Heroin Self-administration Behavior Research Articles

Mouse model of the OPRM1 (A118G) polymorphism: differential heroin self-administration behavior compared with wild-type mice.

Mu-opioid receptors (MOPRs) are the target of heroin and other prescription opioids, which are currently responsible for massive addiction morbidity in the US. The gene coding for the human MOPR (OPRM1) has an important functional single nucleotide polymorphism (SNP), A118G. The OPRM1 A118G genotype results in substantially increased risk of heroin addiction in humans; however, the neurobiological mechanism for this increased risk is not fully understood. This study examined heroin self-administration (SA) behavior in A112G (G/G) mice, harboring a functionally equivalent SNP in Oprm1 with a similar amino acid substitution, in extended (4 h) SA sessions. Adult male and female G/G mice and 'wild-type' litter mates (A/A) were allowed to self-administer heroin (0.25 mg/kg/unit dose, FR1 with a nose poke response) for 4 h/day, for 10 consecutive days. Half of the mice then continued in a heroin dose-response study, while extinction from heroin SA was studied in the other half. In vivo microdialysis was used to measure acute heroin-induced increases of striatal dopamine in the GG vs AA genotypes. Male and female G/G mice responded for heroin significantly more (and thus had greater intake) than A/A mice, in the initial 10 days of heroin SA, and in the subsequent dose-response study. There were no significant differences in extinction of SA between the A/A and G/G mice. Heroin-induced increases in striatal dopamine levels are higher in the GG mice than in the AA mice. Both male and female G/G mice self-administered more heroin than did A/A mice over a 10-day period, possibly because of the greater increases of heroin-induced striatal dopamine in the GG mice. Furthermore, G/G male mice escalated the amount of heroin self-administration across 10 extended-access sessions more than A/A male mice did. These are the first studies to examine the acquisition of heroin SA in this mouse model. These studies may lead to a better understanding of the neurobiological and behavioral mechanisms that underlie greater risk of heroin addiction in carriers of the A118G SNP.

Effect of electro-acupuncture on relapse to heroin-seeking in the heroin self-administrating rats

To observe the effect of electro-acupuncture on the relapse to heroin-seeking induced by heroin-related cues after withdrawal from heroin self-administration in rats. Sixty male Wistar rats were randomized into physiological saline group, withdrawal group A, withdrawal group B, electro-acupuncture (EA) treatment group A and EA treatment group B, with 12 rats in each group. The rats were trained by nose-poke response to self administer heroin (50 μg/kg/per infusion) or saline with one daily 4-h session for 14 consecutive days, the session ended after 25 infusions were earned or 4 hours had passed, the reinforcement schedule was a progressive ratio. Then rats in withdrawal group A and withdrawal group B were withdrawn from heroin for 1 week and 2 weeks respectively, and then they were reintroduced to their training chambers for 4-h relapse testing which was induced by heroin-related environmental cues; And rats in EA treatment group A and EA treatment group B were also withdrawn from heroin for 1 week and 2 weeks respectively, during which they were given EA treatment for 20 min daily, then they received relapse testing; In the meantime, rats in saline group were trained with saline instead of heroin for 14 days as control, after 7 days of withdrawal from saline, they received relapse testing. Following 7–8 days of drug training, the rats began to establish the stable intravenous heroin self-administration behavior; For the stable heroin self-administrating rats that received EA treatment, when they were reintroduced to their training chambers, their heroin-seeking behaviors were obviously inhibited, and this inhibitory effect related to the cumulativeness of EA stimulation. The results suggested that EA could prevent relapse to heroin-seeking to a certain extent.

Prenatal Cannabis Exposure Increases Heroin Seeking with Allostatic Changes in Limbic Enkephalin Systems in Adulthood

Prenatal cannabis exposure is a growing concern with little known about the long-term consequences on behavior and neural systems relevant for reward and emotional processing. We used an animal model to study the effects of prenatal exposure to Delta(9)-tetrahydrocannabinol (THC) on heroin self-administration behavior and opioid neural systems in adult males (postnatal day 62). Rats were exposed to THC (.15 mg/kg) or vehicle from gestational day 5 to postnatal day 2. Both pretreatment groups showed similar heroin intake, but THC-exposed rats exhibited shorter latency to the first active lever press, responded more for low heroin doses, and had higher heroin-seeking during mild stress and drug extinction. THC exposure reduced preproenkephalin (PENK) mRNA expression in the nucleus accumbens during early development, but was elevated in adulthood; no adult striatal changes on preprodynorphin mRNA or PENK in caudate-putamen. PENK mRNA was also increased in the central and medial amygdala in adult THC-exposed animals. THC animals had reduced heroin-induced locomotor activity and nucleus accumbens mu opioid receptor coupling. This study demonstrates enduring effects of prenatal THC exposure into adulthood that is evident on heroin-seeking behavior during extinction and allostatic changes in mesocorticolimbic PENK systems relevant to drug motivation/reward and stress response.

Adolescent Cannabis Exposure Alters Opiate Intake and Opioid Limbic Neuronal Populations in Adult Rats

Cannabis use is a hypothesized gateway to subsequent abuse of other drugs such as heroin. We currently assessed whether Delta-9-tetrahydrocannabinol (THC) exposure during adolescence modulates opiate reinforcement and opioid neural systems in adulthood. Long-Evan male rats received THC (1.5 mg/kg intraperitoneally (i.p.)) or vehicle every third day during postnatal days (PNDs) 28-49. Heroin self-administration behavior (fixed ratio-1; 3-h sessions) was studied from young adulthood (PND 57) into full adults (PND 102). THC-pretreated rats showed an upward shift throughout the heroin self-administration acquisition (30 microg/kg/infusion) phase, whereas control animals maintained the same pattern once stable intake was obtained. Heightened opiate sensitivity in THC animals was also evidenced by higher heroin consumption during the maintenance phase (30 and 60 microg/kg/infusion) and greater responding for moderate-low heroin doses (dose-response curve: 7.5, 15, 30, 60, and 100 microg/kg/injection). Specific disturbance of the endogenous opioid system was also apparent in the brain of adults with adolescent THC exposure. Striatal preproenkephalin mRNA expression was exclusively increased in the nucleus accumbens (NAc) shell; the relative elevation of preproenkephalin mRNA in the THC rats was maintained even after heroin self-administration. Moreover, mu opioid receptor (muOR) GTP-coupling was potentiated in mesolimbic and nigrostriatal brainstem regions in THC-pretreated animals. muOR function in the NAc shell was specifically correlated to heroin intake. The current findings support the gateway hypothesis demonstrating that adolescence cannabis exposure has an enduring impact on hedonic processing resulting in enhanced opiate intake, possibly as a consequence of alterations in limbic opioid neuronal populations.

Contingent and non-contingent effects of heroin on mu-opioid receptor-containing ventral tegmental area GABA neurons

Opiate activation of mu-opioid receptors (μORs) in the ventral tegmental area (VTA) modulates γ-aminobutyric acid (GABA) neurotransmission within the mesocorticolimbic dopamine (DA) reward system. We combined in vivo extracellular electrophysiological recordings in anesthetized and freely behaving rats with intracellular Neurobiotin™ filling and immunocytochemistry to characterize the effects of opiates on VTA GABA neurons, evaluate their discharge activity during opiate self-administration, and identify the cellular sites for opiate activation. We identified a subpopulation of VTA GABA neurons that was characterized by location, spike discharge profile, activation by microelectrophoretic DA, and response to internal capsule (IC) stimulation. Systemic administration of heroin or microelectrophoretic application of the selective μOR agonist [ d-Ala2, N-Me-Phe4, Gly-ol]-Enkephalin (DAMGO) reduced VTA GABA neuron firing rate (heroin IC 50 = 0.35 mg/kg) and was blocked by the μOR antagonist naloxone. Heroin also reduced IC-evoked post-stimulus spike discharges, a manifestation of gap-junction-mediated electrical coupling between VTA GABA neurons. The baseline firing rate of VTA GABA neurons significantly increased (239%) following the acquisition of heroin self-administration behavior and transiently increased during each response for heroin (105%), but decreased (49%) following heroin, similar to non-contingent heroin. Electrophysiologically characterized VTA GABA neurons were filled with Neurobiotin™ and labeled dendrites contained plasmalemmal μOR immunoreactivity. Dually labeled μOR dendrites contained dendrodendritic appositions characteristic of gap junctions. These findings indicate that inhibition of this population of GABAergic neurons by opiates acting on dendritic μORs has implications for modulation of electrical coupling between VTA GABA neurons and dopamine (DA) neurotransmission in the VTA and terminal field regions.

Effect of electro-acupuncture on drug-seeking behavior of the heroin self-administrating rat

Objective: This present study is to establish a rat model of intravenous heroin self-administration and observe the effect of electro-acupuncture on the heroin-seeking behavior of the heroin self-administrating rat. Methods: Six Male Wistar rats were surgically implanted with an intra-jugular intravenous catheters under sodium pentobarbital anesthesia, following a minimum recovery of 7 days, the rats were trained by nose-poke response with one daily 4-hour session for 14 consecutive days to self administer heroin (50μg/kg/per injection), the session ended after 25 infusions were earned or 4 hours had passed, whichever came first, the reinforcement schedule was fixed ratio 1 (FR1) that the rat received a heroin injection for each nose poke response. And then the rats were given electro-acupuncture treatment daily 30min prior to each session and then were trained with one daily 4-h session for 7 consecutive days. Results: Stable intravenous heroin self-administration behavior of rats was established after 7–8 days' drug training, electro-acupuncture given to the stable heroin self-administrating rat 30 min prior to each session could reduce the drug self-administration behavior, namely the total heroin intake in each session was reduced, especially the 1st hour heroin intake, the initiation of first nose-poke response in each session was relayed, and the haste heroin-seeking behavior also became slower. Conclusions: The above results suggested that the electro-acupuncture had better detoxification effect.

A rat model of heroin relapse behavior induced by drug-related environmental cues

目的 建立环境线索诱导的大鼠海洛因复吸行为模型.方法训练雄性SD大鼠通过鼻触反应进行海洛因静脉自身给药 (每次剂量0.05 mg/kg, 限量每日25次) ,共14d, 每天4h.强化程序为累进比率.起始反应条件为1,每5次海洛因注射后增加1,用灯光作为辨别和条件性刺激信号.停药两周后,大鼠重新返回实验笼进行复吸测试,连续两小时,前1h为实验笼空间环境诱导,后1h为条件性刺激诱导.结果训练7d后大鼠建立稳定的海洛因静脉自身给药行为,获得25次海洛因注射所需时间为(165±16)min,有效鼻触反应为(82±5)次.复吸测试时鼻触反应主要发生在有效鼻触,实验笼空间环境诱导的反应为(28±5)次,条件性刺激为(99±10)次.结论经过一段时间后,海洛因相关的空间环境和条件性刺激可以再次恢复大鼠原来的自身给药反应行为.该模型可用于环境因素诱导的复吸的神经生物学机制研究以及用于与反应恢复模型的比较,作为开发抗复吸模型的有效性有待进一步研究。

Dopamine in the nucleus accumbens: cellular actions, drug- and behavior-associated fluctuations, and a possible role in an organism's adaptive activity

This review expounds the idea that the analysis of dopamine (DA) action on target cells under behaviorally relevant conditions and behavior-related changes in DA activity can offer new information to clarify the functional significance of mesocorticolimbic DA. In contrast to the traditional association of DA with certain behavioral processes and mechanisms (activation, arousal, conditioning, motivation, reinforcement, sensorimotor integration, etc.), evaluation of DA activity during well-controlled behaviors established by different reinforcers can provide important clues for determining the role of DA in the development and regulation of goal-directed behavior. This review summarizes the results of our microiontophoretic studies of striatal neurons in awake, unrestrained rats, particularly the action of DA on spontaneously active and glutamate (GLU)-stimulated cells, the pattern of DA–GLU interaction, and the role of tonic DA release in regulating the activity and afferent responsiveness of these units. We present the results of our iontophoretic studies of ventral tegmental area (VTA) neurons in freely moving animals suggesting the complexity and limitations in their identification as DA- and non-DA cells under behaviorally relevant conditions. We also consider technical and methodological problems related to electrophysiological and electrochemical evaluation of DA transmission in behaving animals. Finally, we discuss parallels and differences in the activity of presumed DA VTA neurons and changes of nucleus accumbens DA-dependent electrochemical signal during heroin self-administration (SA) behavior.

Blockade of ionotropic glutamatergic transmission in the ventral tegmental area reduces heroin reinforcement in rat.

While the role of the mesocorticolimbic (MCL) dopamine (DA) system in mediating the reinforcing properties of drugs of abuse has been well established, how and where other neurotransmitter systems interact to modify this system is less well understood. The present study sought to assess whether blockade of ionotropic glutamate receptors in the ventral tegmental area (VTA) would modulate heroin self-administration (SA) behavior in rats. The effects of systemic or regional administration of ionotropic glutamate receptor antagonists into the VTA on the maintenance of heroin SA were assessed. Rats were reinforced each time they responded on a lever with a single injection of intravenous heroin. To determine the specificity of their effects on heroin SA, the ability of these antagonists to modify locomotion and food-reinforced behavior was also examined. Systemic or regional administration of the non-competitive NMDA antagonist dizocilpine into the VTA significantly increased the rate of heroin SA and shifted the heroin dose-response curve to the right. Similarly, when systemically administered, ketamine, another non-competitive NMDA antagonist, also increased the rate of heroin SA. However, when administered directly into the VTA, ketamine or AP5 [ D-(-)-2-amino-5-phosphonopentanoic acid, a competitive NMDA antagonist], dose-dependently blocked heroin SA. In contrast, 6,7-dinitroquinoxaline-2,3-dione (DNQX), an AMPA/kainate receptor antagonist, significantly increased heroin SA. These data suggest that ionotropic glutamate receptors in the VTA, presumably by modulating MCL DA efferents and/or tegmental interneurons, modulate opiate reinforcement.

Nucleus accumbens dopamine release modulation by mesolimbic GABA A receptors—an in vivo electrochemical study

The role of GABA receptors in regulating the mesolimbic dopamine (DA) system and drug reinforced behaviors has not been well characterized. Using fast-cyclic voltammetry, the effects of specific GABA receptor modulation on DA release in the nucleus accumbens (NAcc) and heroin self-administration (SA) behavior was investigated. The GABA A agonist muscimol, administered either intravenously or directly into the ventral tegmental area (VTA), significantly increased DA release in the NAcc in 7 of the 10 rats tested. DA release decreased in the remaining three rats; both effects were blocked by pretreatment with the GABA A receptor antagonist bicuculline. In contrast, the GABA B agonist baclofen decreased, while 2-OH-saclofen (a GABA B antagonist) increased DA release in the NAcc. However, when VTA GABA B receptors were previously activated or inactivated by microinjections of baclofen or 2-OH-saclofen, systemic injections of muscimol caused an inhibition of NAcc DA release. These results suggest that GABA A receptors may be co-localized on both DA neurons and non-DA (GABAergic) interneurons in the VTA, with the effects of GABA A determined by the net effect of both direct inhibition and indirect disinhibition of DA neurons. Finally, although a DA releaser, muscimol was neither self-administered in drug naive rats, nor did it substitute for heroin in rats previously trained to self-administer heroin, suggesting that GABA A receptors appear to play a complex role in mediating drug reinforcement, depending upon the dynamic functional state of GABA A receptors on both tegmental DA and non-DA neurons.

Behavioral significance of phasic changes in mesolimbic dopamine-dependent electrochemical signal associated with heroin self-injections.

High-speed chronoamperometry with monoamine-selective carbon fiber electrodes was used in rats to monitor, during 5-6 consecutive daily sessions, changes in DA-dependent electrochemical signal in the nucleus accumbens (NAcc) during intravenous heroin (0.1 mg/kg) self-administration (SA) behavior and passive repeated drug injections performed with a temporal scheme similar to that in the SA experiment. In trained animals, biphasic signal fluctuations time-locked to the individual lever-presses were found to accompany all but the first daily SAs. The signal gradually increased by 30-40 nM for the 10 minutes preceding the SA, reached a peak at the moment of lever-press and decreased abruptly by approximately 40 nM for 3-4 min after heroin SA. The cycle then repeated, reaching a new peak at the moment of the next lever-press. Rapid bi-directional fluctuations in signal associated with individual heroin SAs were superimposed on substantial tonic increase in signal baseline (400-500 nM). This increase quickly developed after presentation of heroin-related light cue and the first SA, was relatively stable during all subsequent SAs and decreased towards the baseline after the last SA of a session. Changes in signal baseline induced by repeated heroin SAs depended strongly upon the signal's basal level (r = -0.787); that signal preferentially increased when its basal values were low (0-300 nM), and decreased when signal was tonically elevated (> 600 nM). Repeated passive heroin injections also induced biphasic signal fluctuations and a similar tonic increase in signal baseline. Although a transient signal decrease (25 nM for 2-4 minutes) followed by a prolonged signal increase occurred after each but not the first passive injection, the gradual pre-injection signal acceleration was absent. Although DOPAC, a principal DA metabolite, may significantly contribute to the tonic increase in electrochemical signal seen during SA session, the changes in extracellular DA may be the main contributor to both the rapid signal increases preceding drug-taking and the transient signal decreases following heroin SA. If so, the present findings suggest that activation of mesolimbic DA cells and increase in DA transmission may be involved in the mediation of motivational and/or activational components of drug-seeking and drug-taking behavior. An acute termination of previous drug- and behavior-associated DA activation with a transient inhibition of DA release, immediately following heroin SA may correlate with the drug's rewarding action, representing a part of a mechanism regulating drug-taking behavior.

Behavior-associated changes in blood pressure during heroin self-administration.

Changes in arterial blood pressure (ABP) were studied in freely moving rats during the development and performance of operant IV heroin self-administration (SA) behavior (100 micrograms/kg/injection). Heroin SA was accompanied by bidirectional, phasic ABP fluctuations in the absence of significant alterations in long-term, basal ABP levels. In trained rats, ABP gradually increased starting 5 min before each lever-press for the drug, reached a peak at the moment of lever-press and abruptly decreased after heroin infusion. This biphasic pattern corresponded to a preresponding behavioral activation followed by a postheroin sedation. These ABP fluctuations were absent during the initial heroin self-injections in drug-naive rats and during the first self-injections of a session in trained rats. A slight hypo- and hypertension were seen in these cases, respectively. The postdrug ABP decrease became more pronounced after rats received a double dose of heroin. With training, nonreinforced lever-presses and sound stimulation previously associated with heroin self-injections also significantly decreased ABP. Thus, a gradual ABP increase appears to be an essential correlate of drug-seeking and -taking behavior, while a subsequent ABP decrease may be related to the alleviation of these behaviors by heroin and possibly correlate to its rewarding (euphorigenic) action.

Heroin self-administration in rats under a progressive ratio schedule of reinforcement.

Heroin self-administration behavior under a progressive ratio (PR) schedule of reinforcement was evaluated in rats. The schedule was designed to restrict drug intake, minimize opiate dependency, and quantify the number of responses emitted (final response ratio) in order to receive a limited number of heroin infusions. Final ratios were found to be stable and did not increase with chronic (31 days) PR reinforcement. The ability of the PR schedule to detect changes in heroin reinforcement was demonstrated by evaluating the effect of naltrexone pretreatment and unit dose alteration on final ratios. Naltrexone (0.4 mg/kg) reduced final ratios and an inverted U dose-response relationship was established for the unit heroin doses 12.5-100 micrograms/injection. Maximal final ratios occurred with 50 micrograms/injection heroin reinforcement. This PR schedule may provide a useful method for evaluating the effects of pharmacological manipulations or lesions on opiate reinforcement.

The ventral pallidum plays a role in mediating cocaine and heroin self-administration in the rat

The hypothesis that the ventral pallidum is an important site mediating psychomotor stimulant and opiate reinforcement was tested in rats trained to self-administer i.v. cocaine or heroin. Ibotenic acid lesions of the ventral pallidum produced significant decreases in cocaine and heroin self-administration behavior maintained on a fixed-ratio 5 schedule of reinforcement, suggesting an attenuation of the reinforcing value of cocaine and heroin. On a progressive-ratio schedule, ventral pallidal lesions produced significant decreasese in the highest ratio obtained in rats self-administering cocaine. Similar results were observed with heroin in a progressive-ratio procedure modified to produce higher levels of responding; lesions of the ventral pallidum produced a significant decrease in the highest ratio obtained. Further, the i.v. co-administration of naxolone and heroin produced a decrease in progressive-ratio responding relative to heroin alone using the modified progressive-ratio schedule. These results suggest that the ventral pallidum is an important site mediating the reinforcing effects of cocaine and heroin and that the nucleus accumbens-ventral pallidum circuit may be a common pathway for both stimulant and opiate reinforcement.

Microinjection of oxytocin into limbic-mesolimbic brain structures disrupts heroin self-administration behavior: A receptor-mediated event?

The systemic injection of oxytocin (OXT) decreases the self-administration of heroin in heroin-tolerant rats. Since OXT-ergic binding sites are present in limbic and mesolimbic brain regions, the effects of intracerebral microinjections of OXT were investigated. In heroin-tolerant rats, the microinjection of OXT (2 ng) into the anterodorsal part of the nucleus accumbens or into the ventral hippocampus disrupted the self-administration of heroin. The effect of intrahippocampal microinjections lasted longer than that of intraaccumbens injections. The administration of N−acetyl−(2−0−methylrosine)−oxytocin (ACME-OXT), an inhibitor of oxytocin receptors, prevented the disruptive effect of intrahippocampal OXT injections on heroin self-administration. It is concluded that limbic-mesolimbic brain structures have an essential role in the expression of the disruptive action of OXT on heroin self-administration. It appears that OXT-ergic binding sites mediate the effects of OXT.

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.

Effects of endogenous hyperprolactinaemia on opiate-induced behavioral changes in rats

Endogenous hyperprolactinaemia, as induced by pituitary homografts under the kidney capsule, was followed by an inhibition of heroin self-administration in rats. This effect was mimicked by intracerebroventricular (i.c.v.) injection of rat prolactin (PRL) or peripheral administration of a hyperprolactinaemia-inducing drug, domperidone. I.c.v. injection of anti-PRL serum totally abolished the effect of hyperprolactinaemia on heroin self-administration behavior and facilitated it in rats with normal plasma PRL levels. The development of tolerance to morphine was facilitated in hyperprolactinaemic animals or in rats injected i.c.v. with rat PRL. This effect was abolished in hyperprolactinaemic animals by i.c.v. injection of anti-PRL serum. Furthermore, rats with normal plasma PRL levels showed an inhibited development of tolerance to morphine after i.c.v. injection of anti-PRL serum. Morphine-induced analgesia appeared to be potentiated in hyperprolactinaemic rats tested in the hot-plate test. It is concluded that endogenous hyperprolactinaemia can affect opiate-induced behavioral changes in rats, possibly through central mechanisms involving opioid transmission.

Reinstatement of heroin and cocaine self-administration behavior in the rat by intracerebral application of morphine in the ventral tegmental area

In rats trained to self-administer heroin or cocaine intravenously, non-contingent priming injections of heroin or cocaine, respectively, reinstated responding after a period of extinction. In rats similarly trained to self-administer heroin or cocaine intravenously, morphine sulphate was applied centrally to sites in the ventral tegmental area (VTA), the periventricular grey (PVG) and the caudate nucleus following a period of extinction. Self-administration behavior was reinstated by morphine application to sites in the region of the VTA, but not to other sites, in both heroin and cocaine-trained animals. This priming effect of morphine was blocked or attenuated by prior administration of naltrexone, given intraperitoneally. Morphine in the VTA is known to activate mesolimbic dopamine neurons, suggesting that dopamine activity in this system may underline the priming effects of both opiates and stimulants. Furthermore, the fact that the mesolimbic system is implicated in the positive motivational actions of both drug groups, suggests that morphine reinstates drug-taking behavior in these animals by activating appetitive motivational systems of the brain.

Conditioned and unconditioned drug effects in relapse to opiate and stimulant drug self-administration

1. 1. Humans and laboratory animals given access to opiate and stimulant drugs frequently become compulsive users of these drugs, and often, in spite of prolonged periods of abstinence, persist in drug-seeking behavior and relapse to drug-taking. Evidence suggests that such drugs act on positive appetitive systems of the brain to maintain drugtaking and that, in the absence of drugs, stimuli previously associated with the drug state might acquire the ability to arouse motivational states similar to those activated by the drugs themselves. 2. 2. In rats previously trained to self-administer cocaine or heroin intravenously, noncontingent ‘priming’ intravenous infusions of cocaine or heroin lead to reinstatement of drugtaking behavior. Priming infusions of pharmacologically related drugs and drugs with similar stimulus properties also reinstate responding. 3. 3. Application of morphine to the cell body region of dopaminergic neurons of the ventral tegmental area (VTA), a site known to support morphine self-administration, reinstates both heroin and cocaine self-administration behavior. Reinstatement is blocked by pretreatment with naltrexone. Morphine applied to several other brain areas rich in opiate receptors does not reinstate the behavior. 4. 4. Application of morphine to the VTA, a site known to support conditioned place preferences as well as self-administration, causes increased locomotion that is naloxone reversible. This locomotor activity shows sensitization upon repeated administration; an effect that is specific to the environment in which morphine is administered. Conditioned increases in activity are observed in the same environment. Neither conditioning nor sensitization develops when animals are pretreated with pimozide. 5. 5. These findings support the view that, opiates and stimulants are administered because of their effects on positive appetitive systems of the brain and that, through conditioning, stimulus events that are associated with these positive appetitive actions of opiates and stimulants acquire the ability to elicit neural states that mimic aspects of those elicited by the drugs themselves. The arousal of these states may act to reinstate (facilitate relapse) and to maintain drug-taking behavior. This positive incentive account of compulsive drug-taking and relapse differs from the ‘drive-reduction’ view that continued drug use depends primarily on efforts to reduce or avoid symptoms of withdrawal, and that conditioned stimuli associated with drugs can initiate and maintain drug-taking behavior through the elicitation of withdrawal-like, drug-opposing, conditioned responses.

Effects of passive immunization against morphine on heroin self-administration

Antimorphine antibodies produced in Rhesus monkeys immunized with morphine-6-hemisuccinate-BSA were passively administered to recipient monkeys trained to self-administer heroin and cocaine. Following antibody administration, changes in heroin self-administration behavior were observed which were similar to those achieved with low doses of naloxone. Both manipulations increased heroin self-administration without affecting cocaine responding.