BASIC CONCEPTS OF PSYCHOPHARMACOLOGICAL RESEARCH · a better local anesthetic than procaine. It is...

ACTA NEUROBIOL. EXP. 1974, 34: 641562

BASIC CONCEPTS OF PSYCHOPHARMACOLOGICAL RESEARCH AS APPLIED TO THE PSYCHOPHARMACOLOGICAL ANALYSIS OF

THE AMYGDALA ,

J. Steven RICHARDSON

Department of Pharmacology and Department of Psychiatry College of Medicine, University of Saskatchewan

Saskabon, Canada

Abstract. Since the \neural impulses in the brain are transmitted from one neuron to the next 'by various chemical medi,ators such as madrenaline, dopamine, serotonin, acetylcholine, etc., the use of drugs acting specifically on clne or m'ore of these mediators s h u l d iUuci,date the chemical substrates of behavior. However, recent data indicating exten~~ive Bntwactim betnveen the var iou neurotrsmmit- ters on a cellular and even synapti ,~ level, suggests th'at interpreting the behavioral effects of h g s in t e r n of anly one neurotransmitter is a potentially misleading oversimplificatian. Perhaps, rather than the action of a single newatrammitter, it is the .balance between nenmtrammitter systems that determines behavior. Because of its ri'ch innervartiwn by noredrenaline, d,apamine, semtoniln and acetylcholi~ne syn- opses, the amygdala is i,deally suited for monitoring the balance between these n e u r o t r a ; d t t e r s and altering d a d a p t i v e b e h a v h based m fluctuati,ons ifn neurotransmitter balance.

NEUROTRANSMISSION

Neurons, the morphologically discrete cell units of the nervous system, are functionally connected at specialized points of junction (synapses) by a chemical communication process. The synaptic gap between neurons is bridged by the release, caused by neural impulses in the first neuron, of small quantities of a chemical neurotransmitter substance that diffuses across the synapse to contribute to the initiation of a neural impulse in the second neuron. Although many chemicals in the body are potential neurotransmitters, much experimental evidence indicates that two of the major synaptic transmitters are acetylcholine and noradrenaline. The existence and functional significance of cholingergic and adrenergic synapses in the peripheral nervous system are now well estab-

544 J. S. RICHARDSON

lished. Even though there appear to be cholinergic and adrenergic synapses in the central nervous system, the functional significance of cholinergic and adrenergic neurotransmitters in the brain is not yet understood.

The enzymes necessary for the synthesis of the neurotransmitter are located in the cell body, some enclosed in storage granules, and trans- ported down the axon to the synapse. Most of the neurotransmitter which is released into the synaptic cleft by a nerve impulse is formed at the nerve ending. After release, the transmitter molecules diffuse across the synapse and alter the polarization of the postsynaptic neuron by interacting in some way with a receptor substance. In the synaptic cleft, the neurotransmitter undergoes enzymatic inactivation, is reabsorbed into the neuron, or diffuses into the surrounding tissue or into the circula- tion. The numerous drugs that alter neuron firing rate can affect one or several of these steps: synthesis (13, 134), storage (23), transport (25), release (23), catabolism (136), receptor activation (99), or reuptake (19). For the neural impulse - itself a complex interaction of sodium and potassium ions with changes in nerve cell membrane permeability - to trigger release of the neurotransmitter, the presence of calcium ions in the extracellular fluid surrounding the synapse (109) is required. The theory of receptor sites and transmitter-receptor interaction mechanisms is based on a pharmacological definition required by the stereospe- cificity and structural variations of chemical agents having similar effects on neurons (37, 99). Although the receptor site has not been identified morphologically, the enzyme adenyl cyclase has been suggested as a possible receptor molecule (91, 128, 129).

Cholinergic-adrenergic interaction

Several attempts have been made to integrate drug-produced behavioral effects into a general theory of brain neurotransmitter function. Carlton (20, 21) proposed a theory of central nervous system cholinergic action in which acetylcholine was responsible for behavioral habituation and the suppression of punished responses. But more recent evidence indicates that the adrenergic system has an identical action (85, 136). Grossman (44, 45) and Russell, Singer, Flanagan, Stone and Russell (110) demonstrated a cholinergic modulation of drinking and thirst mechanisms, but so did Leibowitz (80) for the adrenergic system. Grossman (44, 45) also reported that adrenergic hypothalamic activity was responsible for eating and hunger. But Stark, Totty, Turk and Henderson (122) reported a cholinergic interaction with the hypothalamic eating system. Several authors have presented evidence implicating the adrenergic system in affective mood disorders (15, 22, 53, 116). But irnipramine

PSYCHQPHM3MACOLOGICAL ANALYSIS OF AMYGDALA 5 45

and desipramine, two drugs commonly used in the treatment of depression, also have an anti-cholinergic action (14, 139). Thus, it appears that interpreting the behavioral effects of drugs in terms of only one neurotransmitter system is a misleading oversimplification.

It is not only on the behavioral level of analysis that there is a close relationship of the effects of acetylcholine and noradrenaline. On the cellular level, Salmoiraghi (112), suggested that cholinergic synapses were made on the cell body and adrenergic synapses were made on the dendrites of the same neuron. There seems to be a close interaction of these two neurotransmitters at the synaptic level too. Burn and Rand (16, 17) suggested that the similar effects of acetylcholine and naradrena- line was due to the involvement of acetylcholine in the release of noradrenaline at adrenergic synapses. According to this hypothesis, the inco- ming neural impulse triggers the release of noradrenaline which in turn triggers the release of noradrenaline which then depolarizes the postsynaptic membrane. Although the original formulation of the Burn-Rand hypothesis is no longer tenable, an extension of this hypothesis has been applied to behavioral data (105) suggesting that a buildup of noradrenaline is the synaptic mechanism for the similar behavioral effects of cholinergic blockade by atropine or scopolamine and adrenergic stimulation by amphetamine. This mechanism is supported by the recent demonstration that cholinergic blockadge by atropine increases endogenous levels of noradrenaline in the brain (104~). Moreover, cholinergic activation by physostigmine decreases endogenous brain noradrenaline (67). Thus the neurochemistry of the brain is a complex interaction of cholinergic, adrenergic and other neurotransmitters acting not specifically on different parts of the brain or not necessarily on different behaviors, but perhaps on the same behavior or on the same neuron or even within the same synapse.

Receptors and behavior

Within the cholinergic transmission system there are two types of receptors. Both are activated by acetylcholine but the one type of receptor ig also activated by nicotine and blocked by curare but is relatively unaffected by muscarine and atropine or scopolamine, the chemicals that activate and block, respectively, the second type of receptor. Not sur- prisingly, these types of receptors are called nicotinic and muscarinic. Although the mapping of nicotinic and muscarinic synapses in the peri- phery has delineated a rather specific functional separation of nicotinic and muscarinic effects, a pharmacological analysis of cholinergic synapses in the central nervous system indicates the presence of both types of synapses but gives no suggestion as to their functional significance.


Based on differential reactivity to various chemicals, noradrenergic neurotransmitter receptors can be separated into two main classes: alpha and beta. Comparing reactions to the two naturally-occurring adrenergic compounds found in the peripheral nervous system, alpha receptors are more sensitive to adrenaline while beta receptors in different tissues can be more sensitive to either noradrenaline or to adrenaline (38). This dichotomy of alpha and beta adrenergic receptors is further supported by the manufacture of new compounds differentially affecting these two classes of receptors (38, 82). The action of the alpha receptor is blocked bv phentolamine; the action of the beta receptor is blocked by propranolol. However, the experimental data defining alpha and beta receptors have been collected from peripheral organs receiving adrenergic innervation such as the heart, spleen and trachea (38). The existence of alpha and beta receptors in the brain has not yet been verified.

There is, however, evidence suggesting that two types of adrenergic receptors can be identified in brain tissue. Goldstein and Munoz (42) injected systemically a variety of adrenergic stimulating and blocking compounds and concluded that adrenergic stimulation and depression of EEG activity might resemble alpha and beta actions, respectively. Marley (86) also suggested that adrenergic excitation of the central nervous system is mediated by alpha receptors while adrenergic depression is a beta receptor phenomenon. More recent evidence indicates that this functional dichotomy is not a simple relationship. Blocking the alpha receptors bv dibenarnine (88) or phentolamine (64) produces cortical EEG arousal de- svnrhronization, not the EEG depression expected if alpha receptors were excitatory. Beta blockade by propranolol either depresses spontaneous EEG to a resting pattern and blocks the short term EEG arousal produced by adrenaline (88), or has no effect on spontaneous EEG but blocks EEG arousal produced by dihydroxyphenylalanine (DOPA), a noradrenaline precursor (64). From these data, i t appears that it is the alpha receptors that are involved in inhibition of the cortical EEG and the beta receptors that are involved in the excitation of the cortical EEG. Both phentolamine and propranolol directly depress the activity of neurons in the spinal cord (24), thus suggesting that both alpha and beta receptors are involved in spinal inhibition. Recently, an interacting system of alpha and beta receptors controlling food and water intake has been reported in the hypothalamus (78-80). It therefore appears that alpha and beta receptors play a role in central adrenergic neurotransmission but the exact nature of this role is not yet clear. The various compounds (e.g. propranolol) having specific synaptic blocking properties should prove to be useful tools in future neuropharmacolopical and psvchophar- macological research. But research using these tools is fraught with many

PSYCHOPHARMACOLOGICAL ANALYSIS OF AMYGDALA 547

difficulties and pitfalls. A description of the shortcomings of propranolol as a tool in central nervous system research emphasizes the need for caution in interpreting data obtained from experimental investiga- tions using new and poorly understood pharmacological tools.

Propranolol

Since its synthesis in the early 1960's, propranolol has been subjected to much experimental investigation. Although most of the research has been in connection wth the use of propranolol in cardiac malfunctions, propranolol has recently been used as a neuropharmacological tool. Pro- pranolol readily enters the brain following either intraperitoneal (87) or oral (50) administration, but it does not alter brain levels of noradrenaline, dopamine, serotonin, or metabolites of any of these, and is cleared from the brain within 8 to 16 hr (76). In the brain, propranolol seems to have two independent actions, with the depressant and anti-con- vulsant actions (81) not related to the beta blockade actions (92). Vau- ghan Williams (131) demonstrated that propranolol, in addition to beta receptor blockade, has a non-specific membrane depressant effect on heart muscle similar to the action of quinidine that makes propranolol a better local anesthetic than procaine. It is perhaps the quinidine-like action of propranolol that is responsible for the central nervous system depressant action.

The non-specific quinidine-like membrane anesthesia action of propranolol is not sensitive to changes in adrenergic neurotransmitter levels because nerve action potentials are attenuated at the axonal membrane and neurotransmitters do not affect action potentials along the axon. The specific receptor-blocking action of propranolol is sensitive to increases in noradrenaline levels because increased adrenergic activity in the synapse would tend to overcome the competitive receptor blockade by propranolol, thus increasing synaptic transmission. Leszkovskv and Tardos (81) noted that propranolol reduces amphetamine toxicity in group caged mice. Estler and Ammon (32-34) reported that propranolol blocks the amphetamine-induced increase in spontaneous motor activity of mice and increases brain glycogen levels in addition to preventing the amphetamine-induced decrease in brain glycogen levels. The proprano- 101-induced increase in brain glycogen levels is in turn prevented by dihydroxyphenylalanine (DOPA), a noradrenaline precursor, and is therefore related to specific synaptic blockade. Similarlv, since amnhetamine increases adrenergic synaptic activity by increasing the release and by preventing the reuptake of noradrenaline ( I l l ) , and since both amphetamine group-caged toxicity and motor activity effects can be blocked bv drugs that reduce adrenergic activity (100, 126) as well as by proprano-


101, it is probable that here too the mode of action of propranolol is through beta adrenergic blockade. Side effects with possible central nervous system origin in humans receiving propranolol for cardiac indications include: hallucinations (54); graded, dose-related depression (54, 133) and anxiety reduction (54). The anti-anxiety effect of propranolol is signifi- cantly better than placebo (43) and is as effective as chlordiazepoxide (137), but whether the mechanism of anti-anxiety action is a peripheral reduction of the autonomic nervous system symptoms of anxiety or is a functional alteration of anxiety-producing structures in the central nervous system either by beta blockade or by quinidine-like actions is not yet established.

Following administration, propranolol quickly spreads throughout the body where it antagonizes the effects of adrenergic neurotransmitters on various peripheral organs. Propranolol blocks smooth muscle contraction in the rat uterus, rabbit ilium, and guinea pig lung and blocks the decrease in blood pressure produced, under certain conditions, by adrenaline, noradrenaline or isoproterenol (11, 120) as well as numerous other effects of adrenergic compounds (38). The mechanism of action of propranolol has been considered to be competitive blockade of the beta- receptor site (82). De Robertis and Fiszer de Plazas (108) support the receptor blocking theory of propranolol action by demonstrating a high concentration of radioactively labeled propranolol associated with iso- lated nerve membranes taken from the hypothalamus and basal ganglia of cats, while no propranolol was found to be associated with mitochon- dria. This indicates that propranolol is bound on nerve membrane, perhaps to receptor sites.

Propranolol inhibits the lipid facilitated transport of calcium ions (93) and, therefore, might be expected to have an effect on the nerve membrane other than just at the receptor site, since the entry of calcium ions through the lipid-containing cell membrane into the presynaptic nerve ending is a prerequsite for transmitter release (109). Propranolol's membrane action can also be seen from its effects on action potentials. Pro- pranolol does not alter the resting potential or the membrane repolariza- tion after an impulse, but does reduce greatly the height and rate of rise of the action potential (131), the amplitude of the action potential (24) and the duration of the action potential (9). While these membrane effects of propranolol are probably related more to quinidine-like actions than to beta blockade actions, the precise relationship has not been resolved.

The exact nature of propranolol action is further clouded by the demonstration that propranolol has slight alpha adrenergic receptor stimulant properties. The adrenaline induced increase in blood pressure is


blocked by phenoxybenzamine (an alpha blocker) but if propranolol is then added to the preparation, the blood pressure increase to adrenaline is reinstated (140, 141). However, it seems that the multiple effects of propranolol can be reduced primarily to beta blockade by using only the levo isomer, 1-propranolol (95), or by using very small concentrations of racemic propranolol (48).

In order to understand the behavioral effects of pharmacological compounds, the site(s) of action of the drug must be identified. To understand a particular drug effect on a particular brain structure requires not only that the normal function of that brain structure be known but also that the mechanism by which the drug affects this structure be as- certained. Since normal neural communication is accomplished via neurotransmitters, drug effects usually involve alterations in the action of neurotransmitters, as discussed above. Thus, the neurotransmission system of the amygdala must be delineated prior to an examination of the effects of drugs on amygdaloid functioning.

PSYCHOPHARMACOLOGY OF THE AMYGDALA

The neurotransmitters of the amygdala

The amygdala, one of the structures of the limbic system, is compri- sed of a collection of subnuclei that, based on current behavioral analysis, can be divided into two functional units: the corticomedial amygdala and the basolateral amygdala. The major neurotransmitter systems are seemingly well represented in the amygdala. Although, using histolo- gical techniques, it is not yet possible to identify directly acetylcholine in brain structures, the enzyme that inactivates acetylcholine, acetylcholinesterase, is found in the amygdala and other brain areas. While the best indication of cholinergic activity in a particular brain structure would be the identification of acetylcholine in that structure, the histoche- mica1 demonstration of the presence of acetylcholinesterase ih a useful and probably sufficient index (70). Although several investigators have demonstrated cholinergic activity in the amygdala (51, 66, 118), the functional significance of the cholinergic innervation of the amygdala has not yet been demonstrated. The cholinergic input to the amygdala probably arises from cell bodies in the brain stem (117) and projects via the septa1 area (73, 83) to make muscarinic synapses in the amygdala as well as in other forebrain structures (72). Amygdaloid neural units are activated by acetylcholine, but this activation has a very slow onset (127). The amygdala can also be activated by the nicotinic compound, carbachol ( lo) , and by nicotine (27). The amygdaloid response to both acetylcholine and nicotine is blocked by atropine (27), a muscarinic blocker, which


suggests that the cholinergic response in the amygdala is not a pure nicotinic reaction but that these cholinergic receptors react to nicotinic stimulation in a manner that can be blocked by anti-muscarinic agents. Lesions in the septa1 area (89) reduce amygdaloid levels of the enzymes producing noradrenaline, acetylcholine, and serotonin, another potential neurotransmitter. Eidelberg, Goldstein and Deza (29) presented evidence of serotonin in the amygdala and demonstrated that serotonin, but not noradrenaline, depressed the spontaneous activity of neural units in the amygdala. Thus, the amygdala receives input from cholinergic and from serotonergic systems, but the contributions of these neurotransmitters to normal amygdaloid activity have not been determined.

Electrical stimulation of the amygdala not only produces a defensive- aggressive rage reaction in cats (35, 36, 56), but also decreases levels of noradrenaline in the telencephalon (49, l o ] ) , in other forebrain structures and in the hypothalamus but not in the mesencephalon and lower brainstem structures (41). Fuxe (40) and Hillarp, Fuxe and Dahlstrom (55), using fluorescent histochemical techniques, traced adrenergic fibers from the brain stem to many forebrain structures, including the amygdala. Dopamine, the immediate biochemical precursor of noradrenaline but a potential neurotransmitter in its own right, is found in the central amygdaloid nucleus. The basolateral amygdala contains only noradrenaline terminals while the corticomedial amygdala contains both noradrenaline and serotonin terminals (40). It appears that the adrenergic system of the forebrain originates in the brainstem as does the cholinergic system described by Shute and Lewis (117). Lesions in the ventral me- sencephalic area decrease catecholamine levels in the medial forebrain bundle, the hypothalamus, the hippocampus and the amygdala (26). That the adrenergic system arising in the brainstem projects to the amygdala via the medial forebrain bundle is indicated by the demonstration that lesions in the medial forebrain bundle markedly decrease the noradrenaline (52, 135) and the serotonin (52, 55) content of the amygdala. The amygdaloid noradrenaline system shown by Heller and Moore (52) seems to be a one-way relationship because amygdaloid lesions do not alter the noradrenaline content of the hypothalamus (28) even though amygdaloid stimulation does (41). Since rewarding self-stimulation of the medial forebrain bundle releases noradrenaline in the amygdala (125) and since noradrenaline (as well as serotonin) reduces the electrical activity of neural units in the amygdala (127) the amygdala, therefore, might be under the inhibitory influence of the medial forebrain bundle reward system with noradrenaline as inhibitory neurotransmitter, as was suggested by Stein (123, 124). Although Eidelberg, Miller and Long (31) found that a reduction in noradrenaline abolished amygdaloid activity, von

PSI'CHOPHARMACOLOGICAL ANALYSIS OF AMYGDALA ,551

Orden and Sutin (94) demonstrated that an increase in noradrenaline decreases the response in the ventromedial hypothalamus evoked by amygdaloid stimulation, as would be expected if noradrenaline inhibited amygdaloid activity. It is somewhat difficult to reconcile the amygdaloid excitatory function of noradrenaline proposed by Eidelberg et al. (31) with the amygdaloid inhibitory function of noradrenaline presented by others. To further emphasize both the complexity of the neurotransmitter interaction in the amygdala and the need for controlled experimenta- tion in standardized biochemical, histochemical and behavioral test situations, some authors have reported that noradrenaline is not to be found in the amygdala (29) and that noradrenaline has no effect at all in the amygdala (4, 5). Neurotransmitter theories of amygdaloid action have been presented for adrenergic (85, 124) and serotonergic (75) systems, but the plethora of lacunae in our knowledge of neuropsychopharmaco- logy demands that these theories obtain much additional support. Part of the existing support for these hypotheses comes from the drug-induced alteration of amygdaloid function.

Pharmacological analysis of the amygdala

Grossman (46) demonstrated that carbachol injected into the amy- \ gdala increases drinking by water-deprived rats. Subsequent research

has shown this to be true only if the animal is already drinking; if not, then carbachol stimulation of the amygdala will not elicit drinking (110). If drinking is induced by carbachol stimulation of the lateral hypothalamus, then carbachol injected into the amygdala increases drinking and atropine blockade of the amygdala decreases drinking (119). Theorefore, the amygdala seems to be involved in a cholinergic drinking system. Other authors (4,5) have reported that cholinergic stimulation of the amygdala produces an alerting, attention-exploring response and an increase in motor activity (62) that seems to be similar to the response elicited by the electrical stimulation of the amygdala (63). Unfortunately, cholinergic stimulation, just as electrical stimulation, produces epilepti- form seizure afterdischarges in the amygdala (4, 5, 44, 46, 47), thus producing a functional lesion of the amygdala. A parametric analysis of carbachol stimulation of the amygdala utilizing simultaneous EEG monitoring, might reveal that the increase in ongoing drinking following injections of carbachol into the amygdala is due more to the seizure-produced lesion than to mimicing the normal cholinergic activity of the amygdala. However, stimulation of the beta-adrenergic receptors of the amygdaln by injections of isoproterenol directly into the amygdala (103, 121) does not cause seizures but rather improves performance on an operant con- ditioning schedule requiring the inhibitory control of behavior (DRL-203,


whereas amygdaloid ablation disrupts DRL performance (97). Therefore, while the contributions of cholinergic activity to the normal function of the amygdala has not yet been demonstrated, it appears that the beta- adrenergic receptors of the amygdala might be involved in successful performance of a DRL schedule.

Imipramine, an anti-depressant drug, blocks both cholinergic- (4, 5) and electrically- (1,6, 98) induced amygdaloid seizures as well as de- creasing general amygdaloid reactivity (102). An imipramine-amygdala interaction is also suggested by data presented by Furgiuele, Aumente and Horovitz (39) and by Allikmets and Lapin (3) which show a differential effect of imipramine in normal rats and in rats with amygdaloid lesions; an increase in activity is produced by imipramine in rats with amygdaloid lesions, while imipramine inhibits activity in normals. Penaloza-Ro- jas et a1 (98) also observed that imipramine had an excitant action on the lateral hypothalamus. The behavioral excitant action of imipramine in rats with amygdaloid lesions might be due to stimulation of the lateral hypothalamus and not represent the normal mechanism of action of imipramine at all.

In other situations, imipramine and other drugs used as anti-depressants have the same effects on behavior as amygdaloid lesions. Karli, Vergnes and Didiergeorges (65) demonstrated that amygdaloid lesions abolish mouse killing in rats; so does imipramine (58-60, 74), amphetamine (74), and thiazesim (59). Thiazesim blocks the electrical activity of the amygdala (57), raises the amygdaloid afterdischarge seizure threshold (8), and disrupts passive avoidance just as amygdaloid lesions do (7). Ei- delberg, Long and Miller (30) suggested, based on electroencephalogra- phic data, that the amygdala is an important site of action of hallucinogenic drugs. This hypothesis received support when Barratt and Pray (8) demonstrated that thiazesim blocked the behavioral effects of LSD-25. Thus, the amygdala seems to be involved in the effects of hallucinogenic compounds. Since the hallucinogenic effects of Ditran, atropine and scopolamine are very similar to those of LSD-25 (138), and since the behavioral effects of Ditran are blocked by propranolol (71) as the effects of LSD are by thiazesim, it is possible that the amygdala is involved in the behavioral response to atropine, scopolamine and Ditran and that propranolol blocks this behavioral response by acting on the amygdala as thiazesim does. Other situations also implicate the amygdala in the behavioral effects of propranolol. A decrease in shock-induced fighting is produced by propranolol (92) and by amygdaloid ablation (2). Proprano- lo1 disrupts the performance of rats on a DRL-20 schedule (106, 107) in a manner closely analogous to the DRL disruption produced by lesions of the amygdala reported by Pellegrino (97). Traditional anti-anxiety


drugs decrease the activity of the amygdala (114, 132) and the amygdala has been implicated in the production of anxiety (11-3). The demonstration that propranolol is as effective as chlordiazepoxide for the treatment of anxiety (137) also suggests that propranolol could be acting to reduce amygdaloid activity.

But to return to the normal state of psychopharmacologica1 confusion and conflicting data, atropine and scopolamine also produce effects analogous to amygdaloid lesions. Amygdaloid lesions disrupt passive avoidance learning (97) and so does scopolamine (18, 20, 21, 84, 90); active avoidance is disrupted by amygdaloid lesions (61, 130) and by scopolamine (96); two way shuttle box performance is improved by amygdaloid lesions (68) and by scopolamine (84); amygdaloid lesions decrease the effects of nonreward (97) and so does scopolamine (7, 20, 69); amygdaloid lesions disrupt non-signalled but not signalled alternation responding (97) and so does scopolamine (77). Although ablation of other parts of the brain also disrupt these behaviors, and although it is impossible to specify the necessary site of action of a systemically administered drug, the behavioral parallels between amygdaloid lesions and systemic drug effects can be used to provide hypotheses concerning a possible sufficient site of action of a drug. The demonstration that propranolol or scopolamine injected into the basolateral amygdala (103) has the same disruptive effects on DRL performance as systemic propranolol or scopolamine, or as lesions of the basolateral amygdala, suggests that the basolateral amygdala is a sufficient site of action of propranolol and scopolamine. The existence of other sufficient sites of action would indicate that the amygdala is only a part of the necessary neural system underlying these behaviors. Lesion experiments (97) demonstrate that some behaviors that are disrupted by lesions of the basolateral amygdala are not affected by lesions of the corticomedial amygdala. Histochemical data (40) indicate different neurotransmitters in the basolateral than in the corticomedial amygdala. The behavioral contributions not only of the neurotransmitters in the corticomedial amygdala but also of the interactions of noradrenaline, dopamine, acetylcholine and serotonin between the different parts of the amygdala have not yet been investigated.

Obviously much work remains before the contributions of the various neurotransmitters to the functions of the amygdala can be delineated. The demonstration of behavioral parallels between the ablation of tissue in the central nervous system and the systemic administration of a drug is useful only for providing hypotheses to be tested in a more molecular analysis. One such molecular approach would entail the injection, directly into the various areas of the amygdala, of many dose levels of a wide range of compounds known to disrupt one of the steps in the process of

554 J. 6. RICHARDSON

neurotransmission, i.e., synthesis, storage, transport, release, catabolism, receptor attachment or reuptake. Blocking the effects of a neurotransmitter at each of these steps and testing the resulting effect in many different behavioral paradigms while monitoring the electrical activity of multiple neural units in each of the various amygdaloid nuclei, should provide data indicating the functional significance of a particular neurotransmitter in a particular part of the amygdala. Alternatively, the functioning of the amygdala may involve the subtle interaction of neurotransmitters with the anatomical location of the synapses on the next neuron. Scheibel and Scheibel (115) presented evidence suggesting that the location of a particular synapse- on a cell body, on a dendrite shaft or on a dendrite spine - contribute as much to the effects on the postsynaptic membrane as does the particular neurotransmitter released. If this con- cept is demonstrated to represent accurately the mechanism of neural communication, then the psychopharmacologica1 analysis of the amygdala must await data from the recording of amygdaloid postsynaptic potentials as well.

In summary, noradrenaline, dopamine, acetylcholine, and serotonin are all well represented in the amygdala, probably in the pre-terminals of neurons whose cell bodies are located in the brain stem. The direct action of these neurotransmitters on postsynaptic amygdaloid neurons has not yet been established unequivocally. It appears that, instead of a particular neurotransmitter having a particular behavioral effect, it is rather the balance between several neurotransmitter systems that determines behavior. Specific behavioral patterns might be associated with the predominance of a specific neurotransmitter, but the subordinate neurotransmitter systems are also necessary for the successful completion of the behavior pattern. Because of the rich innervation of the amygdala by noradrenergic, dopaminergic, cholinergic and serotonergic terminals, the amygdala may be a very important brain area for the interpretation of the balance between the various neurotransmitter systems. The amygdala could then modulate behavioral patterns based on changes in the balance of these systems.

Since environmental influences alter the neural input to the amygdala, this interpretation of neurotransmitter balance within the amygdala might be a way of conceptualizing the neurotransmiter mechanism where- by the amygdala is involved in the modification of old or maladaptive behavioral patterns to meet new environmental reinforcement contin- gences as suggested previously (104).

Portions of this paper w a x ~~ while the author was a Pastdoctoral Fellow, Lmtiitute of Neurological Sciences, University of Pennsylvania, Philadelphia, Pem- sylvan@ USA and while la Fellow of the Foulnd~ations' Fund for Research 1n Psy- chiatry at the L a h a t o r y of Clinical Science, NIMH, Bethesda, Malryland, USA.

PSYCHOPHARMACOLOGICAL ANALYSIS OF AMYGDALA

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Received 20 August 1973

J. Steven RICHARDSON, Department of Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Canada, S7N OWO.

BASIC CONCEPTS OF PSYCHOPHARMACOLOGICAL RESEARCH · a better local anesthetic than procaine. It is...

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