Discriminating between reward and performance: a critical review of intracranial self-stimulation methodology.

Despite numerous pharmacological investigations of intracranial self-stimulation (ICSS), the substrates of this behavior have yet to be completely understood. In view of the likelihood that inadequate methodology has hindered the quest for these substrates, the present review was undertaken. Criteria for ICSS methodology should include not only the ability to discriminate reward from gross performance deficit, but also adequate capacity (ability to generate experimental data at a reasonable rate). For numerous reasons, bar-pressing on a continuous reinforcement schedule fails the first criterion despite its ease and rapidity. The use of partial reinforcement schedules may alleviate some of these shortcomings. Analysis of drug-induced response decrement patterns can discriminate gross motoric incapacity from other variables, although the question of subtle response maintenance deficits remains to be answered. Measurements of response rates using alternative operants do not differentiate reward and performance adequately. More promising, "rate-free" measures using locomotion as an operant include the two-platform method of Valenstein and the "locus of rise" method. Comparison of drug effects on ICSS with those on alternate tasks are fraught with pitfalls including the problems of assuring equivalent rates and patterns of responding. The use of differential electrode placements is ideally suited for neurochemically well-characterized drugs, particularly if "double dissociations" can be established during studies of multiple placements. Presentation of different current intensities or frequencies permits the compilation of rate-intensity functions, and drug-induced shifts in these functions have considerable analytical power. Self-regulation of current intensity constitutes a powerful tool that has yet to realize its full potential in the pharmacological study of ICSS. Extensive studies involving self-regulation of stimulation duration ("shuttlebox" studies) suggest that this method may be highly versatile despite several practical difficulties. It is concluded that at least six of these methods appear to do a reasonable job of excluding gross performance deficit. However, the possible influences of other factors, such as subtle response maintenance deficit, incentive or arousal, remain to be resolved in view of the multifactorial nature of ICSS. Multiple tests for ICSS drug or lesion studies are advocated whenever feasible, as no single test appears capable of resolving all theoretical complexities.

Anxiety, anxiolytics and brain stimulation reinforcement.

The premise of this review is that neuronal substrates of anxiety are amenable to investigation using brain stimulation techniques. Anxiolytics such as meprobamate and the benzodiazepines may enhance intracranial self-stimulation (ICSS) behavior. Although demonstrated by numerous investigators, this effect shows considerable variability between and within laboratories. Some of this variability is explained by sedative/muscle relaxant effects, which are dissociable from drug-induced increases in ICSS and which may mask these increases. The anticonvulsant actions of anxiolytic drugs are unlikely to account for the increases in ICSS. Rather, anxiolytics appear to increase ICSS by attenuating concurrent aversive properties of stimulation. Consistent with this explanation, anxiolytic drugs attenuate escape from aversive dorsal tegmental stimulation. The neuronal substrates of this centrally mediated escape behavior differ from those mediating footshock-induced escape. Barbiturates also enhance ICSS, possibly due in part to an excitatory component that is not involved in benzodiazepine action. Inverse benzodiazepine agonists attenuate ICSS behavior in a manner that cannot be explained by nonspecific performance impairment. These substances, however, may not necessarily enhance stimulation-induced aversiveness. A strategy is proposed to integrate brain stimulation studies with molecular approaches to anxiety. Specifically, stimulation of sites associated with fear induction or fear reduction may selectively alter the release of endogeneous anxiogens or anxiolytic substances.

Antinociceptive profile of sulfated CCK-8. Comparison with CCK-4, unsulfated CCK-8 and other neuropeptides.

The antinociceptive activity of sulfated cholecystokinin octapeptide (CCK-8-S) was characterized by comparison with two other endogenous forms, unsulfated CCK-8 (CCK-8-U) and the carboxyl tetrapeptide fragment (CCK-4) and two other peptides present in the gut and brain: bombesin and neurotensin. By the intracerebroventricular (i.c.v.) route, CCK-8-S was antinociceptive in the hot plate and phenylquinone-induced writhing assays, but CCK-8-U and CCK-4 were active only in the latter test. By systemic administration, CCK-8-S retained anti-writhing activity but CCK-8-U and CCK-4 did not. Therefore, CCK receptors in brain may be involved in the apparent antinociception produced by CCK-8-U and CCK-4. Bombesin produced potent antinociceptive activity, along with a distinct, head-scratching syndrome, in both the writhing and hot plate tests. Naloxone reversed bombesin-induced elevation of latencies of mouse jump but not the head-scratching syndrome, indicating that the analgesic effect in the hot plate test was independent of the scratching behaviour. Neurotensin, unlike CCK-8-S, elevated tail-flick latencies, and was more potent in the writhing than in the hot plate test. Several differences between CCK-8-S and opioid substances included the need for relatively large doses of naloxone to block the effects of CCK-8-S in the phenylquinone-induced writhing test and the lack of effect of CCK-8-S in the tail-flick test. Global sedation can account for some, but not all, of the effects of CCK-8-S.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of 5-HT1A agonists and 5-HT2 antagonists on haloperidol-induced dyskinesias in squirrel monkeys: no evidence for reciprocal 5-HT-dopamine interaction.

Dyskinetic movements and dystonic postures may be induced by neuroleptics in monkeys that have undergone previous neuroleptic treatment, and these motor abnormalities constitute a primate model of drug-induced extrapyramidal symptomatology. In view of previous suggestions that brain serotonergic systems may tonically inhibit dopamine neurons, the effects of several new and selective 5-HT2 receptor antagonists and 5-HT1A receptor agonists were investigated in this model. Setoperone, a dopamine D2 receptor antagonist with extremely potent 5-HT2 antagonism, caused dyskinetic movements. Although ritanserin is a potent 5-HT2 antagonist with very weak dopamine antagonist properties, this drug did not antagonize dyskinesias but induced them when administered at a high dose (30 mg/kg). Buspirone induced dyskinesias and blocked apomorphine-induced climbing, supporting prior reports that it has dopamine antagonist effects. Gepirone, a 5-HT1A agonist with less marked dopamine antagonist properties, induced dyskinesias in only one of six monkeys at 30 mg/kg and did not block haloperidol-induced dyskinesias. 8-OH-DPAT partly attenuated haloperidol-induced dyskinesias, an effect possibly attributable to its weak dopamine agonist properties. Tonic inhibition of brain extrapyramidal dopamine systems by serotonin systems does not appear to characterize neuroleptic-related dyskinesias in squirrel monkeys.

Rotational behavior induced by 8-hydroxy-DPAT, a putative 5HT-1A agonist, in 6-hydroxydopamine-lesioned rats.

Rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the ascending nigro-striatal pathway have been shown to rotate in response to dopamine (DA) agonists that are not considered to have postsynaptic DA stimulant properties in intact animals, suggesting a relative loss of DA receptor selectivity in the denervated striatum. The present experiments assessed the possibility that this loss of selectivity may extend to serotonin (5HT) agonist drugs. The 5HT-1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), at doses of 0.3-3 mg/kg SC, induced robust contralateral rotational behavior (RB) in 6-OHDA-lesioned rats that had been preselected on the basis of high responsiveness to the atypical DA agonists 3-PPP and SKF 38393. Rats with unilateral dorsal raphe lesions induced by 5,7-dihydroxytryptamine (5,7-DHT) showed contralateral RB in response to similar doses of 8-OH-DPAT but with a different behavioral pattern. The putative 5HT-1b agonist RU 24969 produced contralateral RB in 5,7-DHT-lesioned rats while showing a much weaker effect in 6-OHDA-lesioned rats. Striatal DA levels were depleted by 99% in representative 6-OHDA-lesioned rats but striatal 5HT levels were unaffected. The effects of 8-OH-DPAT in 6-OHDA-lesioned rats were therefore not attributable to destruction of ascending 5HT-containing neurons. These effects may result from indirect actions, mediated by 5-HT neurons or neuronal receptors, that result from asymmetry of brain DA systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of dopamine agonists, catecholamine depletors, and cholinergic and GABAergic drugs on acute dyskinesias in squirrel monkeys.

It has been suggested that the neuroleptic-induced acute dyskinetic syndrome in monkeys may be a useful model of extrapyramidal dysfunction. Various drugs that have well-characterized effects on clinical extrapyramidal syndromes and on catecholaminergic, cholinergic, or GABAergic neurotransmission were assessed in dyskinesia-susceptible squirrel monkeys. Catecholamine depletors (alpha-methyl-p-tyrosine, tetrabenazine) induced the syndrome, as do dopamine (DA) receptor antagonists, and d-amphetamine reversed the effects of tetrabenazine. The haloperidol-induced syndrome was reversed by the indirectly acting DA agonists amantadine and L-dopa. Neither of the DA autoreceptor agonist TL-99 or 3-PPP elicited this syndrome, suggesting that these agents lack extrapyramidal involvement. Anticholinergics reversed haloperidol-induced dyskinesias and the cholinomimetic arecoline was capable of inducing dyskinesias. When coadministered repeatedly with haloperidol, benztropine suppressed the emergence of susceptibility to neuroleptic-induced dyskinesias. These results confirm that the acute dyskinetic syndrome in the monkey is characterized by DA deficiency and acetylcholine excess. Diazepam and baclofen, which have been reported to have some clinical benefit in tardive dyskinesia, suppressed haloperidol-induced acute dyskinesias without causing gross motor depression. Pharmacological manipulation of GABAergic pathways from striatum may constitute a fruitful approach to the treatment of dyskinetic motor disorders.

Heterogeneous rotational responsiveness in 6-hydroxydopamine-denervated rats: pharmacological and neurochemical characterization.

Qualitative differences in pharmacological responsiveness to various types of dopamine agonists have been reported in rats that have undergone unilateral 6-hydroxydopamine (6-OHDA)-induced denervation of the nigro-striatal pathway. The present experiments further characterize these differences, pharmacologically and neurochemically. Rats were classified as having high rotational sensitivity (0.03 mg/kg SC apomorphine sufficient to induce more than 100 rotations/20 min) or low sensitivity (0.3 mg/kg SC apomorphine required to meet this criterion). High sensitivity rats showed marked contralateral rotational behavior (approximately 150 rotations/20 min) in response to apomorphine (ED50 = 0.08 mg/kg IP), CGS 15855A (ED50 = 0.07 mg/kg), CGS 15873A (ED50 = 0.43 mg/kg), (+)-3-PPP (ED50 = 2.3 mg/kg), (-)-3-PPP (ED50 = 0.87 mg/kg) and quinpirole (peak effective dose, 0.03 mg/kg). In low sensitivity rats, 3- to 10-fold higher doses of apomorphine induced a maximal rate of rotational behavior, but only partial effects were produced by quinpirole, CGS 15855A, CGS 15873A, (+)-3-PPP, and (-)-3-PPP (40-80 rotations/20 min). Because apomorphine is a nonselective D1 and D2 agonist, it is proposed that activation of either D1 or D2 receptors suffices to induce high rates of rotation in high sensitivity rats, whereas in low sensitivity rats, D1 or D2 agonism alone induces submaximal rotation rates. The ipsilateral rotational behavior induced by d-amphetamine was more pronounced and occurred at lower doses in the high-sensitivity rats. Striatal dopamine depletion on the lesioned side did not differ between the groups, but low sensitivity rats showed two-fold higher DOPAC/DA ratios on the lesioned side than did high-sensitivity rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Progressive changes in the acute dyskinetic syndrome as a function of repeated elicitation in squirrel monkeys.

Various neuroleptic-induced motor disorders that appear in primates previously treated with neuroleptics are collectively designated the acute dyskinetic syndrome. The relative incidence of these motor disorders was examined as the syndrome was repeatedly elicited by haloperidol and other dopamine antagonists in individual monkeys. After several weekly or biweekly treatments with haloperidol (1.25 mg/kg orally), catalepsy began to appear, which was then accompanied by athetoid movements (writhing and limb extensions) as intermittent neuroleptic treatment continued. Other dyskinetic movements ('duck walk', oral dyskinesias, pushing of the head into a cage corner, and perseverative circling) that were suggestive of hyperkinesia subsequently began to be elicited by haloperidol and other neuroleptics after additional treatments with these drugs had intervened. As intermittent treatments continued, tolerance to the athetoid movements gradually developed and, eventually, only circling and pushing could be consistently elicited by haloperidol. In monkeys that had reached this phase, the athetoid movements were not again induced by higher doses of haloperidol (up to 5 mg/kg), chlorpromazine (3 mg/kg), or metoclopramide (3 mg/kg). In these tolerant monkeys, haloperidol impaired Sidman avoidance performance less and benztropine more than in drug-naive monkeys. Neither pharmacokinetic changes nor behavioral tolerance could readily account for these results. It is hypothesized that they reflect progressive functional alterations in dopaminergic or cholinergic neurotransmission.

Acute dyskinesias in monkeys elicited by halopemide, mezilamine and the "antidyskinetic" drugs, oxiperomide and tiapride.

Oxiperomide and tiapride are dopamine receptor antagonists claimed to have "antidyskinetic" properties in animal models and the clinic. Halopemide and mezilamine are other dopamine antagonists predicted to lack extrapyramidal side effects in man on the basis of animal studies. Acute dyskinesias, a neuroleptic-induced acute extrapyramidal syndrome, were elicited in squirrel monkeys by oxiperomide (1 mg/kg), tiapride (30 mg/kg), and halopemide (10 mg/kg). The dyskinesias were virtually indistinguishable from those caused by a standard behaviorally equivalent dose of haloperidol (1.25 mg/kg PO) in the same individual monkeys. Mezilamine (0.3 mg/kg) also induced dyskinesias, which appeared to be less pronounced than those following haloperidol. The antidyskinetic properties of oxiperomide and tiapride evidently do not confer protection against dyskinetic movements induced by dopamine antagonism.

Differential reversal of various dopamine antagonists by anticholinergics in Sidman avoidance: possible relationship to adrenergic blockade.

Various dopamine receptor antagonists have divergent clinical and neurochemical properties. The relative ability of anticholinergics (benztropine and scopolamine) to reverse these drugs was assessed in squirrel monkeys and rats performing a Sidman avoidance task. In monkeys, benztropine markedly attenuated the effects of oxiperomide, metoclopramide, halopemide, tiapride and mezilamine as well as haloperidol. Chlorpromazine and fluphenazine were antagonized to a moderate extent; thioridazine and perlapine were not antagonized; and clozapine was actually potentiated by benztropine. In the rat, benztropine antagonized haloperidol strongly but reversed fluphenazine, thioridazine or clozapine only weakly or not at all. The overall effects of scopolamine in both species were similar to those of benztropine. The dopamine receptor antagonists that were most completely reversed by benztropine were found to inhibit 3H-spiroperidol more strongly than 3H-WB-4101 binding in calf caudate, while the reverse was true for drugs that were antagonized only moderately or not at all by benztropine. These results support a previous suggestion that anticholinergic reversal is less marked against dopamine antagonists with alpha-adrenergic blocking properties. Benztropine reversal of experimental dopamine receptor antagonists in the squirrel monkey Sidman avoidance test may contribute to their preclinical characterization.

Comparative effects of beta 2-adrenoceptor agonists on intracranial self-stimulation, Sidman avoidance, and motor activity in rats.

The effects of beta-adrenoceptor agonists were compared in various operant behavioral tasks, particularly intracranial self-stimulation (ICSS). Clenbuterol, salbutamol, and terbutaline all reduced responding by rats that lever-pressed for low stimulation intensities. The effects of clenbuterol in this test were completely reversed by propranolol, and those of salbutamol were partly reversed. Intermediate doses of clenbuterol and salbutamol slowed the initiation of rewarding brain stimulation in a shuttlebox but had little or no effect on the termination latencies. However, higher doses of both drugs lengthened the termination latencies. Motor activity was reduced at doses that attenuated ICSS responding. Complete tolerance occurred within 4 days to the effects of clenbuterol and salbutamol on lever-pressing ICSS and to the effects of clenbuterol on motor activity. The apparent performance deficits induced by these drugs were overcome by more intense motivation. For example, even at high doses, clenbuterol reduced ICSS lever-pressing only partially when animals bar-pressed for high rather than low stimulation intensities. Furthermore, all three drugs failed to alter Sidman avoidance responding at doses up to 100 times those that attenuated ICSS responding. It is concluded that although beta-adrenoceptor agonists cause apparent sedation in rats, this sedation is limited and shows rapid tolerance.

Antagonism of morphine analgesia by CCK-8-S does not extend to all assays nor all opiate analgesics.

The conditions under which CCK-8-S may block opiate-induced analgesia were examined in detail. A U-shaped dose-response relationship was observed for the ability of CCK-8-S to attenuate (by approximately 50%, at most) morphine-induced tail flick analgesia. The analgesic effects of morphine in the hot plate or acetic acid-induced stretching tests were not altered by CCK-8-S at doses that antagonized morphine in the tail flick test. Tail flick latency elevations induced by meptazinol, a putative mu-1 receptor agonist, were also attenuated by CCK-8-S according to a U-shaped dose-response relationship, but those induced by U-50,488, a kappa agonist, were not antagonized by CCK-8-S doses that attenuated morphine analgesia. Thus, the ability of CCK-8-S to antagonize opiate analgesia does not follow a conventional dose-response relationship, does not extend to all tests of analgesia and may not extend to all opioid drugs. Analgesia mediated by the mu-1 opioid receptor subtype may be more amenable to antagonism by CCK-8-S than that mediated by the kappa receptor subtype.

Unsulfated CCK-8 not blocked by proglumide or CR 1409 in the mouse abdominal irritant-induced stretching assay: possible central site of action.

Previous studies have shown that unsulfated cholecystokinin octapeptide (CCK-8-U) shares with the sulfated octapeptide (CCK-8-S) and the carboxyl-terminal tetrapeptide (CCK-4) the ability to block abdominal irritant-induced stretching when administered intracerebroventricularly. The effects of CCK-8-U, however, are not naloxone-reversible and do not appear upon systemic administration. To assess the hypothesis that the antistretching effects of CCK-8-U are mediated by central-type (CCK-B), rather than peripheral-type (CCK-A) receptors, the present experiments examined the reversal of these effects by CR 1409, a CCK receptor antagonist with in vitro selectivity for CCK-A receptors, and by proglumide. Both antagonists, when administered ICV, blocked the antistretching effects of CCK-8-S and CCK-4 (ICV), but not those of CCK-8-U. CR 1409 was approximately 40 times more potent against CCK-8-S by the ICV route than subcutaneously, indicating a likely action on CCK-A receptors in the brain. The effects of morphine, bombesin and neurotensin (ICV) were not blocked by CR 1409, indicating specificity for CCK receptor-mediated effects. The antistretching effects of CCK-8-U do not appear to be mediated by CCK-A receptors, and the possibility of a CCK-B receptor site of action must be considered.

Unique behavioral effects of the NMDA antagonist, CPP, upon injection into the medial pre-frontal cortex of rats.

Injection of the specific N-methyl-D-aspartate (NMDA) antagonist, 3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), into the frontal cortex of rats, induced hyperactivity characterized by unique episodic darting behavior. This behavioral profile contrasts sharply with the ataxia and hyperactivity seen after intracerebroventricular CPP and other NMDA antagonists.

The N-methyl-D-aspartate antagonists CGS 19755 and CPP reduce ischemic brain damage in gerbils.

N-Methyl-D-aspartate (NMDA) antagonists reduce ischemic brain damage and associated hypermotility. Two potent, selective and competitive NMDA antagonists, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) and 4-(3-phosphonopropyl)-2-piperazine-carboxylic acid (CPP), were characterized in the gerbil ischemia model with respect to dose-response and time course effects. Both drugs were effective in reducing ischemia-induced hippocampal brain damage as well as hypermotility. In this model, CGS 19755 was more potent than CPP, and had protective effects when given after longer delays between ischemia and drug administration.

Antinociceptive effects of baclofen and muscimol upon intraventricular administration.

The effects of intraventricularly administered baclofen and muscimol were investigated on tail-flick responding and on vocalization and motor responses to nociceptive pinch. Baclofen (1 microgram) and muscimol (0.1 microgram) strongly reduced responding to pinch, particularly vocalization, without altering tail-flick responding. When given systemically, however, baclofen markedly attenuated tail-flick as well as pinch responding. Muscimol produced only weak antinociception by systemic administration, suggesting that it may have poor access to brain. At antinociceptive doses, i. vent. muscimol produced less apparent muscle relaxation than did baclofen. These results suggest that baclofen's antinociceptive action may be mediated in part by a supraspinal, GABAergic substrate, in addition to a spinal component which may not directly involve GABA.

Evidence for heterogeneous rotational responsiveness to apomorphine, 3-PPP and SKF 38393 in 6-hydroxydopamine-denervated rats.

Several novel dopamine (DA) agonists (SKF 38393, 3-PPP, TL-99) have been reported to induce rotational behavior (RB) in rats unilaterally denervated of the nigro-striatal pathway by 6-hydroxydopamine. Other reports have indicated no RB, however, and these drugs do not cause other behavioral manifestations of postsynaptic DA agonism. In the present experiments, two groups of 6-hydroxydopamine-denervated rats were distinguished by their relative responsiveness to apomorphine-induced RB. A highly sensitive group showed maximal RB in response to doses as low as 0.03 mg/kg, while a less sensitive group exhibited comparable RB only in response to 15- to 20-fold higher doses. The high sensitivity group exhibited RB in response to SKF 38393, 3-PPP and pergolide, but the low sensitivity group did not show appreciable RB after these drugs, even at doses 50 to 100-fold higher. Haloperidol markedly attenuated apomorphine-induced RB in the low sensitivity subgroup, but only reduced by approximately one-half the number of turns induced by apomorphine or SKF 38393 in the high sensitivity group. The atypical antipsychotics, clozapine and RMI 81582, and the muscle relaxant, methocarbamol, reduced RB in all groups, but only at doses that caused performance impairment in a rotorod test. These results appear to reflect qualitative differences in responsiveness to different DA agonists. Behavioral preselection of 6-hydroxydopamine-denervated animals is necessary to achieve consistent pharmacological results with the 6-hydroxydopamine RB model.

Postsynaptic dopamine agonist properties of TL-99 are revealed by yohimbine co-treatment.

The claim that TL-99 (6,7-dihydroxy-2-dimethylaminotetralin hydrobromide) is a selective dopamine autoreceptor agonist relies partly upon indirect behavioral evidence, particularly the absence of stereotyped behavior in treated rats. The possibility was examined that concurrent alpha 2-adrenoceptor agonist properties of TL-99 could have masked postsynaptic dopamine agonist activity. Co-administration of yohimbine or piperoxan with a high dose of TL-99 (30 mg/kg) dramatically increased motor activity in reserpinized rats, whereas each drug by itself had no effect. Contralateral rotational behavior in 6-hydroxydopamine-lesioned rats resulted from combined treatment with yohimbine and a high dose of TL-99 (30 mg/kg) but appeared to be suppressed by concurrent flaccidity if TL-99 was given by itself. Yohimbine failed to alter the effects of 3-PPP (N-n-propyl-3-(3-hydroxyphenyl)-piperidine), another putative dopamine autoreceptor agonist, in either model of postsynaptic dopamine agonism. It is concluded that a concurrent behaviorally depressant action of TL-99, possibly alpha 2-agonism, masks the stimulation of postsynaptic dopamine receptors by high doses of TL-99.

Avoidance and ICSS behavioral models dissociate TL-99 and 3-PPP from dopamine receptor antagonists.

The behavioral effects of the putative dopamine autoreceptor agonists, TL-99 and 3-PPP, were explored in animal procedures that reveal highly characteristic effects of neuroleptics currently in clinical use. Sidman avoidance responding in rats was not altered appreciably by doses up to 10 mg/kg TL-99 or 30 mg/kg 3-PPP. Higher doses of TL-99 attenuated Sidman avoidance performance in squirrel monkeys, although 3-PPP had no effect. Lever pressing for intracranial self-stimulation (ICSS) was attenuated in a dose-related fashion by TL-99 and 3-PPP, with relatively shallow dose-response relationships. A low dose of haloperidol (0.03 mg/kg) partly reversed the effects of 3-PPP (3 mg/kg) on lever pressing ICSS, but not those of TL-99 (3 mg/kg). Yohimbine (3 mg/kg) failed to alter the effects of TL-99 at a dose that abolished the suppressant effect of clonidine on ICSS. Analysis of within-session ICSS response decrement patterns indicated that TL-99 reduced ICSS to a greater extent towards the end of the session than during the first 5 min. No such within-session trend was produced by 3-PPP, suggesting that 3-PPP attenuates ICSS by virtue of a performance deficit. Similar conclusions were reached using a shuttlebox task that involved self-regulation of ICSS duration by rats. Therefore, the clinical profile of neuroleptics is unlikely to be mimicked precisely by 3-PPP or TL-99. Clinical trials of DA autoreceptor agonists for antipsychotic efficacy will indicate whether or not avoidance and ICSS behaviors are relevant to the detection of the intrinsic antipsychotic activity of drugs.

Antagonism of L-5-hydroxytryptophan-induced head twitching in rats by lisuride: a mixed 5-hydroxytryptamine agonist-antagonist?

Lisuride antagonized L-5-hydroxytryptophan (5-HTP)-induced head twitches at doses lower than those sufficient to induce the serotonin (5-HT) syndrome. Among several other 5-HT agonists tested, only LSD and 1-(m-trifluoromethylphenyl)-piperazine (TFMPP) shared this paradoxical profile. Assessment of various dopamine (DA) agonists revealed a lack of correlation between DA-mediated stereotyped behavior (indicative of postsynaptic DA agonism) and blockade of 5-HTP-induced head twitches. Lisuride displaced specific ligand binding from putative S1a, S1b and S2 receptors at nanomolar concentrations, and other drugs that blocked 5-HTP-induced head twitches also displaced binding at S2 sites. It is proposed that lisuride may have agonist properties at S1a receptors mediating the 5-HT syndrome but antagonist properties at S2 receptors mediating 5-HTP-induced head twitching.