Anxiolytic activity of piracetam, a nootropic agent, following subchronic administration in rodents.

Piracetam (PIR), a cyclic GABA derivative without GABA-mimetic activity, is classified as a nootropic agent, a new class of psychotropic drugs which augment learning acquisition and retention of memory. The present study indicates that PIR has significant anxiolytic activity in rodents following subchronic, but not acute administration, when tested against several paradigms of experimental anxiety. Thus, PIR (250 and 500 mg/kg), administered orally for 7 and 14 days, exhibited anxiolytic activity in the open-field, elevated plus-maze and footshock-induced fighting in paired mice paradigms, as well as in the Vogel's conflict test in rats. In addition, PIR induced significant reduction in rat brain tribulin levels, a putative endocoid marker for anxiety, produced by pentylenetetrazole, an anxiogenic agent. On the contrary, single acute administration of PIR failed to induce any anxiolytic effect. The present study, thus, confirms clinical reports that PIR can induce a delayed antianxiety effect in psychogeriatric individuals and in chronic alcoholism.

Latency of memory consolidation induced in mice by piracetam, a nootropic agent.

Piracetam (PIR), a cyclic GABA derivative, is the prototype of a new class of psychoactive drugs, the nootropic agents, which improve learning acquisition and the retention of the learning as memory. It was proposed that nootropics act on processes essentially involved in information storage, thus facilitating memory. This property can best be investigated by drug administration after the learning trial and assessing subsequent retention performance. The present study was designed to evaluate the effective time period of memory consolidation, induced by piracetam, by assessing the retention of a learned task in two behavioural paradigms, following administration of the drug after learning acquisition. Physostigmine was used as the standard drug because of its well established facilitation of memory storage. PIR (250 and 500 mg/kg, ip) and physostigmine (0.05 mg/kg, ip) were administered in different groups of mice 5 min, 1, 2, 4, 8, 12 and 24 hr after learning acquistion of two passive avoidance tasks and the retention performance was evaluated 3 days later. The results indicate that, while physostigmine induced significant memory consolidation when administered up to 2 hr after learning acquisition, PIR induced retention of learning beyond this period. Thus, the highest effective post-trial interval for the lower and higher dose of the drug was 8 and 12 hr, respectively, in both the test paradigms. The results confirm that nootropics, like piracetam, are capable of memory consolidation, as assessed by retention of learning, even after intervals of 8 to 12 hr between learning and drug treatment.

Dopaminergic modulation of footshock induced aggression in paired rats.

Footshock induced aggression (FIA) was induced in weight matched paired rats and three paradigms of aggressive behaviour was recorded, namely, the latency to fight (LF), total period of physical contact (TPP) and cumulative aggression scores (CAS). Dopamine (DA), administered centrally, and peripherally administered L-dopa (with benserazide, a peripheral decarboxylase inhibitor), a DA precursor, and the postsynaptic D2 receptor agonists, apomorphine, N-n-propyl-norapomorphine (PNA), bromocriptine, lisuride and pergolide, induced a dose-related facilitation of FIA characterized by decrease in LF and increase in TPP and CAS. However, the DA presynaptic receptor agonist, BHT-920, induced a biphasic effect with inhibition of FIA being induced by a lower dose and facilitation of the aggressive behaviour produced by a higher dose. The postsynaptic D2 receptor antagonists, haloperidol, spiperone and pimozide, induced a dose-related attenuation of FIA, an effect not seen with domperidone, a peripheral DA receptor antagonist. The results indicate that central dopaminergic postsynaptic D2 receptors have a modulatory facilitative effect on FIA, while the presynaptic DA autoreceptors mitigate aggressive behaviour. However, the presynaptic DA receptor agonist, BHT-920, appears to lose its receptor specificity on dose increment. Long term administration of haloperidol, followed by withdrawal, or desipramine, induced per se augmentation of FIA and potentiated the aggression-facilitative effects of L-dopa, apomorphine and PNA. Since both these treatments are known to induce supersensitivity of central postsynaptic dopamine D2 receptors, the effects are likely to be related to augmented function of dopamine neurones. The findings, in conjunction with a recent report from this laboratory indicating an increase in rat brain DA levels in FIA, support the contention that the central DA system has a facilitative effect on FIA.

Receptor-operated calcium-channels in isolated rabbit jejunum.

Calcium channels were studied in isolated spontaneously rhythmic rabbit jejunum using the muscarinic agonist carbachol as stimulant. Carbachol failed to produce the characteristic phasic and tonic components of smooth muscle contractions. A variety of chemically distinct calcium antagonists, viz. bepridil, diltiazem, isradipine (PN 200-110), nifedipine, and verapamil, non-competitively inhibited the contractions. Diltiazem was most potent (-logIC50 = 8.30) and bepridil least potent (-logIC50 = 6.19) in inhibiting the contractions. The findings conclude with the presence of pharmacologically distinct receptor-operated calcium-channels, besides the potential-dependent calcium-channels, in the rabbit jejunum.

Effects of muscarinic receptor agonists and antagonists on response of non-extensor rats to maximal electroshock.

Rats which do not respond consistently to maximal electroshock by exhibiting the classical hindlimb extensor response, are designated as 'flexors', and can serve as a useful experimental model for investigating seizure mechanisms. 20-25% Charles Foster rats exhibit the flexor status and were used in this study. The flexor rats were converted to extensors by acetylcholine (icv), physostigmine (ip) and the selective muscarinic M1 receptor agonists, arecholine (ip) and McN-A-343 (icv). This conversion of flexors to extensors was significantly attenuated by M1 receptor antagonists scopolamine (ip) and pirenzepine (icv). The M2 receptor agonist, carbachol (icv), had no effect in lower doses but induced conversion of flexor rats to the extensor status only in very high doses which may be due to loss of receptor specificity on dose increment. The M2 receptor antagonists, gallamine (icv) and AF-DX 116 (ip), also induced significant conversion of flexors to extensors, which was dependent upon the availability of neuronal acetylcholine since the effects were attenuated following pretreatment with hemicholinium, an inhibitor of acetylcholine synthesis. The results suggest that the central cholinergic system has a facilitatory pro-convulsant effect, mediated through the muscarinic M1 receptors, an action modulated by the M2 receptors.

Thermic response of selective muscarinic agonists and antagonists in rat.

Effect of some selective agonists and antagonists of cholinergic M receptor subtypes on rectal temperature was investigated in rats at an ambient temperature of 25 degrees +/- 2 degrees C. Centrally administered acetylcholine (ACh) induced transient hypothermia, whereas the muscarinic M1 receptor agonists, arecholine (ip) and McN-A-343 (McN) (icv), induced sustained and dose-related hypothermia. However, the nonspecific muscarinic receptor agonist, oxotremorine, and physostigmine, induced hypothermia at a lower dose and hyperthermia, accompanied by tremors, at higher doses. The muscarinic M2 receptor agonist, carbachol (icv) also produced a dose-related dual effect, hyperthermia and hypothermia being induced by the lower and higher doses, respectively. The M1 receptor antagonists, scopolamine (ip) and pirenzepine (icv), induced hyperthermia, whereas the M2 receptor antagonists, gallamine (icv) and AF-DX 116 (AFDX) (ip), produced hypothermia. The hypothermic effects of ACh. arecholine, McN, physostigmine, oxotremorine and carbachol were attenuated by scopolamine and pirenzepine. However, although scopolamine also inhibited the hyperthermic and tremorogenic effects of the higher dose of oxotremorine, it had a synergistic effect with the hyperthermia-inducing higher dose of physostigmine. AFDX attenuated the hyperthermic effect of the lower dose of carbachol, indicating that it was M2 receptor-mediated. Hemicholinium, an ACh synthesis inhibitor, had a transient hypothermic effect followed by slight hyperthermia. However, it markedly antagonized the hypothermic effects of gallamine and AFDX, indicating that their effects were dependent upon the availability of neuronal ACh. The results indicate that cholinergic hypothermia is a function of central muscarinic M1 receptors, with the M2 receptors serving as automodulators.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of selective muscarinic receptor agonists and antagonists on active-avoidance learning acquisition in rats.

Effect of some selective muscarinic receptor agonists and antagonists was investigated on learning acquisition in an active-avoidance paradigm in rats which records an anticipatory conditioned avoidance apart from the classical conditioned avoidance response. The muscarinic M1 agonists, arecholine, pilocarpine and McN-A-343, facilitated learning acquisition, which was attenuated by the selective M1 antagonist, pirenzepine. On the other hand, M2 receptor agonist, carbachol, and physostigmine, induced a dose-related dual response, with lower doses retarding and higher doses facilitating the learning acquisition. The former effect was attenuated by gallamine, a muscarinic M2 antagonist, while the latter response was inhibited by pirenzepine, indicating that these putative M2 receptor agonist lose their receptor specificity on dose increment. The selective M2 receptor antagonists, gallamine and AF-DX 116, facilitated learning acquisition, which was inhibited by pirenzepine and the acetylcholine synthesis inhibitor hemicholinium. The results support the cholinergic hypothesis of learning and memory and indicate that M1 receptor agonists and M2 receptor antagonists are likely to prove beneficial in memory deficits. The data also indicates that the clinical dose of some drugs, like physostigmine, needs to be carefully established for optimum therapeutic benefit.

Potential-dependent calcium channels in rabbit jejunum.

Potential-dependent calcium channels have been studied in the isolated rabbit jejunum. A biphasic response was observed, a transient and rapid contraction followed by partial relaxation and a sustained contraction attaining a plateau state. These are similar to the phasic and tonic responses observed in the isolated smooth muscles of other species. Both the responses are susceptible to blockade by the calcium antagonists bepridil, diltiazem, nifedipine, PN 200-110 (isradipine), and verapamil. Two calcium pools or the presence of two channels affecting the two responses are proposed.