Effects of quipazine and of tryptamine on self-stimulation of median raphé nucleus and of lateral hypothalamus in rats

Separate groups of male Wistar rats were trained to lever press on a continuous reinforcement schedule under which behaviour was maintained by electrical stimulation of the median raphé nucleus (N = 6) or the lateral hypothalamus (N = 6). The effects of several doses of quipazine (2.5-7.1 mg/kg) and of tryptamine (10-80 mg/kg) were assessed with each group. Administration of quipazine resulted in a decrease of median raphé self-stimulation at 5.0 and 7.1 mg/kg. This compound had no statistically significant effect on lateral hypothalamic self-stimulation. Administration of tryptamine resulted in significant decreases in self-stimulation at both sites, however, whereas the effects of this drug were significant at 20, 40 and 80 mg/kg with median raphé self-stimulation, a significant decrease in lateral hypothalamic self-stimulation was only observed at 80 mg/kg. As baseline response rates differed in the two self-stimulation sites, a second group of animals with lateral hypothalamic sites (n = 6) were tested with quipazine (2.5-7.1 mg/kg) at an overall baseline response rate matched to that of the median raphé group. Although a tendency to decrease self-stimulation rates was found in this group, these results were not significant. These data suggest, therefore, that median raphé self-stimulation is more sensitive than lateral hypothalamic self stimulation to disruption by the effects of quipazine and tryptamine.     

Antagonism of the effects of the atypical benzodiazepine, Ro 5-4864 on intracranial self-stimulation in the rat

The effects of Ro 5-4864 (chlordiazepam) were examined on responding for self-stimulation of the mid-lateral hypothalamus. Rewarding stimuli were delivered according to a 10-sec variable interval schedule of reinforcement. Ro 5-4864 (10-30 mg/kg, subconsulsive doses in these rats) decreased responding. This effect was antagonized by chlordiazepoxide (5-10 mg/kg) and phenobarbitone (35 mg/kg) but not by the benzodiazepine receptor antagonist Ro 15-1788 (10-20 mg/kg), the ligand for peripheral benzodiazepine receptors PK 11195 (60 mg/kg) or phenytoin (60 mg/kg). The pattern of interactions of Ro 5-4864 with these compounds differs from the pattern obtained with other procedures, and suggests that Ro 5-4864 has effects on systems unrelated to anxiety, convulsive activity or sedation.     

Presynaptic alpha-adenoceptors: the depression of self-stimulation by clonidine and its restoration by piperoxane but not by phentolamine or phenoxybenzamine.

Depression of self-stimulation by clonidine has been ascribed to continuous direct stimulation of alpha-adrenoceptors with consequent disruption of reinforcement signals thought to be conveyed by noradrenergic pathways. This suggestion was tested by administration of alpha-receptor blocking agents (piperoxane, phentolamine and phenoxybenzamine, PBZ) differing in their affinity for pre- and post-synaptic receptor sites. Piperoxane in low doses (0.55-5.0 mg/kg) previously reported to cause specific blockade of pre-synaptic receptors implicated in negative feedback circuits, caused a significant increase in self-stimulation rate and strongly antagonized the depression of self-stimulation by clonidine (0.15 mg/kg). A larger dose of piperoxane (45 mg/kg) and graded doses of phentolamine and PBZ, affecting both pre- and post-synaptic receptors, depressed self-stimulation, and did not antagonize clonidine-induced depression of self-stimulation. It is concluded that depression of self-stimulation by clonidine may depend on clonidine-induced inhibition of NA release exerted via presynaptic receptors, and that the effect of clonidine is not necessarily evidence that noncontingent adrenergic stimulation disrupts reinforcement.     

Actions and interactions of cocaine on self-stimulation behavior in rats

The effect of cocaine, over a dose range of 2–60 mg/kg, i.p., on self-stimulation (SS) behavior was studied in rats with electrodes either in the posterior hypothalamus (PH, monoaminergic) or the area ventralis tegmentum (A10, dopaminergic). The drug increased SS behavior with peak effects at 30 mg/kg in PH rats and 20 mg/kg in A10 rats. Azaperone (an -adrenergic blocker) and haloperidol (an antidopaminergic neuroleptic) given at doses that did not affect baseline SS responses reduced cocaine-induced enhancement of SS in both PH and A10 rats, showing the involvement of both noradrenergic and dopaminergic mechanisms in SS behavior. A scopolamine dose that itself facilitated SS responding enhanced the effect of cocaine on this behavior, thus suggesting an additional involvement of cholinergic mechanism in cocaine effect.     

Effect of morphine on self-stimulation in rats and its modification by chloramphenicol

The effect of morphine was studied on self-stimulation (SS) behavior in rats implanted with bipolar electrodes in the posterior hypothalamus. A single dose (10 mg/kg) of morphine decreased SS responding within 10-20 min, reaching a minimum level between 20-40 min after which the responding gradually returned to normal. The SS responding then increased above the control level at 120-180 min postdrug, then slowly returned to normal, thus showing a rebound effect. The combination treatment with morphine (10 mg/kg) and chloramphenicol (50 mg/kg) on SS behavior produced an accentuation of the initial decrease in responding, which was prolonged before gradually returning to the control levels without showing any rebound effect. The data suggest that alterations in protein synthesis may underlie the suppressed excitatory effect of a high dose of morphine on SS behavior.     

Rate dependent inhibition of self-stimulation by apomorphine

The effect of three doses of apomorphine 0.125, 0.25 and 0.5 were studied on self-stimulation generated by three levels of current intensity. Eight rats exhibited overall dose dependent decreases in self-stimulation obtained at the two lowest current intensities. Self-stimulation at the highest current intensity, however, was unaffected by even the highest dose level of apomorphine (0.5 mg/kg) despite typical signs of stereotypy exhibited by the rats in their home cages. Additionally, self-stimulation obtained under the 0.5 mg/kg dose of apomorphine underwent extinction when reinforcement was discontinued. Thus, brain stimulation can be an effective reinforcement when an animal is given a stereotypy inducing dose of apomorphine if the current intensity is of sufficient magnitude and if the response manipulandum is not compatible with stereotypic responses. These observations appear consistent with a dopaminergic involvement in the response rather than reinforcement aspect of self-stimulation.     

Effectiveness of morphine and ineffectiveness of diazepam and phenobarbital on the motivational properties of hypothalamic self-stimulation behaviour.

The actions of diazepam, phenobarbital, and morphine on self-stimulation were investigated to find out whether the site of action of these drugs is in the reward pathway when facilitation or suppression of responding for brain stimulation is observed. The range of doses tested was 1·25–120 mg/kg for diazepam, 1·25–200 mg/kg for phenobarbital and 1·25–5 mg/kg for morphine. A self-stimulation test at a given intensity of stimulation was always initiated with priming stimuli.Diazepam and phenobarbital at doses of 1·25–10 mg/kg increased the rate of self-stimulation; at doses between 10 and 60 mg/kg the drugs increased the rates in some subjects and decreased the rates in others. Very high doses, 120 mg/kg for diazepam and 200 mg/kg for phenobarbital, were needed to produce suppression of self-stimulation behaviour. Sedation was observed at doses of 10 mg/kg or more in the intervals between testing for self-stimulation at the different intensities. Thus, responding for brain reward was maintained with only minor reductions in rates when the tests were initiated with priming stimuli. Morphine did not increase the rate of responding at low doses, and it suppressed the rate of responding at doses that caused depression or sedation. Tests to determine the time-course of the drugs showed that the time of peak action was between 30–45 min after injection, the time when brain stimulation counteracted the sedation produced by diazepam and phenobarbital. The minor effects of diazepam and phenobarbital at high doses were not due to the development of tolerance because similar effects were obtained in subjects not previously treated with the drugs. The main finding was the absence of a strong depressant effect on the rate of self-stimulation after large doses of diazepam and phenobarbital, but the presence of depressant effects on the rate of responding after small doses of morphine. These results indicate the possibility that the first two compounds, at doses that sedate, have minor effects on the motivational properties of hypothalamic stimulation while morphine, at doses that sedate, has major effects on these properties.     

Task-specific effects of nicotine in rats. Intracranial self-stimulation and locomotor activity

The acute effects of nicotine (0.03-1.0 mg/kg) were studied in a locomotor activity procedure and in a series of intracranial self-stimulation (ICSS) paradigms. Nicotine produced a dose-dependent decrease in locomotor activity. When animals were trained to lever-press for intracranial self-stimulation on a continuous reinforcement schedule (CRF), the drug was ineffective except at the 1.0 mg/kg dose, which produced a moderate decrease in the rate of responding. However, when animals were tested in a fixed-ratio:15 (FR:15) paradigm, nicotine produced a steep, biphasic dose-response curve. At the 0.1 mg/kg dose, the response rates were increased to approx. 60% above baseline, while at the 1.0 mg/kg dose, response rates were decreased to approx. 90% below baseline values. The effects of nicotine were also studied in an auto-titration procedure which measured the rewarding value of the stimulus. There was a decrease in performance at larger doses similar to that observed in the continuous reinforcement procedure, but there were no significant changes in the threshold for reinforcement. Nicotine did not produce any change in the detection threshold for stimulation of the brain. In acute studies, therefore, nicotine produced both stimulation and disruption of behavior, effects that were brought to light by the fixed-ratio schedule of reinforcement, and this may relate to the rewarding effects of nicotine.     

Evidence that background GABAergic tone and possible ligand release may alter the action of the 'neutral' benzodiazepine-receptor antagonist, Ro 15-1788, in hypothalamic self-stimulation

Upward or downward shifts in the level of brain GABAergictransmission have been held to be necessary and sufficient to promote release of endogenous ligands ('endocoids') for the benzodiazepine (BZD) recognition site. To investigate this possibility, variable-interval self-stimulation performance was used to monitor 'intrinsic' benzodiazepine-like and anti- benzodiazepine activity by the 'neutral' benzodiazepine-receptor antagonist, Ro 15-1788 (flumazenil) (10 or 30 mg/kg intraperitoneally). Rats were pretreated with either a GABA synthesis blocking agent (isoniazid, 130 mg/kg subcutaneously), or with a GABA agonist (progabide, 30 or 100 mg/kg intraperitoneally). The lower dose of Ro 15-1788 (10 mg/kg), without pretreatment, did not affect self-stimulation; higher doses (30 mg/kg) caused a brief (<20 min) depression. Isoniazid (130 mg/kg) depressed self-stimulation, but did not modify the activity of Ro 15-1788. In rats pretreated with progabide (100 mg/kg), low doses of Ro 15- 1788 (10 mg/kg) that were previously without effect now caused a sharp fall in responding. These findings can be interpreted as showing that even low doses of Ro 15-1788 may affect self-stimulation under certain conditions, and that they do so by competing with an endogenous ligand for the benzodiazepine site, released by upward shifts in GABAergic activity. Alternative explanations in terms of altered receptor function seem less feasible. The results imply that the action of the endogenous ligand would not resemble that of a typical benzodiazepine, but that of an inverse agonist (that is, proconflict and proconvulsant); this conclusion agrees with recent biochemical evidence.     

Effects of chlorpromazine, chlordiazepoxide and pentobarbital on neuronal excitability in the medial forebrain bundle during self-stimulation behavior

The effects of chlordiazepoxide, chlorpromazine and pentobarbital were studied on self-stimulation behavior and simultaneously on neuronal responses driven by the rewarding stimuli. The tests were carried out on rats implanted with microelectrodes in the medial forebrain bundle for recording extracellular potentials and with macroelectrodes in the posterior lateral hypothalamus for producing self-stimulation behavior. The neuronal responses were (1) an excitatory response in the anterior hypothalamus, and (2) an inhibitory response in the middle hypothalamus. Chlordiazepoxide (20 mg/kg), chlorpromazine (4 mg/kg) or pentobarbital 10 mg/kg) were given intraperitoneally to suppress self-stimulation. (+)-Amphetamine (2 mg/kg) was given 30 min after the first compound to restore self-stimulation.

The results showed that chlordiazepoxide and pentobarbital acted nonspecifically on the excitatory response by reducing the spontaneous rate of firing at the time when self-stimulation was suppressed. Chlorpromazine abolished the driven excitatory responses in the anterior hypothalamus which were correlated in a 100% fashion with self-stimulation behavior. All three compounds had insignificant effects on the inhibitory responses.

The results give some basis for supposing that the effects of chlorpromazine were indices of effects on neuronal activity mediating positive reinforcement.     

Catecholamines and self-stimulation: evidence suggesting a reinforcing role for noradrenaline and a motivating role for dopamine.

Investigation of the role of noradrenaline (NA) and dopamine (DA) in self-stimulation showed that d-amphetamine (which releases more DA than does l-amphetamine, but not more NA) was much more effective than l-amphetamine in enhancing self-stimulation of NA sites in the locus coeruleus and near-lateral hypothalamus. In DA sites in the substantia nigra and far-lateral hypothalamus the effects of the 2 isomers were confirmed to be more nearly equal. Thymoxamine HCl (10 mg/kg IP), a specific alpha-adrenergic receptor blocker, depressed self-stimulation at all sites, but significantly more severely at DA sites. Thus the drugs most effective in influencing self-stimulation at a particular site were those acting predominantly on the unstimulated system. These findings were interpreted in terms of a hypothesis that DA and NA play complementary roles in self-stimulation and that both are essential; or, more specifically, that DA pathways, implicated in other motivational activites, contribute to a state of drive or arousal necessary for self-stimulation; while response-contingent noradrenergic activity (elicited by the electrodes directly via a transsynaptic route) mediates reinforcement. Further predictions from this hypothesis were tested as follows: (1) Direct pharmacological stimulants of adrenergic alpha-receptors should disrupt self-stimulation by acting randomly on the reinforcement system and disrupting response-reward contingencies; this was confirmed by the finding that the alpha-receptor stimulant clonidine HCl (0.05 mg/kg) depressed self-stimulation at all sites tested. (2) Drect stimulants of DA receptors should enhance self-stimulation of NA sites by augmenting dopaminergic motivational activity; but in rats with DA electrodes, noncontingent stimulation of DA receptors would also impose similar noncontingent activity on the transsynaptic noradrenergic reinforcement pathways and thus depress self-stimulation; this was confirmed by the finding that apomorphine (0.3-1.0 mg/kg) was strongly stimulant for NA electrodes but strongly depressant for DA electrodes, and that the degree and direction of these effects was highly correlated with the differential effects of d- l-amphetamine (rho = .65, p less than 0.01). Neither effect of apomorphine depended on the occurrence of motor stereotypy. These results can be interpreted in terms of 2-component models for self-stimulation, with the predominant transmitter of the drive component being identified as DA and that g the reinforcing component as NA.     

Enhancement of endocannabinoid neurotransmission through CB1 cannabinoid receptors counteracts the reinforcing and psychostimulant effects of cocaine

Cannabinoids, in contrast to typical drugs of abuse, have been shown to exert complex effects on behavioural reinforcement and psychomotor function. We have shown that cannabinoid agonists lack reinforcing/rewarding properties in the intracranial self-stimulation (ICSS) paradigm and that the CB1 receptor (CB1R) agonist WIN55,212-2 attenuates the reward-facilitating actions of cocaine. We sought to determine the effects of the endocannabinoid neurotransmission enhancer AM-404 (1, 3, 10, 30 mg/kg) on the changes in ICSS threshold and locomotion elicited by cocaine and extend the study of the effects of WIN55,212-2 (0.3, 1, 3 mg/kg) on cocaine-induced hyperlocomotion. AM-404 did not exhibit reward-facilitating properties, and actually increased self-stimulation threshold at the highest dose. Cocaine significantly reduced self-stimulation threshold, without altering maximal rates of responding. AM-404 (10 mg/kg) attenuated this action of cocaine, an effect which was reversed by pretreatment with the selective CB1R antagonist SR141716A. WIN55,212-2 decreased locomotion at the two highest doses, an effect that was blocked by SR141716A; AM-404 had no effect on locomotion. Cocaine caused a significant, dose-dependent increase in locomotion, which was reduced by WIN55,212-2 and AM-404. SR141716A blocked the effects of WIN55,212-2 and AM-404 on cocaine-induced hyperlocomotion. SR141716A alone had no effect on ICSS threshold or locomotion. These results indicate that cannabinoids may interfere with brain reward systems responsible for the expression of acute reinforcing/rewarding properties of cocaine, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for the treatment of psychostimulant addiction and pathological states associated with psychomotor overexcitability.     

Comparative involvement of dopamine and noradrenaline in rate-free self-stimulation in substantia nigra,lateral hypothalamus,and mesencephalic central gray

Summary Previous research has shown that self-stimulation (SS) is found in substantia nigra (SN) and that SS in other loci is altered by drugs preferentially influencing dopaminergic neurotransmission. In the first part of this investigation the effects of pimozide (0.35 and 0.5 mg/kg), apomorphine (0.25, 0.5, 0.75 and 1.5 mg/kg), d-amphetamine (0.1, 0.25, and 1.0 mg/kg) and L-amphetamine (0.25, 1.0, and 2.5 mg/kg) on SS in lateral hypothalamus (HL) and SN were separately determined. To reduce possible confounding of drug effects on SS with non-specific changes in motor activation, a rate-free test of SS was employed. Pimozide (0.5 mg/kg) reduced SS more strongly in SN than in HL, confirming the existence of a dopaminergic substrate of SS in SN, but HL SS was also reduced by this drug. Low doses of apomorphine (0.25 and 0.5 mg/kg) elevated SS in HL while not influencing or slightly reducing SS in SN. Higher doses of apomorphine reduced SS in both regions. The enhancing effect of 0.1 mg/kg d-amphetamine on SS was greater in HL than in SN. However, d-amphetamine tended to increase SS more strongly than did L-amphetamine in SN as well as HL. It was concluded that HL SS may be mediated by both noradrenergic and dopaminergic substrates.An investigation was also undertaken into the possibility of noradrenergic or dopaminergic mediation of SS in other brain regions. Self-stimulation in the dorsal raphé area of mesencephalic central gray matter was not increased by 0.1 or 0.25 mg/kg d-amphetamine and was elevated only at 1.0 mg/kg, a dose level well above that needed to elevate HL or SN SS. In this region, therefore, SS did not appear to have either a noradrenergic or a dopaminergic substrate.This report is based on portions of a dissertation submitted by J. M. L. in partial fulfillment of the requirements for the Ph. D. degree at the University of California, Los Angeles.     

Actions and interactions of amphetamine on self-stimulation in rats.

The dose-response relationship for d-amphetamine (0.125-2 mg/kg, IP) and its l-isomer (0.125-3 mg/kg, IP) was studied in self-stimulation behavior of rats each with an electrode at posterior hypothalamus (PH, mainly monoaminergic) or area ventralis tegmentum (A10, dopaminergic). The drug effects increased with the dose reaching a peak (at 0.5 mg/kg with d-amphetamine and at 1.0 mg/kg with 1-amphetamine) and then decreased. The d-isomer was approximately twice as potent as the l-isomer in enhancing intracranial self-stimulation (ICSS) rate with electrodes at either site. Azaperone (mainly an alpha-adrenergic blocker) and haloperidol (an antidopaminergic neuroleptic) used in small doses (0.05 and 0.008 mg/kg respectively) which did not affect the baseline responding, blocked amphetamine-induced enhancement of ICSS in both groups of rats. Thus, amphetamine-induced facilitation of ICSS at both PH and A10 areas and its blockade by an alpha-adrenergic blocker as well as an antidopaminergic neuroleptic show the involvement of both noradrenergic and dopaminergic mechanisms in self-stimulation behavior.     

SR141716, a CB1 receptor antagonist, decreases the sensitivity to the reinforcing effects of electrical brain stimulation in rats

RATIONALE: The endogenous cannabinoid system is thought to play a role in reinforcement processes. OBJECTIVES: We tested the effects of five doses of the cannabinoid receptor 1 (CB1) antagonist SR141716 [0, 0.3, 1, 3 and 10 mg/kg intraperitoneal (IP)] on intracranial self-stimulation at the level of the median forebrain bundle (MFB). Self-stimulation was assessed 30 min and 210 min after SR141716 administration. We compared the effect of SR141716 with the effect of a decrease in the magnitude of stimulation (-100 microA) and the effects of a cocaine injection (1, 5 and 10 mg/kg IP). METHODS: a protocol of rate-frequency curve for self-stimulation was applied. Two rate-frequency curves were established daily, 3 h apart. The frequency required to produce half-maximal performance (M50) and the maximal performance (RMax) were used as the parameters to characterize the rate-frequency functions. RESULTS: SR141716 decreased the sensitivity to the electrical brain stimulation. SR141716 induced a shift to the right of the rate-frequency curve. This effect depended on the dose administered and the time after injection. Thirty minutes after the injection, 1, 3 and 10 mg/kg SR141716 induced a significant decrease in sensitivity to electrical stimulation, as shown by an elevation in the M50 value. RMax showed a tendency to decrease with increasing doses. At 210 min after administration, 3 and 10 mg/kg SR141716 maintained their decreasing effect on the sensitivity to the stimulation as shown by the significant increase of the M50, however, the maximal response was restored to the basal value. A decrease in self-stimulation intensity produced an effect comparable to the one observed 30 min after either 3 or 10 mg/kg SR141716, while cocaine (5 and 10 mg/kg) produced the opposite effect. Neither condition affected the rate-frequency curve measured 3 h later. CONCLUSIONS: In accordance with recent observations, these experiments suggest that the endogenous cannabinoid system facilitates the perception or the effects of positive reinforcers. They also suggest that this neurochemical system could be a target of interest for treating psychopathologies implicating the reinforcing system.     

Dopamine--acetylcholine "balance" in nucleus accumbens and corpus striatum and its effect on hypothalamic self-stimulation.

Three experiments investigated the suppression of hypothalamic self-stimulation in rats by neuroleptics and its restoration by centrally acting anticholinergic agents. Scopolamine (0.1--1.0 mg/kg i.p.) and benztropine (1.0--10.0 mg/kg i.p.) each enhanced self-stimulation when administered alone, and partially restored performance suppressed by spiroperidol (0.05--0.15 mg/kg i.p.). Benztropine strongly inhibits transmitter reuptake at DA synapses but scopolamine does not, thus inhibition of DA reuptake cannot fully account for the stimulant or antineuroleptic action of anticholinergic drugs. Neuroleptic and anticholinergic effects on self-stimulation rate were mutually subtractive, and statistical evidence of interaction was not obtained. Scopolamine was shown also to restore performance extinguished by discontinuation of the stimulating current. Smaller doses of scopolamine (50 nmol; 19 microgram) injected directly into the nucleus accumbens septi partially restored responding suppressed by spiroperidol, though similar doses of scopolamine injected bilaterally into the caudate-putamen were ineffective. These findings suggest that hypothalamic self-stimulation may be influenced by ACh-and DA-containing systems which exert independent effects on a third system controlling performance. These effects appear to reflect the level of arousal or motivation rather than the reinforcement process itself.     

Differential effects of ondansetron, haloperidol and clozapine on electrical self-stimulation of the ventral tegmental area

The effects of 5-HT(3), receptor blockade with ondansetron (0.025-0.2mg/kg) on intracranial self-stimulation of the ventral tegmental area were compared with effects of the typical antipsychotic drug haloperidol (0.01-0.3mg/kg) and the atypical antipsychotic drug clozapine (1.25-10mg/kg). Rats were trained to self-stimulate using unipolar ventral tegmental electrodes (200μm diameter) to deliver 1s trains of 0.2ms cathodal pulses of constant current stimulation as a reinforcer. The animals were tested daily in frequency threshold tests. The frequency that maintained half maximal response rates (M50) and the maximal number of responses at a single frequency (RMAX) and the number of responses per session (TRESP) were used to measure drug effects. Ondansetron had no effects on the behavioural measures in this study. Haloperidol induced a significant increase in M50 at 0.3mg/kg without altering RMAX; TRESP was reduced by 0.1 and 0.3mg/kg of this drug. Clozapine increased M50 at 5.0mg/kg; following 10.0mg/kg of clozapine responding was completely abolished and no M50 measure could be calculated. Clozapine reduced RMAX at 1.25, 5.0 and 10.0mg/kg; TRESP was decreased by 5.0 and 10.0mg/kg of clozapine. The present results indicate that ondansetron had no measurable effects under conditions in which haloperidol and clozapine increase reinforcement thresholds and decrease response rates maintained by ventral tegmental self-stimulation.     

Intracranial self-stimulation in rats as a function of various stimulus parameters

The effects of different subcutaneous doses of fentanyl (0.02, 0.04, 0.08, and 0.16 mg/kg), piritramide (0.63, 2.50, 10.0, and 40.0 mg/kg), and morphine (2.50, 5.00, 10.0, and 20.0 mg/kg) on self-stimulation in rats were studied. Different stimulus parameter combinations (SPC) inducing low, high, or intermediate control response rates (CRR) were applied during the same experimental sessions. The three narcotic analgesics induced response depression (RD) and response stimulation (RS). RS was mostly observed at low dose levels; RD was dose-related. SPC's inducing low CRR were more sensitive than those inducing high CRR. Fentanyl was more potent than piritramide and than morphine. The RD is related to motor incapacitation, as the doses needed to effectively reduce self-stimulation also induced obvious catatonia. The RS probably is a more specific effect reflecting sensitization of structures involved in reinforcement of behavior.     

The 5 -HT3 receptor antagonists, granisetron and ondansetron, do not affect cocaine-induced shifts in intra-cranial self-stimulation thresholds

The effects of the 5-HT( 3) receptor antagonists, granisetron and ondansetron, were investigated on behaviour maintained by intracranial self-stimulation (ICSS). Rats, implanted with bipolar electrodes in the lateral hypothalamus, were trained to lever press on a continuous reinforcement schedule for positively reinforcing trains of electrical stimulation. The frequency at which responding reached 50% of maximum (M50) and the maximum rate of responding (asymptote) were used to measure drug effects. Granisetron (0.01-0.1 mg/kg i.p ) and ondansetron (0.03-0.3 mg/kg i.p ) had no effect on either parameter. In contrast, cocaine (20 mg/kg i.p ) potentiated rewarded responding, reducing M50 values, but neither granisetron (0.01-3.0 mg/kg i.p ) nor ondansetron (0.03-0.3 mg/kg i.p ) blocked this effect. Neither did granisetron (0.1-10.0 mg/kg i.p ) alter the effect of lower doses of cocaine (10 mg/kg i.p.). These data suggest that 5 -HT( 3) receptors do not play a significant role in mediating responding maintained by ICSS in the rat through hypothalamic electrodes. Neither do they modulate cocaine-induced potentiation of the behaviour.     

Lowered brain stimulation reward thresholds in rats treated with a combination of caffeine and N-methyl-D-aspartate but not alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate or metabotropic glutamate receptor-5 receptor antagonists

Previous studies suggested that adenosine A1 and A2A receptor agonists counteract behavioral effects of N-methyl-D-aspartate (NMDA) receptor antagonists while adenosine receptor antagonists may produce opposite effects enhancing the actions of NMDA receptor antagonists. To further evaluate the effects of combined administration of adenosine receptor antagonist caffeine and various NMDA and non-NMDA glutamate receptor antagonists on brain stimulation reward (discrete-trial threshold current intensity titration procedure), rats with electrodes implanted into the ventral tegmental area were tested after pretreatment with NMDA receptor channel blocker MK-801 (0.01-0.3 mg/kg), competitive antagonist D-CPPene (0.3-5.6 mg/kg), glycine site antagonist L-701,324 (1.25-5 mg/kg), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist GYKI-53655 (1-10 mg/kg), metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP (1-10 mg/kg) alone and in combination with caffeine (1-30 mg/kg). MK-801 (0.056 and 0.1 mg/kg) was the only tested glutamate antagonist that lowered self-stimulation thresholds, while D-CPPene (5.6 mg/kg) and MPEP (5.6 and 10 mg/kg) had the opposite effects. Threshold-increasing effects of D-CPPene, but not of MPEP, however, were associated with marked impairment of operant performance, reflected by longer latencies to respond and higher rates of responding during the inter-trial intervals. Operant performance was also disrupted by the highest dose of MK-801 (0.3 mg/kg). For subsequent experiments, caffeine (1-30 mg/kg) was combined with the highest doses of NMDA receptor antagonists that did not lower the brain stimulation reward thresholds and did not impair operant performance. Caffeine had no appreciable effects on self-stimulation behavior when given alone. A low dose of caffeine (3 mg/kg) significantly lowered self-stimulation thresholds only when given together with MK-801 (0.03 mg/kg) or D-CPPene (3 mg/kg). Combined with the same antagonist drugs, higher doses of caffeine (10 and 30 mg/kg) facilitated time-out responding. These results indicate that, within a limited dose range, caffeine in combination with an NMDA receptor channel blocker and a competitive antagonist significantly lowers brain stimulation reward thresholds in rats.