AMITRIPTYLINE- AND MIANSERIN-INDUCED CHANGES IN ACQUISITION OF PAIRED-ASSOCIATION LEARNING-TASK
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Br. J. clin. Pharmac. (1978),5, 149-153 AMITRIPTYLINE- AND MIANSERIN-INDUCED CHANGES IN ACQUISITION OF PAIRED-ASSOCIATION LEARNING-TASK R. LIUEQUIST, T. SEPPALA & M.J. MAlTILA Departments of Pharmacology and Psychology, University of Helsinki, Helsinki, Finland I The double-blind study on twenty healthy students was an attempt at assessing the effects of 2- week's treatment with amitriptyline (25 mg three times a day) and mianserin (10 mg three times a day), each alone or separatively inbibed with alcohol (0.5 g/kg) on the immediate memory and on the ac- quisition of a paired-association learning-task. 2 Amitriptyline impaired both the short-term memory-span and acquisition, and alcohol potentiated these effects. The action of mianserin did not deviate significantly from that of the placebo, and it also failed to interact with alcohol. 3 It is concluded that the decrement in learning capacity, that occurs after the 2-week's treatment with therapeutic doses of amitriptyline, reflects changes in both the intrinsic and the regulatory mechanisms of learning. Introduction Previous results from this laboratory (Liljequist, 1976; Ghose, Coppen & Turner, 1976; Coppen, Linnoila & Mattila, 1974) indicate that low Cupta, Montgomery, Ghose, Bailey, Burns & De therapeutic doses of nortriptyline, given three times a Ridder, 1976). day to healthy human subjects, impaired learning, probably by interfering with the acquisition processes. In these conditions another tricyclic antidepressant Methods chlorimipramine, proved ineffective and even an- tagonized the alcohol-induced impairment. Of these Subjects and treatments antidepressants, chlorimipramine affected more peripheral sympathetic nerve terminals, as Twenty healthy subjects, fourteen males and six demonstrated by the tyramine pressor test (Seppila, females, aged 21.1 + 1.4 years (mean + s.d.) and Linnoila, Elonen & Mattila, 1975). This effect is weighing 67.9 + 9.9 kg, served as paid volunteers. probably due to the chlordesimipramine formed from None of the subjects were regularly on drugs nor had the parent drug during prolonged treatment (Nagy, a history of psychiatric illness. The participants were 1974). informed of the objects and the procedure of the ex- In addition to their affecting the availability of periment and consented to volunteer the experiment. cyclic monoamines on the synapses, antidepressants Mianserin hydrochloride (10 mg) (Tolvong, also have an antimuscarinic effect. This might interfere Bolvidorg, Organon), amitriptyline hydrochloride with cognitive processes, as demonstrated with (25 mg) (Tryptizols, Merck, Sharp & Dohme), or atropine and scopolamine (Whitehouse, 1964; lactose placebo were administered in identical tablets Buresova, Bures, Bochanecky & Weiss, 1964; three times a day, double-blind cross-over for 2 weeks Bochdanecky & Jarvik, 1967). For this reason we each. A one week's drug-free period was allowed have compared the effects of amitriptyline and between the treatments. The sequence of treatments mianserin on those variables which represent acquisi- was ordered according to the Latin square design. tion stages in learning processes. Mianserin is a When the subjects came to the testing sessions, they tetracyclic compound with clinical antidepressant ingested an alcoholic or nonalcoholic bitter drink, the action (Murphy, 1975; Kafoe & Leonard, 1973). dose of ethyl alcohol being 0.5 g/kg body weight. The Unlike amitriptyline, it does not block the amine drinks were ingested chilled, the drinking time was 10 uptake in vivo experiments, and it also lacks an- min. The test began 30 min after the ingestion of ticholinergic effects (Raiteri, Angelini & Bertollini, drugs.
150 R. LILJEQUIST, T. SEPPALA & M.J. MATTILA
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Figure 1 Effects of amitriptyline (AT), mianserin calculated by using Student's paired t-test
(M), alcohol (A) and placebo (P) on immediate (**PEFFECT OF AMITRIPTYLINE AND MIANSERIN ON LEARNING 151
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E AT AT M M A152 R. LIUEQUIST, T. SEPPALA & M.J. MATTILA
Subjective evaluation properties than did amitripyline, contraindicates the
role of general sedative effects. Vigilance, coordination,
Drowsiness was subjectively reported by fourteen sub- and reaction capacity appeared unchanged during the
jects when being on mianserin and by ten subjects learning tests (Seppila, 1977).
when being on amitriptyline and by one subject after If it is accepted, that amitriptyline and alcohol, at
placebo. Eight subjects reported dryness of the mouth the time of rising blood alcohol concentration, in-
after amitriptyline and none after mianserin or terfere with the process of consolidation, it would be
placebo. relevant to find the loci of action.
The mechanism of short-term memory has been
proposed as reflecting a synaptic transmission efficacy
(Eccles, 1964), whereas the formation of memory-
Discussion trace more specifically depends on the cholinergic
mechanisms of the limbic system, and the connections
The present study demonstrates that amitriptyline in to the cortex and reticular activating system
therapeutic doses impairs memory functions, whereas (Il'yuchenok, 1965). Thus, part of the effects of
the effects of mianserin do not differ from those of the amitriptyline are mediated through inhibition in the
placebo. The exact nature of the impairment of the cholinergic brain structures, and through a block in
cognitive functions remains unanswered until after a the corresponding components of the reticular forma-
more systematic study of memory processes. tion. Consequentally, the cortex is de-afferented, and
During mianserin and placebo treatment, the short- the spatial and temporal activity between the nerve
term memory storage was within the normal cells is diminished (Il'yuchenok, 1975). This might
range, i.e. approximately seven items. After manifest as a deterioration of short-term memory
amitriptyline, performance corresponded lower limits span.
to be accepted as normal. Alcohol alone significantly Small, single doses of ethanol are (possibly) accom-
reduced the short-term memory span. The results of panied by changes in central catecholamine
the present study, concerning the effects of relatively metabolism (Corrodi, Fuxe & Hokfelt, 1966; Carlsson
small, acute doses of alcohol, tally well with previous & Lindqvist, 1973). There is evidence that drugs
studies (Liljequist et al., 1974). When alcohol and which block catecholamine synthesis (a-methyltrosine)
amitriptyline were administered simultaneously, the or storage (reserpine) may impair learning by secon-
short-term memory test indicated momentary impair- dary rather than by primary actions (Izquierdo, 1975).
ment in general intelligence (Wechsler, 1944). Therefore, the mechanisms of the effects of alcohol on
Since the experimental population consisted of memory are difficult to explain.
students, we expected their verbal learning capacity to The different actions of amitriptyline and mianserin
be high or normal. Therefore, amitriptyline and alcohol on memory are possible to explain, except by
can impair sequential verbal learning, and if they are cholinergical properties, also by their action on brain
acting at the same time, also other cognitive functions amine metabolism. Mianserin possibly increases the
are affected. turnover of noradrenaline and, to a lesser degree, of
The performance factors often interfere with the dopamine, thus increasing the availability of
learning capacity. The experimental procedure used in noradrenaline to the receptors (Kafoe & Leonard,
this study excludes the possibility, that the impaired 1973). In contrast, amitriptyline reduces the turnover
learning capacity during amitriptyline and alcohol of both noradrenaline and serotonin by inhibiting the
treatment resulted from inadequate attention during re-uptake of these amines (Kafoe & Leonard, 1973).
acquisition, since the subjects had to repeat the Perhaps due to this property of mianserin, it even fails
response syllable to reach the learning criterion. to induce depression in the stable reticular activating
Nevertheless, the learning scores which measure the system, as demonstrated by Vargaftig, Coignet, de
acquisition stage (Atkinson & Shiffrey, 1968), were Vos, Grijsen & Bonta ( 1971) in rabbits.
significantly impaired. Since the indication of learning Nortriptyline, which is structurally related to
required success in recalling, there is the possibility, amitriptyline, caused significant but weaker impair-
that the only stage affected was the retrieval from ment than amitriptyline under similar experimental
immediate memory. However, since the other tests conditions. Chlorimipramine and mianserin behaved
(Seppala, 1977) were adequately performed, this in a similar manner, except that a slight alcohol-
possibility is not probable. antagonizing effect was found with chlorimipramine
If it is accepted that the formation of the long-term which in a 2-week study showed a strong action to
memory traces was impaired, it is still unclear, as to adrenergic nerve function (Liljequist et al., 1974).
whether this reflects specific memory, or properties of a Therefore, the interpretation done in that study, i.e. the
more general sedative effect of the drugs used. The change in noradrenergic tone is an essential property
observation that mianserin in spontaneously reported for memory functions, is supported by the results of
questionnaires appeared to have more sedative the present study.EFFECT OF AMITRIPTYLINE AND MIANSERIN ON LEARNING 153 This study was supported by a grant from Sigrid Juselius like to thank Organon B.V., for providing the drugs and Foundation to Professor M.J. Mattila. The authors would drinks and for financial support. References ATKINSON, R.C. & SHIFFREY, R.M. (1968). Human on the turnover of dopamine, noradrenalin and serotonin memory: A proposed system and its control processes. in the rat brain. Arch. Int. Pharmacodyn, 206, 389. In The Psychology of Learning and Motivation, eds. KANNENGIESSER, M.H., HUNT, P. ( RAYNAUD, J.P. Spence, K.W. & Spence J.T., 2, 89-195, New York: (1973). An in vitro model for the study of psychotropic Academic Press. drugs and as a criterion of antidepressant activity. BISHOP. M.P., GUTHRIE, M.B. & HORNSBY, L.D. Biochem, Pharmac., 22, 73-84. (1969). 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