Antagonism of footshock stress-induced inhibition of intracranial self-stimulation by naloxone or methamphetamine

Rats were trained to lever-press for intracranial self-stimulation (ICSS) with electrodes implanted in the ventral tegmental area (VTA). The effect of inescapable footshock on response rates to ICSS was examined in the present study. Markedly decreased response rates to ICSS were observed 15 min to 24 h following inescapable footshock. Naloxone (10.0 mg/kg) itself was without effect on response rates to ICSS, but completely antagonized the decreased response rates by the stressor treatment. A relatively low dose of methamphetamine (0.5 mg/kg), which showed no effect on ICSS rates in naive rats, also antagonized the decreased response rates to ICSS. The present results suggest that inescapable footshock may release endorphin in the mesolimbic or mesocortical area; the released endorphin may act on dopaminergic nerve endings and interrupt dopaminergic transmission. The decreased activity of dopaminergic neurons may cause the decreased response rates to ICSS.     

Catecholamine systems as the neural substrate for intracranial self-stimulation: a hypothesis

The hypothesis was investigated that activation of central catecholamine (CA) systems is essential for intracranial self-stimulation (ICSS). Brain sites that support ICSS in the rat were found to be highly correlated with electrodes in 3 major CA systems: the mesolimbic and nigrostriatal dopaminergic systems and the dorsal noradrenergic system. Stimulation at ICSS loci in the brain stem causes release of catecholamines at terminals in ascending CA systems. Lesion studies show suppression of ICSS proportional to the degree of damage to the stimulated CA system. Drugs influence ICSS in accordance with their effects on transmission at dopaminergic and noradrenergic synapses. Enhancement of nicotinic-cholinergic mechanisms facilitates ICSS, but the effect requires that CA mechanisms be intact. Neurophysiological experiments suggest that two systems characterized by different axonal refractory periods are involved in ICSS. The data are insufficient to determine whether these correspond to the dopamine and norepinephrine systems. Norepinephrine has an inhibitory effect at many postsynaptic receptor sites, and ICSS is often accompanied by reduction or cessation of cellular discharges in NE terminal areas. Food ingestion has also been demonstrated to produce an inhibitory effect on cells in a noradrenergic terminal area.ICSS has been demonstrated in numerous species, including man, in brain areas that overlap considerably with loci whose stimulation supports ICSS in the rat. Stimulation of ICSS loci in man is commonly associated with verbal reports of intense pleasurable sensations.     

Regional alpha-synuclein aggregation, dopaminergic dysregulation, and the development of drug-related visual hallucinations in Parkinson's disease

Visual hallucinations in Parkinson's disease are usually treatment-related and occur in at least 30% of patients. Although their clinical and epidemiological features have been extensively reviewed, their etiopathogenesis remains a matter of debate. Based on the current evidence available, this review suggests that regional neurodegeneration of the ventral dopaminergic pathway, as evident in the aggregation of the protein alpha-synuclein, is the main event linked to the development of visual hallucinations in Parkinson's disease. Denervation supersensitivity of dopaminergic receptors in ventral striatal and mesocorticolimbic areas as well as defective synaptic buffering ability due to the loss of dopaminergic presynaptic terminals and dopamine transporter may be among the key factors leading to visual hallucinations in Parkinson's disease.     

PHNO, a novel dopamine agonist, in animal models of parkinsonism

PHNO, a naphthoxazine compound, was investigated in animal models of central dopaminergic activity. The drug in doses of 5-300 micrograms/kg when administered subcutaneously, or transdermally, induced stereotypic behavior in rats which was blocked by haloperidol but not by reserpine pretreatment. In rats with unilateral 6-hydroxydopamine lesions of the substantia nigra PHNO induced dose-dependent contralateral turnings. The drug caused emesis in dogs and hypothermia in mice. PHNO bound to D-2 dopamine receptors in the rat striatum. Chronic injection with PHNO did not induce behavioral supersensitivity or increase dopamine receptor density. These data indicate that PHNO is a direct acting dopamine agonist that is highly potent. PHNO differs from other dopaminergic drugs and may be useful in the treatment of Parkinson's disease.     

Supersensitivity of central neurons--a brief review of an emerging concept.

The concept that "denervation" or "pharmacological disuse" supersensitivity develops in central neuronal systems subsequent to sustained attenuation of normal neurohumoral mechanisms is reviewed. Particular emphasis is placed on biochemical and electrophysiological parameters of supersensitivity in dopaminergic (striatal) neuronal systems. The possible applicability of theories invoking changes in receptor sensitivity to the phenomenon of narcotic tolerance and physical dependence and to psychoactive drug therapy is discussed.     

Neuroleptic-induced supersensitivity psychosis: clinical and pharmacologic characteristics

Tardive dyskinesia is thought to result from neostriatal dopaminergic receptor supersensitivity induced by chronic treatment with neuroleptics. The authors suggest that dopaminergic supersensitivity also occurs in the mesolimbic region after chronic neuroleptic exposure, resulting in the development of a supersensitivity psychosis. Neuroleptic-induced supersensitivity psychosis is illustrated by data from 10 patients that demonstrate the syndrome's clinical and pharmacologic characteristics. An implication of neuroleptic-induced mesolimbic supersensitivity is that the tenaency toward psychotic relapse in such patients is determined by more than just the normal course of the illness.     

Evidence of brain dopamine deficiency in schizophrenia

It is proposed that the increased dopamine function suggested by the dopamine hypothesis of schizophrenia is a dopaminergic postsynaptic receptor supersensitivity resulting from a dopamine deficiency. In support of this, three double-blind controlled studies conducted on drugs which alter brain dopaminergic activity in a manner different from that of classic neuroleptics are reported. 1) alpha-methyldopa-neuroleptic interaction proved efficacious for schizophrenic positive symptoms but only on a short-term basis. 2) Rubidium improved negative symptoms rapidly, and in contrast has a late onset of action on positive symptoms of schizophrenia. 3) Tryptophan-benserazide was efficacious in controlling both negative and positive symptoms of schizophrenia (although less so than chlorpromazine). It is concluded that currently accepted modes of pharmacological therapy (classical neuroleptics) are in the short-term controlling the dopamine supersensitivity secondary to a deficiency, but contributing in the long-term to increase the dopamine deficiency, and so exacerbate the supersensitivity. More effective forms of treatment may involve the use of agents which alter dopamine activity without inducing dopamine supersensitivity.     

Neuropeptide-dopamine interactions. III. Cyclo(His-Pro) and persistence of dopaminergic supersensitivity on withdrawal from one year continuous neuroleptic treatment

When rats are given dopaminergic antagonists (neuroleptics) continuously for several days behavioral supersensitivity to dopaminergic agonists results. This supersensitivity, however, declines rapidly on neuroleptic withdrawal. The data presented here, however, are the first to show that the supersensitivity persists for a longer duration (greater than 100 days) if the neuroleptic is administered continuously for 1 year. Oral administration of 0.76 +/- 0.13 mg/kg/day cyclo(His-Pro), a peptide exhibiting dopaminergic agonist-like properties, during neuroleptic withdrawal did not change the course of dopaminergic supersensitivity reversal.     

LTP in the lateral amygdala during cocaine withdrawal

The amygdala plays key roles in several aspects of addiction to drugs of abuse. This brain structure has been implicated in behaviours that reflect drug reward, drug seeking, and the aversive effects of drug withdrawal. Using a model that involves repeated cocaine injections to approximate 'binge' intoxication, we show in rats that during cocaine withdrawal, the impact of rewarding brain stimulation is attenuated, as quantified by alterations in intracranial self-stimulation (ICSS) behaviour. These behavioural signs of withdrawal are accompanied by enhancements of glutamatergic synaptic transmission within the lateral amygdala (LA) that occlude electrically induced long-term potentiation (LTP) in tissue slices. Synaptic enhancements during periods of cocaine withdrawal are mechanistically similar to LTP induced with electrical stimulation in control slices, as both forms of synaptic plasticity involve an increase in glutamate release. These results suggest that mechanisms of LTP within the amygdala are recruited during withdrawal from repeated exposure to cocaine. As such, they raise the possibility that the development and maintenance of addictive behaviours may involve, at least in part, mechanisms of synaptic plasticity within specific amygdala circuits.     

Role of dopamine tone in the pursuit of brain stimulation reward

Dopaminergic neurons contribute to intracranial self-stimulation (ICSS) and other reward-seeking behaviors, but it is not yet known where dopaminergic neurons intervene in the neural circuitry underlying reward pursuit or which psychological processes are involved. In rats working for electrical stimulation of the medial forebrain bundle, we assessed the effect of GBR-12909 (1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-4-[3- phenylpropyl]piperazine), a specific blocker of the dopamine transporter. Operant performance was measured as a function of the strength and cost of electrical stimulation. GBR-12909 increased the opportunity cost most subjects were willing to pay for a reward of a given intensity. However, this effect was smaller than that produced by a regimen of cocaine administration that drove similar increases in nucleus accumbens (NAc) dopamine levels in unstimulated rats. Delivery of rewarding stimulation to drug-treated rats caused an additional increase in dopamine concentration in the NAc shell in cocaine-treated, but not GBR-12909-treated, rats. These behavioral and neurochemical differences may reflect blockade of the norepinephrine transporter by cocaine but not by GBR-12909. Whereas the effect of psychomotor stimulants on ICSS has long been attributed to dopaminergic action at early stages of the reward pathway, the results reported here imply that increased dopamine tone boosts reward pursuit by acting at or beyond the output of the circuitry that temporally and spatially summates the output of the directly stimulated neurons underlying ICSS. The observed enhancement of reward seeking could be attributable to a decrease in the value of competing behaviors, a decrease in subjective effort costs, or an increase in reward-system gain.     

Antagonizing effect of lithium on the development of dopamine supersensitivity in the tuberoinfundibular system

We investigated wether receptor supersensitivity occurs in the tuberoinfundibular dopaminergic system, as reported in the nigrostriatal and mesolimbic areas. Animals received either haloperidol or saline for 2 weeks. Five days after the last injection of haloperidol, animals pretreated with haloperidol showed a significantly longer lasting inhibition of prolactin (PRL) secretion by apomorphine, compared with the controls. This dopamine receptor supersensitivity was also observed on the 12th, but not the 33rd day after the cessation of haloperidol administration.The effect of lithium on this dopamine supersensitivity in PRL release was investigated. All rat were treated with haloperidol and fed either a diet containing lithium carbonate or a diet without lithium for 2 weeks. Lithium administration with haloperidol resulted in the inhibition of PRL-lowering action of apomorphine at 5 days of withdrawal from haloperidol, indicating that the supersensitivity of dopamine receptors on pituitary lactotrophs were decreased by lithium. This action of lithium may be related to the prophylactic effect of the drug on the manic-depressive disease.     

Reversal of stress-induced dendritic atrophy in the prefrontal cortex by intracranial self-stimulation

The mammalian prefrontal cortex (PFC) has been implicated in a variety of motivational and emotional processes underlying working memory, attention and decision making. The PFC receives dopaminergic projections from the ventral tegmental area (VTA) and contains high density of D1 and D2 receptors and these projections are important in higher integrative cortical functions. The neurons of the PFC have been shown to undergo atrophy in response to stress. In an earlier study, we demonstrated that the chronic stress-induced atrophy of hippocampal neurons and behavioral impairment in the T-maze task were reversed by the activation of dopaminergic pathway by intracranial self-stimulation (ICSS) of the VTA. The stress-induced decrease in hippocampal dopamine (DA) levels was also restored by ICSS. Whether the reversal of stress-induced behavioral deficits by ICSS involves changes in the morphology of PFC neurons is unknown and the current study addresses this issue. Male Wistar rats underwent 21 days of restraint stress followed by ICSS for 10 days. The dendritic morphology of the PFC neurons was studied in Golgi-impregnated sections. Stress produced atrophy of the layer II/III and V PFC pyramidal neurons and ICSS to naïve rats significantly increased the dendritic arborization of these neurons compared to control. Interestingly, ICSS of stressed rats resulted in the reversal of the dendritic atrophy. Further, these structural changes were associated with a restored tissue levels of DA, norepinephrine and serotonin in the PFC. These results indicate that the behavioral restoration in stressed rats could involve changes in the plasticity of the PFC neurons and these results further our understanding of the role of dopaminergic neurotransmitter system in the amelioration of stress-induced deficits.     

Schedule-controlled brain self-stimulation: Has it utility for behavioral pharmacology?

We review evidence that schedule-controlled intracranial self-stimulation (ICSS) has properties in common with conventional reinforcements, such as food and water, but unlike the latter, animals will respond for ICSS for long periods of time at a near-constant rate. Schedule-controlled ICSS has proven to be more sensitive to drug-induced changes than has ICSS on a continuous reinforcement schedule, and it permits a more fine-grained analysis of the pattern of responding that results in the reinforcement. Evidence is accumulating that the schedule of ICSS itself leads to neurochemical changes in areas of the brain, such as the nucleus accumbens, in which reward processes occur. Results obtained from schedule-controlled ICSS would complement those obtained by drug self-administration studies which generally use intermittent reinforcement. A systematic examination of ICSS schedules at different brain sites would greatly facilitate our interpretation of drug effects and this would have utility for behavioral pharmacology.     

Dogma disputed: is tardive dyskinesia due to postsynaptic dopamine receptor supersensitivity?

The most popular theory of the pathophysiology of neuroleptic-induced tardive dyskinesia (TD) attributes the movement disorder to central postsynaptic dopamine receptor supersensitivity. This hypothesis is based on circumstantial evidence. A consideration of the available clinical and animal data suggests the following: (1) Central catecholaminergic overactivity is present in TD and it could result from presynaptic and/or postsynaptic disturbances. (2) Postsynaptic dopamine receptor supersensitivity is a normal consequence of neuroleptic administration and is not sufficient to explain why TD develops only in a proportion of patients receiving long-term neuroleptic treatment. Postsynaptic dopaminergic supersensitivity may be responsible for withdrawal dyskinesias, but clinical studies do not support the supersensitivity hypothesis in most patients with persistent TD. (3) Noradrenergic hyperactivity and presynaptic dopaminergic overactivity may be necessary for the induction of at least certain subtypes of TD.     

Postnatal lead exposure induces supersensitivity to the stimulus properties of a D2-D3 agonist.

To examine the impact of lead (Pb) exposure during the ontogeny of dopaminergic (DA) systems on resultant DA function, rats were exposed postnatally (0-21 days of age) via the lactating dam to 0, 100 or 350 ppm Pb acetate in drinking water. At 2 months of age, the postnatally Pb-exposed rats were trained to discriminate the stimulus properties of either the D1 receptor agonist SKF38393 (6.0 mg/kg) or the D2-D3 receptor family subtype agonist quinpirole (0.05 mg/kg) from saline using a standard two-lever operant food-reinforced drug discrimination paradigm. In each training group, dose-effect curves describing drug lever responding to lower doses of the training drug and to preadministration of selective DA antagonists were obtained to examine Pb-induced changes in DA sensitivity, and doses of non-DA compounds were substituted to determine the specificity of any changes in DA sensitivity. In the D1/saline training condition, Pb exposure was not associated with any specific or consistent changes in DA sensitivity. In contrast, exposure to Pb was associated with D2-D3 receptor subtype supersensitivity as was indicated by significantly elevated levels of drug lever responding in the presence of quinpirole and haloperidol and to at least one dose of apomorphine. No differences in the dose-effect curves for either (+)-amphetamine or NMDA were observed in the D2-D3-trained control and Pb-exposed groups, but an increase in drug lever responding in the presence of pentobarbital was noted in the Pb-exposed group relative to control. Taken together, these findings are consistent with a Pb-induced functional D2-D3 supersensitivity possibly mediated via autoreceptors. Moreover, this functional D2-D3 supersensitivity necessarily represents a permanent effect of postnatal Pb exposure since both blood and brain Pb levels were negligible at the time drug discrimination training began.     

The therapeutic latency of neuroleptic drugs and nonspecific postjunctional supersensitivity

It is suggested that the antidopaminergic effects of neuroleptics are not directly responsible for the antipsychotic effect but, rather, that the antipsychotic effect is related to secondary changes in the efficacy of transmission at corticostriatal excitatory synapses. Arguments are presented in support of the following: (1) acute dopaminergic antagonism produces a relatively nonspecific sedation or deactivation, but most of the amelioration of psychosis develops slowly; (2) the development of dopaminergic supersensitivity is responsible for tolerance to the sedative effects of neuroleptics; and (3) excitatory synapses of the corticostriatal pathway, mediated by glutamic acid, are located on the same dendritic spines as the striatal dopaminergic synapses. Concomitant with the development of dopaminergic supersensitivity, these glutamate synapses become subsensitive. The glutamatergic subsensitivity is a result of the nonspecific nature of postsynaptic denervation supersensitivity. It is suggested that subsensitivity of striatal glutamate-mediated synapses is directly responsible for the antipsychotic effect of neuroleptic drugs. In support of this hypothesis, chronic neuroleptic administration was found to decrease the behavioral responsivity of mice to the glutamate agonist, quisqualic acid, and to the the antagonist, glutamic acid diethyl ester.     

Sulpiride and the role of dopaminergic receptor blockade in the antipsychotic activity of neuroleptics

It is now generally recognized that dopamine receptors exist in the CNS as different subtypes: D₁ receptors, associated with adenylyl cyclase activity, and D₂ receptor, uncoupled to a cyclic AMP generating system. In order to understand the role of D₁ and D₂ receptors in the antipsychotic action of neuroleptics, we have performed subchronic treatment with haloperidol, a drug which acts on D₂ receptors, and sulpiride, a selective antagonist to D₂ receptors. Long-term treatment with haloperidol does not induce significant supersensitivity of the D₂ receptors. In fact under these conditions ³H-(-)-sulpiride binding, which is a marker of D₂ receptor function, does not increase in rat striatum, while the long-term administration of sulpiride itself produces supersensitivity of D₂ receptors. Moreover, sulpiride does not induce supersensitivity of the D₁ receptors, characterized by ³H-spiroperidol binding. These data suggest that both types of dopamine receptors may be involved in the clinical antipsychotic effects of neuroleptics. Unilateral lesion of the nigrostriatal dopaminergic pathway produces an increase of striatal dopaminergic receptors, measured either by ³H-spiroperidol and ³H-(-)-sulpiride binding. These findings suggest that D₁ and D₂ receptors are present in postsynaptic membranes while it is still not known whether they exist in the same cellular elements.     

Diltiazem or verapamil prevents haloperidol-induced apomorphine supersensitivity in mice

Summary Chronic thioridazine treatment in animals has been reported to produce less dopaminergic supersensitivity than other neuroleptics. This difference may be due to the potent calcium channel inhibitory effect of thioridazine. To test this hypothesis Swiss-Webster mice were treated chronically (28 d) with calcium channel inhibitors (CCI's) — diltiazem, nifedipine or verapamil — with or without haloperidol. Following three days of drug withdrawal, mice were tested for amphetamine-induced locomotion and apomorphine-induced cage climbing. Co-administration of diltiazem or verapamil (but not nifedipine) prevented the development of haloperidol-induced behavioral supersensitivity to apomorphine. Co-administration of CCI's with haloperidol did not affect the development of amphetamine supersensitivity. These data support the hypothesis that coadministration of haloperidol and a CCI (verapamil or diltiazem, but not nifedipine) would mimic the effects of thioridazine treatment alone.     

Dopaminergic supersensitivity after long-term administration of phenytoin in rats

Male albino rats (n = 10) were injected with phenytoin (PHT) every day for 20 consecutive days and were tested on days 21 and 28 for their response to 1 mg/kg apomorphine, a dopamine-receptor agonist. Rats treated with PHT showed an increased responsiveness to apomorphine-induced stereotypy on day 28, which is evidence for dopaminergic supersensitivity after long-term treatment with the drug. In experiment 2, a supersensitivity response to apomorphine-induced stereotypy was noted on day 14 after 10 days of PHT administration. In experiment 3, after 17 days of PHT administration, rats were also supersensitive to the climbing response induced by apomorphine. These results may explain, in part, the clinical findings of orofacial dyskinesias produced by PHT in epileptic patients.     

Intracranial self-stimulation from the sulcal prefrontal cortex in the rat: The effect of 6-hydroxydopamine or kainic acid lesions at the site of stimulation

An electrode cannula system was used to elicit intracranial self-stimulation (ICSS) from the sulcal prefrontal cortex in rats to test the behavioral effects of local infusions of 6-hydroxydopamine (6-OHDA) or kainic acid (KA) into the brain area surrounding the electrode tip. In experimental I sulcal ICSS animals received injections of 6-OHDA with or without desipramine (DMI) pretreatment to block 6-OHDA uptake into noradrenergic (NA) terminals. Those animals that received DMI pretreatment were subsequently shown to have sustained sulcal cortical dopaminergic (DA) denervation while sulcal molecular layer NA systems were spared as revealed with glyoxylic acid-induced catecholamine histofluorescence. Those animals not receiving DMI pretreatment sustained near-complete denervation of both NA and DA sulcal cortical systems. Neither treatment had a lasting effect on sulcal ICSS suggesting that sulcal ICSS is not dependent on the presynaptic release or DA of NA into that brain area.In experiment II KA injections that lesioned neurons in sulcal cortical layers V and VI resulted in the abolition of sulcal ICSS for the duration of a 21 day postlesion trial period. These results suggest that activation of a descending corticofugal system originating in the sulcal cortex is responsible for the mediation of sulcal prefrontal cortical ICSS. This system was mapped by the selective silver impregnation of degenerating neural elements resulting from effective lesions.