Self-administration

Experiments are conducted in commercially available operant chambers (Coulboum Instruments, Allentown, PA 18106, USA), equipped with two response levers, a food hopper and receptacle, stimulus lights and an exhaust fan. Male rats (225-250 g) are housed individually and maintained under a non-inverted 12/12 hr light/dark cycle with restricted access to food (15 g per day). Lever training begins under a continuous reinforcement schedule of food presentation. Daily sessions are terminated after 1 hour or 50 food presentations, whichever occurs first. Subsequently, the response requirement is increased by one response per daily session up to FR5. Once rats receive 50 food pellets in a single session under the FR5 schedule (typically within 5 days), food training is suspended and 

Chapter I.C Central Nervous System (CNS) Safety Pharmacology Studies 

After responding for cocaine stabilizes (i.e. when the variability in the number of infusions delivered per session does not exceed 20% over 4 consecutive sessions), saline is substituted for cocaine until the number of infusions per session is less than 8 for 4 consecutive sessions. Once this criterion is satisfied, a specified dose of the test substance is substituted for saline for 10 sessions or until the number of infusions per session either does not vary by more than 20 % or is less than 8 per session over 4 consecutive sessions. Next, saline is substituted for the test substance until the criteria listed above are satisfied. Finally, cocaine is substituted for saline until the criteria listed above are satisfied. 

Each dose is studied in a minimum of 8 and a maximum of 12 rats with each subject used to study only a single dose of test substance. 

The basic parameters measured during self-administration studies are the number of infusions taken and the response rate (responses per second) per daily session. 

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Addiction potential. The ability of a compound to elicit compulsive self-administration. 

In its reinforcing capacity, a drug of abuse increases the frequency of preceding responses, and accordingly is called a reinforcer. All drugs of abuse are primary reinforcer and lead to self-administration. 

Deficient knowledge is die absence or deficiency of cognitive information to a specific subject. In the case of self-administration of dm die patient lacks sufficient knowledge to administer the drug regimen correctiy. It may also relate to a lack of interest in learning, cognitive limitation, or the inability to remember. 

Many postoperative patients require less narcotics when they are able to self-administer a narcotic for pain. Because the self-administration system is under the control of the nurse, who adds the drug to die infusion pump and sets the time interval (or lockout interval) between doses, the patient cannot receive an overdose of the drug. 

This drug is used for complete or partial reversal of narcotic depression, including respiratory depression. Narcotic depression may be due to intentional or accidental overdose (self-administration by an individual), accidental overdose by medical personnel, and drug idiosyncrasy Naloxone also may be used for diagnosis of a suspected acute opioid overdosage. 

Petrakis IL, Buonopane A, O Malley S, et al The effect of tryptophan depletion on alcohol self-administration in non-treatment-seeking alcoholic individuals. Alcohol Clin Exp Res 26 969-975, 2002... 

Rodd-Henricks ZA, McKinzie DL, Melendez Rl, et al Effects of serotonin-3 receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats. Psychopharmacology (Berl) 165 252—259, 2003... 

Ryabinin AE, Bachtell RK, Freeman P, et al ITF expression in mouse brain during acquisition of alcohol self-administration. Brain Res 890 192—195, 2001... 

Smith BR, Amit Z The role of gamma-aminobutyric acid (GABA) in the regulation of ethanol and acetaldehyde self-administration. Prog Neuropsychopharmacol Biol Psychiatry 9 759-763, 1985... 

Griffiths RR, Wolf B Relative abuse liability of different benzodiazepines in drug abusers. J Clin Psychopharmacol 10 237-243, 1990 Griffiths RR, Weerts EM Benzodiazepine self-administration in humans and laboratory animals—implications for problems of long-term use and abuse. Psycho-pharmacology (Berl) 134 1-37, 1997... 

Braida D, Pozzi M, Cavallini R, et al Intracerebral self-administration of the cannabinoid receptor agonist CP 55,940 in the rat interaction with the opioid system. EurJ Pharmacol 413 227-234, 2001... 

Fattore L, Cossu G, Martellotta CM, et al Intravenous self-administration of the Cbl receptor agonist WIN 55,212—2 in rats. Psychopharmacology (Berl) 156 410-416, 2001... 

Martellotta MC, Cossu G, Fattore L, et al Self-administration of the cannabinoid receptor agonist WIN 55,212—2 in drug-naive mice. Neuroscience 85 327—330, 1998... 

Substance Abuse and Mental Health Services Administration The BASIS Report Marijuana Use Secondary to Other Substances of Abuse. Rockville, MB, Substance Abuse and Mental Health Services Administration, 2003 Tanda G, Munzar P, Goldberg SR Self-administration behaviour is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci 3 1073— 1074, 2000... 

Dependence and withdrawal can occur with all of the stimulants. Cocaine is one of the most strongly reinforcing drugs in self-administration paradigms in animals and also has a psychological withdrawal syndrome. A typical pattern of withdrawal includes a ravenous appetite, exhaustion, and mental depression, which may last for several days after the drug is withdrawn. Because tolerance develops quickly, abusers may take large doses, compared with those used medically, for example, as anorexiants. 

Collins SE, Kantak KM Neuronal nitric oxide synthase inhibition decreases cocaine self-administration behavior in rats. Psychopharmacology (Berl) 159 361-369,... 

Pryor GT Persisting neurotoxic consequences of solvent abuse a developing animal modelfortoluene-inducedneurotoxicity. NlDAResMonogr 101 136—166,1990 Pudiak CM, Bozarth MA The effect of nitric oxide synthesis inhibition on intravenous cocaine self-administration. Prog Neuropsychopharmacol Biol Psychiatry 26 189— 196, 2002... 

Wood RW, Grubman J, Weiss B Nitrous oxide self-administration by the squirrel monkey. J Pharmacol Exp Ther 202 491 99, 1977 Wood RW, Coleman JB, Schuler R, et al Anticonvulsant and antipunishment effects of toluene. J Pharmacol Exp Ther 230 407 12, 1984 World Health Organization The lCD-10 Classification of Mental and Behavioural Disorders Clinical Descriptions and Diagnostic Guidelines. Geneva, World Health Organization, 1992... 

Similarly, self-administration of MDMA in monkeys trained to self-administer amphetamine (Kamien et al. 1986) or in monkeys or baboons trained to self-administer cocaine (Beardsley et al. 1986 Lamb and Griffiths 1987) probably reflects a dopaminergic component to the pharmacology of MDMA. This would be consistent with current theories of dopamine involvement in the mechanism of action of drugs with dependence liability (Wise and Bozarth 1987). 

Beardsley, P.M. Balster, R.L. and Harris, L.S. Self-administration of methylenedioxymethamphetamine (MDMA) by Rhesus monkeys. Drug Alcohol Depend 18 149-157, 1986. 

FIGURE 1. Chemical structure of 14 of the 15 phenylethylamines tested to determine whether they maintain drug self-administration... 

In a summary of the human abuse literature on anorectic phenylethylamines, Griffiths et al. (1979) found there was a good correlation between the results of self-administration studies in animals and information about the subjective effects and abuse in man. Specifically, amphetamine, diethyl-propion, and phenmetrazine have been associated with numerous clinical case reports involving abuse, and these three compounds as well as benz-phetamine and /-ephedrine have shown similar subjective effects in drug abuser populations (Griffiths et al. 1979). In addition, fenfluramine was associated with low incidence of abuse in humans and did not maintain self-injection responding in animals. Chlorphentermine was similarly associated with low incidence of abuse in man, but did not maintain selfinjection uniformly in animals (Griffiths et al. 1979). 

The pharmacological properties of phenylethylamines that control selfadministration are complex. The effects of phenylethylamines on a variety of pharmacological measures do not appear to predict the reinforcing effects of these drugs, as measured by the cocaine substitution procedure in primates. Specifically, none of the following behavioral effects of these compounds accurately predict the results of self-administration experiments within the phenylethylamine class (Griffiths et al. 1976 Griffiths et al. 

Griffiths, RR. Brady, J.V. and Bradford, L.D. Predicting the abuse liability of drugs with animal drug self-administration procedures Psyehomotor stimulants and hallueinogens. Adv Behav Pharmacol 2 163-208, 1979. 

Schuster, CR., and Thompson, T. Self-administration of and behavioral dependence on drugs. Annual Review of Pharmacology 9 483-502, 1969. 

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