anxiety with a concomitant increase in competence as measured by the Mood Scale-Elderly. However, using the POMS, we were not able to demonstrate an effect on mood with the same compound given to a similar patient sample for seven days in doses of 5, 10 or 20 mg per day (Branconnier, unpublished data). Therefore, the evidence regarding the sub-chronic effects of CCH on human affect are at present equivocal. See also Pigache and Rigter (1981), who explained the effect of CCH in humans in terms of increased vigilance. 4.4. TESTS OF PSYCHOMOTOR PERFORMANCE AND ATTENTION Evaluation of the effects of pharmacologic agents on the time course of human information processing provides a sensitive assay of their effects on the CNS (Posner, 1978; Adam, 1979). The most rudimentary assessment of this type is simple reaction time (RT) and this technique has been employed in the study of CCH. Three studies in senile dementia have RT measures and all have failed to report significant alteration of RT after acute doses of ACTH4.1o or sub-chronic doses of ACTH4_9 (Ferris et al., 1976, 1980; Will et al., 1978). Likewise, a more complex RT paradigm, disjunctive RT, is not affected by acute doses of ACTH4_10 in either normals or senile dementia patients treated with this agent (Miller et al., 1974; Ferris et al,, 1976). In contrast to these negative findings regarding simple and disjunctive RT, are the reports of significant CCH effects on extended serial RT tasks, Gaillard and Sanders (1975) demonstrated that ACTH4.~0 prevents the increase in reaction time that normally occurs during a long choice RT task. In a subsequent experiment, Gaillard and Varey (1979) replicated this earlier finding showing that ACTH4.9 also exerts a similar effect on serial RT. Branconnier et al. (1979) also employed a serial RT test with senile dementia patients. The results of this study indicated that ACTH4_lo produced a weak suppression of increased RT resulting from continuous performance over 15 min. Therefore, the evidence suggests that CCH are capable of counteracting the effects of reactive inhibition or restoring performance degraded by fatigue during long monotonous performance tests. A considerable number of test paradigms purporting to measure central attention have been used in studies of CCH. In the main, the findings have been negative with the following: The Continuous Performance Test (Miller et aL, 1976; Rapoport et al., 1976); Digit Symbol Substitution Test (Sannita et al., 1976; Miller et al., 1976; Ferris et al., 1976, 1980; Rapoport et al., 1976); Rod and Frame (Sandman et al., 1975, 1977; Miller et al., 1974; Veith et al., 1978); Embedded Figures/Closure Flexibility (Sandman et al., 1975;

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169

Ferris et al., 1976, 1980); Hidden Word (Ferris et al., 1976, 1980); Dot Discrimination (Sandman, et al. 1977); Stroop Color Word (Branconnier, unpublished); Cross-outs (Ferris et al., 1976); Finger Tapping Speed (Ferris et al., 1976, 1980) and Purdue Pegboard (Will et al., 1978). Analysis of the distribution of positive and negative findings with respect to the above revealed that only the Continuous Performance Test and Digit Symbol Substitution Test in the Miller et al. (1976) study were reported as positive. The remaining 19 reports were negative. The probability associated with this distribution has a p < 0.001. Thus, there is little evidence to support the hypothesis that CCH affect attentional mechanisms in humans. 4.5. TESTS OF LEARNING AND MEMORY

Three studies have evaluated visual iconic recall in senile dementia patients treated with both ACTH4.1o and ACTH4.9. These studies have revealed that neither compound significantly affects visual iconic recall as measured by performance on the Sperling Perceptual Trace (Ferris et al., 1976; Branconnier et al., 1979, unpublished). No studies have been published assessing CCH effects on visual icon in normals or echoic memory in either normals or pathological groups. Therefore, the present evidence suggests that CCH do not alter visual sensory memory. Primary Memory has been investigated using Digit Span (Miller et al., 1974; Sannita et al., 1976; Ferris et al., 1976, 1980; Will et al., 1978; Branconnier et al., 1979); The Brown-Peterson Test (Sannita et al., 1976; Dornbush and Nikolovski, 1976; Dornbush and Volavka, 1976) and Running Memory Span (Gaillard and Varey, 1979). Not unexpectedly, all of the studies above with the exception of Miller et al. (1974) have failed to demonstrate C C H effects on PM. These above findings with respect to PM are strengthened further by the study conducted by Ward et al. (1979). In this study, the authors employed the Sternberg Item Recognition test to assess the effects of 30 mg ACTH4_lo, s.c. on PM scanning rate in normal subjects. Their results indicated that this agent had no significant effect on scanning in PM, but did significantly improve the encoding and response selection components of the test. Since the Sternberg has many characteristics of long serial RT task, these data are consistent with the previous suggestion that ACTH4_~o restores an optimal performance state rather than affecting memory directly. Since the distribution of 1 positive and ten negative observations has a p = 0.006, it must be concluded that PM is not significantly altered by CCH. The effects of CCH on recall of both verbal and non-verbal material from SM has been explored extensively. For verbal recall, a number of studies have used Paired Associate Learning (a type of cued recall task) (Miller et al., 1974; Sannita et al., 1976; Rapoport et al., 1976; Dornbush and Volavka, 1976; Ferris et al., 1976, 1980; Ashton et al., 1977; Veith et al., 1978; Will et al., 1978; Gailard and Varey, 1979; Branconnier et al., 1979, unpublished); Paragraph Recall (Miller et al., 1976; Ferris et al., 1976, 1980; Ashton et al., 1977; Veith et al., 1978; Will et al., 1978; Branconnier et al., 1979); Squire Remote Memory (Ferris et al., 1980; Branconnier, unpublished); Kim Object Recall (Will et al., 1978) and The Buschke Selective Reminding Test (Ferris et al., 1980). With the exception of positive findings reported by Ashton et al. (1977) and Veith et al. (1978) the remaining 20 observations are negative. Likewise, recall of non-verbal material has been investigated with the following tests: Benton Visual Retention (Miller et al., 1974, 1976; Sandman et al., 1975; Sannita et al., 1976; Rapoport et al., 1976; Ashton et al., 1977; Veith et al., 1978) and Design Recall (Ferris et al., 1976, 1980; Dornbush and Nikolovski, 1976a; Miller et al., 1976; Will et al., 1978). Since the probabilities associated with the 2 positive, 20 negative distribution of the verbal recall outcomes and the 4 positive, 9 negative distribution of the non-verbal recall outcomes are p < 0.001 and p = 0.133 respectively, it can be concluded that CCH have no significant effect on either verbal or non-verbal recall from SM.

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Since recall performance is dependent on search and is not the most sensitive indicator of what is retained in SM, it is conceivable that CCH could exert an effect on SM without being detected. Therefore, measures of recognition would provide a more sensitive test of retention. In the published literature, there are no studies in which recognition for verbal material was assessed, however two studies examined recognition for non-verbal material. Ferris et al. (1976; 1980) have investigated the effects of ACTH4_lo and ACTH4_9 on a Face Recognition test. No significant effects were observed in either study. In our own laboratory, we have employed a test of Non-Verbal Incidental Learning (Branconnier et al., 1980) to study the effects of 5, 10 or 20 mg ACTH,,_9, p.o. given for 7 days on delayed recognition for geometric designs. Our findings are in agreement with those of Ferris et al. (1976, 1980) as we were unable to demonstrate a significant effect of this agent on 7 day later recognition for designs learned before treatment (Branconnier, unpublished). Therefore, at the present time, there is no evidence to support a claim that CCH enhance retention of non-verbal information. The effects of CCH on retention of an operant have also been evaluated by a relearning paradigm. The Extradimensional Shift (ES) problem requires the subject to learn that one of two discriminative cues is correct and the other incorrect, then after a criterion performance is established the correct and incorrect cues are reversed and the number of trials to learn the reversal is determined (Kendler and Kendler, 1962). Facility to reverse is believed to be inversely related to the strength of initial learning (Macintosh, 1965). Sandman et al. (1976) have reported that ACTH4_lo facilitates the learning of a reversal in the ES problem in retardates. However, in a later study with normals Sandman et al. (1977) could not replicate their earlier findings using the same agent. Furthermore, Veith et al. (1978) found that ACTH4_lo actually impaired reversal learning in the ES problem. The inconsistencies of these findings with respect to relearning, are primarily negative and therefore the conclusion is that SM retention of an operant as measured by relearning is unaffected in normals and possibly enhanced in retardates. However, this latter conclusion must be considered tenuous at this time. There are no published studies concerning the effects of CCH on recall from Semantic Memory. However, Willner (personal communication), has used the Willner Instance Similarities Test, a category retrieval paradigm, to assess the effects of 10 and 20mg ACTH,,_9 administered p.o. for 1 week on Semantic Memory in senile dementia patients. No significant effect was observed. Thus, despite the scarcity of data regarding the effects of CCH on Semantic Memory, its similarity to SM warrants the conclusion that it is improbable that this memory store would be affected. To conclude the discussion of the effects of CCH on human memory, I would like to present two studies that have attempted to replicate findings in the animal studies with humans. Miller et al. (1977) in a double-blind controlled study investigated the effects of 30 mg ACTH4_lo given s.c. on the extinction of an active conditioned avoidance response in eighteen normal volunteers. No significant peptide effects were observed. The authors hypothesized that phylogenetic differences between the rat and man may have contributed to the negative results. The observation that amnesia induced by electroconvulsive shock (ECS) could be reversed by post ECS administration of ACTH4.10 or ACTH4.9 in animals led Small et al. (1977) to study whether a similar phenomenon occurred in humans undergoing ECS for depression. In the first of two experiments, subjects were given a paired associate learning and picture learning task one hour prior to ECS. Following ECS, subjects were given either 15 or 30 mg ACTH4_x0 or placebo s.c. at either 30 min or 23.5 hr post-ECS. Recall and recognition tests were performed at 1, 23, 25 and 47 hr post-ECS. No significant effects on memory were observed. In the second experiment, subjects were given five or six ECS treatments then administered a battery of tests 5 hr after the last ECS. This

Behavioral pharmacology of the common core heptapeptides

171

was followed by an s.c. injection of either 30 mg ACTH4.to or placebo at 28.5 hr after the last ECS. Recall and recognition were then tested at 29, 31 and 47 hr after the last ECS. Again, no significant effects on memory were observed. Taken together, the results of these two studies indicate that CCH effects on active conditioned avoidance and reversal of ECS amnesia observed in animals do not generalize across species to man. 5. DISCUSSION Presented in Table 2 is a summary of the statistical analysis of the nominal outcomes associated with the 'armchair' factor structure. The pattern of positive finds suggests that both central and peripheral electrophysiological measures recorded during task performance as well as performance that has been degraded by fatigue are modified by the administration of CCH. Restoration of optimal performance during long, monotonous tasks accompanied by electrographic signs of increased central attention and peripheral arousal are reminiscent of the behavioral pharmacologic profile of the stimulants as described by Weiss and Laties (1962). Moreover, recent neuropharmacologicai investigations have shown that CCH have pharmacodynamic properties similar to the sympathomimetics (see Versteeg, 1980). Furthermore, Jouhaneau-Bowers and Le Magnen (19791 have recently shown that CCH are positive reinforcers and will support self-administration in rats. Thus, the neuropharmacologic profile suggests that the catecholamines play a principal role in the mediation of the behavioral effects of the CCH. In contrast, there is little evidence to support the assertion that CCH alter affective status or the functioning of any memory store or control process in humans. These findings are in sharp contrast to the animal literature that has consistently shown that CCH do modify avoidance behavior and reverse induced amnesia (Bohus and de Wied, 1980; Rigter and Crabbe, 19801. One possible explanation for the observed discrepancy may be due to phylogeny.

TABLE 2. Summary of Common ('ore Heptupeptide Study Outcome.s Outcomes Positive Negative I.

II.

II1,

IV.

V.

EEG Measures l, Spontaneous EEG 2. Event-Related EEG

3 4

3 1

0.500 0.188

Peripheral Electrophysiology 1. HR/HR variability 2. Forearm Blood Flow 3. Tendon Reflex 4. Electromyographic Action

5 1 I 1

3 0 0 0

0.360 0.500 0.500 0.500

Affect 1. Acute Studies 2. Sub-Chronic Studies

3 1

9 1

0.073 0.500

Psychomotor/Attention 1. Simple Disjunctive RT 2. Serial RT 3. Various Tests

0 3 2

3 0 19

0,125 0.125 <0.001

Learning and Memory 1. Sensory Memory 2. Primary Memory 3. Verbal Secondary Memory 4. Non-Verb. Second. Memory 5. Semantic Memory 6. Active CAR 7. ECS Amnesia Reversal

0 1 2 4 0 0 0

3 10 20 9 1 1 2

0.125 0.006 <0.001 0.133 0.500 0.500 0.250

*Binomial Test.

J.P.T 14 2

t~

p*

172

ROLAND J. BRANCONNIER

I n c o n c l u s i o n , C C H d o a p p e a r t o b e b e h a v i o r a l l y a c t i v e in b o t h a n i m a l s a n d h u m a n s . W h i l e at p r e s e n t , a r o l e f o r t h e s e a g e n t s i n c l i n i c a l m e d i c i n e a n d h u m a n p e r f o r m a n c e h a s not been established; they are an intriguing class of agents that are worthy of further investigation.

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