Ann Robertson

Atypical neuroleptics clozapine and thioridazine enhance amphetamine-induced stereotypy

The effects of the atypical neuroleptics clozapine and thioridazine and the typical neuroleptic pimozide on amphetamine-induced behavior were examined. Pimozide, as expected, blocked both amphetamine-induced locomotion and stereotypy. Thioridazine and clozapine antagonized the increases in locomotion produced by amphetamine, but produced increases in amphetamine-induced stereotypy and lowered the threshold dose for stereotypy. It is suggested that the increased stereotypy might partly account for the decreased locomotion, and that this might be a primary effect of these atypical neuroleptics. The data would also suggest that the use of amphetamine-induced stereotypy as a model for psychosis is inappropriate, as clozapine and thioridazine, which enhance stereotypy, are antipsychotic.

Opposite effects of sulpiride and metoclopramide on amphetamine-induced stereotypy

The effects of the atypical neuroleptic sulpiride (0-20 mg/kg s.c.) and the classical neuroleptic metoclopramide (0-4 mg/kg s.c.) on behaviours produced by D-amphetamine (0-5 mg/kg i.p.) were measured in a time-sampling observational paradigm in rats. Sulpiride had one clear dose-dependent effect: it enhanced amphetamine-induced stereotyped behaviours (repetitive head movements, sniffing down and some gnawing). In contrast, metoclopramide dose-dependently decreased amphetamine-induced stereotypy, locomotion, rearing, and sniffing up, and concurrently antagonized the suppression of lying down produced by amphetamine. Sulpirides facilitatory effects on amphetamine-induced stereotypy follow a pattern previously observed for two other atypical neuroleptics: clozapine and thioridazine. This may be a common effect of atypical neuroleptics. Since these neuroleptics are antipsychotic, amphetamine-induced stereotypy appears to be a poor animal model for human psychoses. It is suggested that sulpirides effects may be mediated through a preferential presynaptic versus postsynaptic action on dopamine neurons in the nigrostriatal bundle.

Amphetamine and increases in current intensity modulate reward in the hypothalamus and substantia nigra but not in the prefrontal cortex

Abstract Amphetamine and increased stimulation current facilitated responding for variable interval scheduled brain stimulation of the lateral hypothalamus (LH) and substantia nigra (SN) while medial prefrontal cortex (PFC) self-stimulation was not increased. This suggests that these treatments increase the rewarding effect of brain stimulation in the LH and SN but not PFC. In confirmation, using a Findley concurrent schedule, it was shown that increasing hypothalamic stimulation current increases the rats preference for LH over PFC stimulation, but increasing cortical stimulation intensity does not alter the preference for PFC relative to LH stimulation. It is concluded that there are differences in the neural substrates of reward produced by stimulation of the PFC and LH and SN.

Effects and interactions of naloxone and amphetamine on self-stimulation of the prefrontal cortex and dorsal tegmentum

Naloxone (0.1 to 10 mg/kg) caused a dose-dependent depression of self-stimulation of the medial prefrontal cortex (PFC) lateral hypothalamus (LH) and a region in the dorsal tegmentum lateral to the central gray (DT). The DT contains many enkephalin fibers and is a site for stimulation-produced analgesia, while the PFC contains little enkephalin and does not support stimulation-produced analgesia. However, self-stimulation rates of the PFC, DT and LH were all equally depressed by naloxone. In order to study possible opiate-dopamine interactions, we examined the effects of naloxone on the facilitatory effects of D- and L-amphetamine (1.0 mg/kg) on self-stimulation of the DT and PFC. If amphetamine mildly facilitated self-stimulation (L-amphetamine on DT self-stimulation and D-amphetamine on PFC self-stimulation) then the addition of naloxone was without effect. If amphetamine greatly increased self-stimulation (D-amphetamine on DT self-stimulation), naloxone caused a depression of the amphetamine effect. It is argued that naloxones effects in this and other reports reviewed is related to the level of self-stimulation performance, and not to the level of enkephalin at the self-stimulation site, nor to amphetamines effects on dopamine activity.

Development of brain stimulation reward in the medial prefrontal cortex: facilitation by prior electrical stimulation of the sulcal prefrontal cortex.

Electrical stimulation of the medial prefrontal cortex (MC) in rats delivered daily for seven days causes a marked improvement in the rate of acquisition of a self-stimulation response. In the present experiment, we looked at whether we could get the same facilitatory effect on self-stimulation of the MC by delivering pre-training stimulation to other points in the brain anatomically related to the MC. Electrical stimulation of the lateral hypothalamus was without effect. However, electrical stimulation of the sulcal prefrontal cortex (SC) either contralateral or ipsilateral to the MC electrode did facilitate acquisition of self-stimulation of the MC. Thus the Sc and MC would appear to be part of the same substrate controlling the development of positive reinforcement in the MC.

Treatment with anticonvulsant drugs retards the development of brain-stimulation reward in the prefrontal cortex

Electrical stimulation of the medial prefrontal cortex in rats daily for nine days caused a marked improvement in the rate of acquisition of a self-stimulation response. Diazepam (1 mg/kg, IP) or phenobarbital (15 mg/kg), but not phenytoin (25 mg/kg), administered during the nine day period of electrical stimulation, attenuated this facilitatory effect. However, diazepam or phenobarbital in the same dosages administered to self-stimulating rats (i.e., after acquisition) failed to alter responding. It was suggested that a kindling-like mechanism may underlie the development of self-stimulation of the prefrontal cortex.

Drinking behavior following electrical stimulation of the subfornical organ in the rat

Electrical stimulation of the subfornical organ (SFO) through implanted stainless-steel electrodes produced drinking in water-sated rats. Drinking was elicited primarily during the interstimulation (OFF) periods. Water intake in rats with hippocampal electrode placements occurred during both ON and OFF periods at current intensities (24-100 microA) similar to rats with SFO placements. These findings support the hypothesis that the SFO is involved in the central control of fluid balance.

5HT blockade and the stimulant effects of D- and L-amphetamine: No interaction in self-stimulation of prefrontal cortex, hypothalamus, or dorsal tegmentum. Unexpected lethality in hippocampal sites

We investigated the role of serotonin in the differential stimulatory effects of D- and L-amphetamine (1.0 mg/kg) on locomotor activity and on self-stimulation (SS) in rats. The serotonin antagonist methysergide (12.5 mg/kg) had no effects alone on activity or on SS. Methysergide enhanced the strong locomotor stimulatory effects of D-amphetamine and the weaker effects of L-amphetamine. D-amphetamine facilitated SS more strongly than L- in hypothalamic, dorsal tegmental, hippocampal and medial prefrontal cortical sites, but the effect of D-amphetamine was much weaker in prefrontal cortex than in other sites. Methysergide did not alter the effects of D- or L-amphetamine in any site except the hippocampus. Here, methysergide plus L-amphetamine suppressed SS; methysergide plus D-amphetamine suppressed SS in some rats and greatly increased it in others. When SS was facilitated by D-amphetamine plus methysergide, the combination was lethal. The possibility that lethality was due to adrenal crisis is discussed.

The effects of some atypical neuroleptics on apomorphine-induced behaviors as a measure of their relative potencies in blocking presynaptic versus postsynaptic dopamine receptors

The effects of the atypical neuroleptics clozapine, thioridazine and sulpiride on behaviors induced by apomorphine were recorded, using a time-sampling observational paradigm. A low dose of apomorphine (0.1 mg/kg, SC) produced hypomotility. Of the neuroleptics tested, only sulpiride antagonized this hypomotility. Apomorphine in higher doses (0.2-1.0 mg/kg, SC) produced stereotyped behaviors (sniffing down and licking or gnawing). All three atypical neuroleptics antagonized stereotypy. The effects of sulpiride on apomorphine-induced hypomotility and stereotypy are consistent with the notion that this drug has strong presynaptic and weak postsynaptic blocking effects at dopamine receptors. The mechanisms of action of clozapine and thioridazine may be different from that of sulpiride. Perhaps the anticholinergic activities of these drugs mediate some of their behavioral effects. The effects of these atypical neuroleptics on apomorphine-induced stereotypy are opposite in direction to their effects on amphetamine-induced stereotypy, suggesting that these two behavioral patterns are not measures of the same neural process.

The role of corticocortical projections in self-stimulation of the prelimbic and sulcal prefrontal cortex in rats

Four experiments were performed to assess the nature of the contribution of the corticocortical projections between the prelimbic and sulcal divisions of the rat prefrontal cortex to self-stimulation (SS) of these sites. The first experiment showed that transection of these projections by parasagittal knife cuts or bilateral electrolytic lesions of the prelimbic cortex had no effect on SS of the sulcal cortex. The second experiment demonstrated that SS of the prelimbic cortex could be obtained after transection of the corticocortical projection path. The third experiment demonstrated that the deficit in prelimbic SS, seen to follow such bilateral transections, is a function of the amount of exposure to the stimulation given to the animals after the lesion. The fourth experiment showed that the stimulation-dependent process underlying the acquisition of prelimbic and sulcal SS could be dissociated by the knife cuts. The discussion focused on the implications of these findings for an account of prefrontal self-stimulation behavior.