Intravenous Heroin Self-administration Research Articles

Heroin self-administration by rats: Influence of dose and physical dependence

Lever-pressing behavior reinforced by intravenous infusion of various concentrations of heroin, and consequent development of physical dependence, were examined in rats. In addition, the influence of opiate dependence, and of its disappearance following withdrawal, on heroin self-administration were investigated. It was found that intravenous self-administration of heroin at 0.03 mg/kg/infusion maintained self-administration behavior without producing physical dependence. Total responses per session decreased with increasing unit dose of heroin, whereas the total amount of drug self-administered was directly related to unit dose. Significantly greater numbers of withdrawal signs and percentage body weight losses in response to naloxone injections were observed following self-administration of heroin at 0.1, 0.3 or 0.6 mg/kg/infusion. Intake of heroin at 0.03 mg/kg/infusion, but not at 0.1, 0.3 or 0.6 mg/kg/infusion, was found to increase significantly in opiate-dependent and postdependent animals. These findings support the previous use of 0.03 mg/kg/infusion as a suitable dose for illustrating the reinforcing effect of heroin without the influence of physical dependence.

Pharmacological regulation of intravenous cocaine and heroin self-administration in rats: A variable dose paradigm

Rats were trained to intravenously self-administer unit doses of cocaine or heroin. Constant supplemental infusion of a portion of each rat's mean hourly intake increased the mean time between successive infusions, but the effect was not statistically reliable from the data of a small sample of animals. A variable dose per infusion (VDI) paradigm was developed which enabled testing of several unit doses of cocaine or heroin within single test sessions. Unit doses of 0.5, 1.0, and 2.0 mg/kg of cocaine or 0.025, 0.05, and 0.1 mg/kg of heroin were made available with equal frequency but in unpredictable sequence to independent groups of rats. The mean time between successive infusions was linearly related to the log dose of the preceding infusion in each case. Pimozide, a drug thought to attenuate the reinforcing effects of both cocaine and heroin, shifted the functions without disturbing the dose-response relations; pimozide reliably decreased the time between successive cocaine infusions across a 4-fold range of pimozide doses. The effect of pimozide on heroin self-administration was not statistically significant and disrupted responding at the highest dose tested. This paradigm thus offers a within-session assessment of the dose-dependent duration of reinforcing actions of cocaine and heroin, and this assessment is sensitive to at least one challenge of intravenous drug reinforcement.

A comparison of the effects of intra-accumbens injections of amphetamine and morphine on reinstatement of heroin intravenous self-administration behavior

In rats previously trained to self-administer heroin intravenously, the application of morphine directly to the ventral tegmental area (VTA) has been shown to reinstate responding after a period of extinction, suggesting that the activation of mesolimbic dopamine neurons might underlie the priming effects of i.v. injections of opiates and stimulants found previously. In the present experiments rats were trained to self-administer heroin intravenously. Following extinction training, and after a period of at least 30 min of no responding, bilateral microinjections of either 0.5 μl saline or 10 μ/0.5 μl (+)-amphetamine sulfate were made into the N. accumbens. Amphetamine, but not saline reinstated self-administration behavior for about 1 h. In contrast, bilateral intra-accumbens injections of either 5 or 10 μg/ increased locomotor activity measured in independent tests. Because the locomotor activity produced by intra-accumbens morphine occurs independent of the mesolimbic dopamine system, unlike that produced by VTA morphine and intra-accumbens amphetamine, and because it does not show sensitization, it is argued that the reinstatement effects of opiates and stimulants on self-administration behavior are mediated by the mesolimbic dopamine system, and may be related to the ability of opiates and stimulant drugs to cause sensitization within that system.

Hypothalamo-neurohypophyseal neuropeptides and experimental drug addiction

Oxytocin, a hypothalamo-neurohypophyseal neuropeptide was found to attenuate the development of tolerance to the analgesic action of morphine, heroin, β-endorphin or D-Pro 2-Met 5-enkephalinamide. The effect of oxytocin on morphine tolerance was prevented by Nα-acetyl-(2-0-methylty-rosine)-oxytocin or penicillamine 1-(2-0-methyltyrosine)-lysine 8-vasopressin, which are antagonists of oxytocin receptors. Oxytocin dose-dependently attenuated various signs of precipitated morphine withdrawal (e.g., stereotyped jumpings, hypothermia, body weight loss). The neuropeptide diminished intravenous self-administration of heroin in heroin-tolerant rats. It is concluded that brain oxytocin interferes with adaptive components of experimental drug addiction.

The effect of the partial dopamine agonist transdihydrolisuride on negative symptoms in schizophrenics : H. Schanz and R. Olbrich Central Institute of Mental Health, J5, P.O. Box 5970, D-6800 Mannheim, FRG

Dopamine partial agonists have been suggested to be potential therapeutic candidates for pharmacological intervention in drug addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are hypothesized to behave as functional antagonists in conditions of high dopaminergic tone. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the dopamine D2 receptor, on intravenous heroin self-administration on fixed- and progressive-ratio schedules of reinforcement. The effects of terguride on oral sweet solution (4% sucrose) self-administration on a fixed-ratio schedule were also tested. Terguride dose-dependently decreased heroin self-administration on the fixed-ratio schedule and decreased the maximum number of responses for heroin self-administration on a progressive-ratio schedule. In contrast, terguride did not significantly affect oral sucrose self-administration. These data suggest that terguride may represent a novel pharmacological strategy for the treatment of opiate addiction.

Vasopressin neuropeptides and acquisition of heroin and cocaine self-administration in rats

The effect of the vasopressin neuropeptide des-glycinamide (Arg 8)-vasopressin (DGAVP) on reducing the acquisition of intravenous heroin self-administration in rats was analyzed. When rats reduced in body weight were allowed to self-administer heroin for 1 h per day in the presence of a fixed time, non contingent food delivery schedule, it appeared that heroin intake was related in an orderly way to the unit dose of heroin delivered. DGAVP decreased heroin intake during days 4 and 5 of acquisition, especially when a high dose of heroin was delivered. DGAVP decreased heroin intake more effectively when rats were tested without the food delivery schedule and for 6 h instead of 1 h sessions per day. Structure activity relationship studies revealed that the peptide (pGlu 4, Cyt 6)AVP-(4–8) was the shortest active sequence mimicking the effect of DGAVP and that this peptide was somewhat more potent than DGAVP in this respect. The peptide (pGlu 4, Cyt 6)AVP-(4–9) increased the heroin intake of the rats. DGAVP and (pGlu 4, Cyt 6)- AVP-(4–8) also decreased cocaine intake of body weight reduced rats given the opportunity to self-administer cocaine intravenously in daily 6 h sessions. It is concluded that vasopressin neuropeptides may decrease the reinforcing efficacy of heroin and cocaine during acquisition of drug self-administration rather than interact with nutritional and environmental factors influencing drug taking behavior.

The dopamine hypothesis of opiate reward challenged

The dopamine hypothesis of opiate reward was directly tested by blocking dopamine receptor systems with haloperidol. Haloperidol was administered either systematically or locally into different brain areas with dopaminergic terminals in rats allowed to initiate and maintain intravenous heroin self-administration. Haloperidol treatment did not block heroin reward. It is concluded that dopamine is not critically involved in opiate reward and that multiple endogenous reward systems are present in the brain.

Behaviorally active oxytocin fragments simultaneously attenuate heroin self-administration and tolerance in rats

Maintenance of intravenous heroin self-administration and the degree of tolerance to the analgesic effect of self-injected heroin were simultaneously measured in heroin-tolerant rats. Subcutaneous injection of oxytocin (OXT-(1–9)) and of its behaviorally active fragments desglycinamide 9 -oxytocin (OXT-(1–8)) and [pGlu 4, Cyt 6]-oxytocin-(4–8) (OXT-(4–8)) decreased the amount of heroin self-injected. The C-terminal tripeptide of oxytocin (prolyl-leucyl-glycinamide, PLG, OXT-(7–9)) and desglycinamide 9-[Arg] 8-vasopressin (AVP-(1–8)) were ineffective in this respect. In spite of the lower amount of self-injected heroin after pretreatment with oxytocin fragments, no differences in the antinociceptive effect of self-injected heroin, as assessed by the lick response using a hot plate device, were observed after pretreatment with placebo and oxytocin fragments. These findings suggest that oxytocin and some of its behaviorally active fragments attenuate heroin tolerance and that this effect may result in a diminished heroin intake in tolerant animals self-injecting heroin.

Toxicity associated with long-term intravenous heroin and cocaine self-administration in the rat

Toxicity associated with long-term intravenous heroin and cocaine self-administration in the rat

Toxicity Associated With Long-term Intravenous Heroin and Cocaine Self-administration in the Rat

Laboratory rats were given unlimited access to intravenous cocaine hydrochloride or heroin hydrochloride. Animals self-administering cocaine quickly developed a pattern of episodic drug intake, with periods of excessive cocaine self-administration alternating with brief periods of abstinence. Subjects allowed continuous access to intravenous heroin showed stable drug self-administration, with a gradual increase in daily heroin intake over the first two weeks of testing. The general health of the animals became markedly different: those self-administering heroin maintained grooming behavior, pretesting body weight, and a good state of general health; rats self-administering cocaine tended to cease grooming behavior, to lose up to 47% of their pretesting body weight, and to show a pronounced deterioration in general health. The mortality rate for 30 days of continuous testing was 36% for animals self-administering heroin and 90% for those self-administering cocaine. These results suggest that cocaine is a much more toxic compound than heroin when animals are given unlimited access to intravenous drug.

Oxytocin reduces intravenous heroin self-administration in heroin-tolerant rats

Intravenous self-administration of heroin was studied in experimentally naive rats, as compared to this behavior in animals rendered tolerant to heroin by multiple injections. The tolerant rats also exhibited mild signs of spontaneous and naloxone-precipitated heroin withdrawal. Self-administration behavior developed earlier in the tolerant rats. In heroin-naive rats, oxytocin treatment did not influence the acquisition of heroin self-administration behavior. In the tolerant rats, on the other hand, oxytocin decreased the acquisition of heroin self-administration. When maintenance of heroin self-administration. was studied in the tolerant rats, graded doses of oxytocin (0.05, 0.5 and 5 ug s.c.) decreased heroin intake. This finding, which is in agreement with previous data indicating that oxytocin attenuates the development of tolerance to and dependence on narcotic analgesics, suggests that the neuropeptide reduced the reinforcing efficacy of heroin in the tolerant organism.

Blockade of nucleus accumbens opiate receptors attenuates intravenous heroin reward in the rat.

A quaternary derivative of naloxone, methyl naloxonium chloride (MN), was administered intracerebrally to rats trained to self-administer heroin intravenously. Increases in intravenous (IV) heroin self-administration rates were found following injections of low doses of MN into the nucleus accumbens (N.Acc), but not following injections of low doses of MN into the ventral tegmental area (VTA). These results were interpreted to suggest that the rewarding properties of IV heroin were decreased following N.Acc opiate receptor blockade. The relative insensitivity of the VTA to MN treatment was taken to suggest that VTA opiate receptors are either not essential or play a secondary role in mediating IV heroin self-administration. The present data support the notion that post-synaptic N.Acc opiate receptors play a crucial role in maintaining IV heroin self-administration.

Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats.

The hypothesis that separate neural systems mediate the reinforcing properties of opioid and psychomotor stimulant drugs was tested by examining the role of mesolimbic dopamine (DA) neurons in maintaining intravenous heroin and cocaine self-administration. After local destruction of the DA terminals in the nucleus accumbens (NAcc) with 6-hydroxydopamine (6-OHDA), rats trained to self-administer cocaine and heroin on alternate days were observed for changes in their drug-seeking behaviors. Postlesion responding for cocaine showed a time-dependent decrease or extinction, whereas heroin self-administration showed a time-dependent recovery. By the fifth trial postlesion, heroin self-administration had recovered to 76% of prelesion baseline levels, but cocaine self-administration had dropped to 30% of prelesion baseline rates. Thus, selective lesions of the DA terminals in the nucleus accumbens significantly attenuate cocaine but not heroin self-administration. These data support the hypothesis that independent neural substrates are responsible for the reinforcing actions of these two drugs.

Ventral tegmental site of opiate reward: Antagonism by a hydrophilic opiate receptor blocker

The ventral tegmental area has been suggested as a possible site of action for the rewarding effect of opiates on the basis of the fact that local morphine injections in this but not other regions are rewarding. That this is a necessary and not just a sufficient site of opiate rewarding action was suggested by the fact that diallyl-normorphinium bromide, a hydrophilic opiate blocker, caused compensatory increases in intravenous heroin self-administration when injected into the ventral tegmental area but not other brain regions.

Opiate rewarding action: independence of the cells of the lateral hypothalamus

The posterior lateral hypothalamic area has been suggested as a possible site of action for the reinforcing effects of opiates on the basis of the finding that rats would lever-press for direct microinjections of opiates into this region. The present study reports the effects of kainic acid-induced lateral hypothalamic cell loss on the intravenous self-administration of heroin. Kainic acid injection resulted in marked cellular depletion yet failed to alter heroin self-administration.

Effects of heroin and naltrexone on plasma prolactin levels in man

Plasma levels of prolactin were increased following intravenous self-administration of heroin by young men with a history of heroin addiction. Following 10 days of controlled heroin usage, tolerance could be demonstrated to the acute prolactin-releasing effect of heroin. There was no evidence that a single dose of naltrexone affected basal prolactin levels.

Modulation of heroin self-administration by neurohypophyseal principles

Neuropeptides related to hypothalamic-neurohypophyseal hormones affect intravenous heroin self-administration behavior in rats. Desglycinamide 9,arginine 8-vasopressin and pressinamide reduced, while oxytocin and its C-terminal tripeptide, prolyl-leucyl-glycinamide facilitated this behavior. The effectiveness of the vasopressin analogue appeared to be of a long term nature. The data indicate a modulating effect of these principles on the reinforcing efficacy of heroin.