Gerald Gianutsos

Behavioral evidence for dopaminergic supersensitivity after chronic haloperidol

Abstract Chronic administration for 16 days of haloperidol (in increasing doses up to 20 mg/kg/day) results in a supersensitivity of dopamine receptors. This supersensitivity is manifested by an enhanced stereotypy and aggression in response to small, otherwise ineffective, doses of apomorphine. Maximum aggression is observed 7 days after the last dose of haloperidol when 2.5 mg/Kg of apomorphine is administered. In addition, “wet shakes”, reminiscent of withdrawal from morphine, are observed in these animals after the cessation of the haloperidol administration. These shakes are blocked by morphine. These results may be interpreted to mean that “wet shakes” and drug induced aggression are the results of hyperactivity of the dopaminergic system.

Effect of apomorphine and nigrostriatal lesions on aggression and striatal dopamine turnover during morphine withdrawal: Evidence for dopaminergic supersensitivity in protracted abstinence

Reliable aggression was seen in rats which were grouped 30 days after undergoing continuous withdrawal from morphine. This withdrawal aggression, associated with long-lasting effects of morphine dependence, was blocked by morphine or lesions of the nigrostriatal bundle, but not by lesions of the median forebrain bundle. When the nigrostriatal lesioned rats were treated with a small dose of apomorphine, the aggression was reinstated. Apomorphine reduced the turnover of dopamine in the 30-day withdrawn rats at doses which were ineffective in similarly housed non-dependent rats. These results suggest that animals undergoing protracted morphine abstinence show aggression due to a latent dopaminergic supersensitivity, similar to that previously reported during acute narcotic withdrawal.

A comparison of narcotic analgesics with neuroleptics on behavioral measures of dopaminergic activity.

Abstract Because of many practical difficulties which are encountered in obtaining direct evidence for the involvement of brain neurotransmitters in the action of narcotic drugs, several indirect procedures are often employed. One such method is to compare on the same measures of drug action the narcotic drugs with a non-narcotic drug having a known mechanism of action. Haloperidol is a prototype non-narcotic drug which blocks dopamine receptors and many of its actions are believed to be associated with this receptor blockade. In this paper we compare various actions of haloperidol or other neuroleptics with morphine or other narcotic analgesics using the same testing parameters. We hope that such a comparison would evaluate the role of dopamine receptors in narcotic action and narcotic dependence. This discussion is limited only to the behavioral measures as a comparison of neurochemical measures was recently reviewed in another paper (1).

Enhancement of apomorphine-induced inhibition of striatal dopamine-turnover following chronic haloperidol

Abstract Following chronic treatment with haloperidol, there was no change in dopamine concentration or turnover in the rat striatum. However, the threshold dose of apomorphine to inhibit dopamine turnover was reduced. These data provide neurochemical evidence for super-sensitivity of dopamine receptors after chronic treatment with neuroleptics.

Effect of loperamide, haloperidol and methadone in rats trained to discriminate morphine from saline

In an operant procedure of lever pressing at FR10 schedule of food reinforcement, rats were trained to respond differentially in order to discriminate the effects of morphine (10 mg/kg) injection from those of saline injection. These rats learned to press a lever on one side after morphine injection and a lever on the opposite side after saline injection. In subsequent testing, these rats reliably emitted responses on the morphine lever after 10 or 20 mg/kg of morphine IP, 50 mg/kg of morphine given orally or 2 mg/kg methadone. Two mg/kg of morphine (or 10 or 20 mg/kg given orally) was recognized as saline. In contrast, after either loperamide (an antidiarrheal drug) given in doses up to 10 mg/kg or haloperidol (a neuroleptic) given in doses up to 0.32 mg/kg, all responses were made on the saline lever. Higher doses suppressed responding. Since neither the antidiarrheal activity nor the neuroleptic activity was sufficient to provide the discriminable cue associated with morphine, it is suggested that specific central effects produced only by narcotic analgesics are the basis for these morphine cues.

Alteration in the action of cholinergic and anti cholinergic drugs after chronic haloperidol: Indirect evidence for cholinergic hyposensitivity

Abstract Following repeated treatment with haloperidol, spontaneous locomotor activity and the locomotor stimulation produced by amphetamine and the anti-cholinergic, dexetimide was enhanced compared with normal rats. The reduction in locomotor activity produced by the cholinergic agonist, pilocarpine, was retarded following this treatment. These results suggest that a dopaminergic supersensitivity and a cholinergic hyposensitivity develop as a result of chronic neuroleptic treatment.

Discriminable Stimuli Produced by Analgesics

Narcotic analgesics are drugs primarily used to relieve pain. Although narcotic drugs were originally natural products, many new drugs are synthetic. All known narcotic analgesics also produce a number of effects other than analgesia which make them valuable for other clinical uses but also constitute potentials for abuse and narcotic dependence. In addition, there are several pharmacological properties which are characteristic of only a few narcotics and are absent in the rest of them. For example, morphine is known to initially cause vomiting and later show a strong anti-emetic property. All synthetic narcotics are purely anti-emetic and are devoid of the initial emetic action. Similarly, various narcotic analgesics differ in their respiratory depressant property. Whereas they all produce respiratory depression, with some a rapid tolerance develops which allows for further use to relieve pain without concommitant depression of respiration.

Selective interaction of drugs with a discriminable stimulus associated with narcotic actions

Abstract Rats were trained to bar press on either one of two levers depending on whether they received an injection of morphine (10 mg/kg) or saline. The rats responded on the morphine-correct lever when injected with another narcotic, fentanyl, but responded on the saline-correct lever when injected with a narcotic antagonist or another CNS active, but non-narcotic, drug (e.g., amphetamine, apomorphine). The narcotic antagonist, naloxone, prevented the occurrence of the narcotic discriminable stimulus, but the rats responded on the morphine-correct lever when injected with morphine plus any of a number of potent CNS active, but non-narcotic compounds. These results are discussed with reference to the specificity of this procedure for detecting drugs with narcotic agonist or antagonist properties.

Paradoxical absence of aggression during naloxone-precipitated morphine withdrawal

Aggression, which is normally seen during withdrawal from narcotics, could not be produced in morphine-dependent rats by the administration of naloxone at doses which cause other signs of withdrawal. Apomorphine injected instead of naloxone was capable of producing aggression, without other withdrawal signs. Naturally occurring aggression (72-hr withdrawal) was enhanced by apomorphine and unaffected by naloxone.

Effects of cholinergic agonists and antagonists on morphine-withdrawal syndrome

The effects of pilocarpine, atropine and dexetimide were studied on the occurrence and intensity of morphine-withdrawal signs observed after cessation of chronic morphine injections. Pilocarpine was effective in reducing both ‘wet-dog’ like body shakes and aggression but it increased diarrhea and weight loss. Pretreatment with atropine blocked all of the effects of pilocarpine on withdrawal signs. Methylscopolamine pretreatment blocked only diarrhea. The administration of atropine or dexetimide produced no significant effect on any of the withdrawal signs. These results indicate a role for central cholinergic mechanism in narcotic withdrawal.