Morphine-seeking Behavior Research Articles

Effect of Inhibition of the Central Nucleus of the Amygdala and Drug Experience on the Regions Underlying Footshock-Induced Reinstatement of Morphine Seeking

This study assessed the effect of inhibition of the central nucleus of the amygdala (CeA) and drug experience on brain regions underlying footshock-induced reinstatement of morphine-seeking behaviour in rats. The difference in time spent in two chambers of a place preference apparatus was used to measure morphine-conditioned place preference. Fos was measured as a marker of neuronal activation in the ventral bed nucleus of the stria terminalis (BNSTv) and ventral tegmental area (VTA). Footshock was found to enhance Fos expression in the BNSTv regardless of drug experience. In the VTA, morphine and footshock had an interactive effect on the increase in Fos expression. Inhibition of the CeA decreased Fos expression in the BNSTv regardless of drug experience, whereas in the VTA this effect only occurred in morphine-treated rats. These results suggest that drug experience has no differential effect on the BNSTv however morphine produces footshock sensitization in the VTA. CeA inhibition modulates the footshock-induced activity of these regions of the brain and attenuates reinstatement of drug seeking behaviour.

The Nucleus Accumbens Core has a More Important Role in Resisting Reactivation of Extinguished Conditioned Place Preference in Morphine-addicted Rats

We investigated the roles of the core and shell subfields of the nucleus accumbens (NAc) in drug- or foot-shock-induced reactivation of extinguished conditioned place preference (CPP) in morphine-addicted rats. Rats were given electrolytic lesions to either the core or shell after CPP was established. After surgery, a reduction of CPP scores to morphine was observed in all groups. During the reacquisition of morphine-seeking behaviour, rats in the shell and sham lesion groups regained their CPP, while the CPP in core lesion rats remained severely impaired. Similarly, foot-shock-induced reactivation of CPP in the core lesion group was significantly lower than that of the shell and sham lesion groups, and there was no significant difference between these latter groups. Our results demonstrate that NAc core and shell lesions elicited dissociable effects on reactivation of extinguished CPP in rats, suggesting that the NAc core might play a more important role in resisting reactivation of extinguished CPP in morphine-addicted rats.

A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement vs Opiate-Seeking Behavior

The adenosine A(2A) receptor is specifically enriched in the medium spiny neurons that make up the 'indirect' output pathway from the ventral striatum, a structure known to have a crucial, integrative role in processes such as reward, motivation, and drug-seeking behavior. In the present study we investigated the impact of adenosine A(2A) receptor deletion on behavioral responses to morphine in a number of reward-related paradigms. The acute, rewarding effects of morphine were evaluated using the conditioned place preference paradigm. Operant self-administration of morphine on both fixed and progressive ratio schedules as well as cue-induced drug-seeking was assessed. In addition, the acute locomotor response to morphine as well as sensitization to morphine was evaluated. Decreased morphine self-administration and breakpoint in A(2A) knockout mice was observed. These data support a decrease in motivation to consume the drug, perhaps reflecting diminished rewarding effects of morphine in A(2A) knockout mice. In support of this finding, a place preference to morphine was not observed in A(2A) knockout mice but was present in wild-type mice. In contrast, robust cue-induced morphine-seeking behavior was exhibited by both A(2A) knockout and wild-type mice after a period of withdrawal. The acute locomotor response to morphine in the A(2A) knockout was similar to wild-type mice, yet A(2A) knockout mice did not display tolerance to chronic morphine under the present paradigm. Both genotypes display locomotor sensitization to morphine, implying a lack of a role for the A(2A) receptor in the drug-induced plasticity necessary for the development or expression of sensitization. Collectively, these data suggest a differential role for adenosine A(2A) receptors in opiate reinforcement compared to opiate-seeking.

Selegiline modifies the extinction of responding following morphine self-administration, but does not alter cue-induced reinstatement, reacquisition of morphine reinforcement, or precipitated withdrawal

Selegiline is an irreversible inhibitor of monoamine oxidase (MAO) with psychostimulant and neuroprotective effects which can prevent decreases in dopamine efflux that follow opiate withdrawal. The present study evaluated effects of selegiline treatment on morphine-seeking behavior and morphine reinforcement in Wistar rats ( n = 26). In additional animals ( n = 30), the ability of single doses of selegiline to modify naloxone-precipitated withdrawal was determined. After pretreatment with noncontingent morphine to establish opiate dependence, rats acquired self-administration of intravenous morphine. Daily intravenous treatment with saline or 2.0 mg kg −1 doses of selegiline was then initiated and continued over 14 days during extinction, reinstatement, and reacquisition of morphine self-administration. To reduce the potential for psychostimulant effects, selegiline was administered approximately 1 h following self-administration, extinction, or reinstatement sessions. In some animals ( n = 23), effects of saline or selegiline administration on locomotor activity were determined following extinction sessions. Daily selegiline treatment decreased the number of ratios completed and increased response latency during extinction, without modifying these measures during reinstatement or reacquisition of morphine self-administration. Chronic selegiline treatment increased locomotor activity recorded between 4 and 7 h after selegiline administration on day 7 of extinction, but otherwise did not alter locomotor activity. Pretreatment with single, 2.0 mg kg −1 doses of selegiline did not modify naloxone-precipitated withdrawal. In conclusion, pretreatment with selegiline produced only a small decrease in responding during extinction of morphine self-administration and did not modify cue-induced reinstatement of morphine-seeking behavior, reacquisition or morphine reinforcement, or precipitated withdrawal.

Limbic acetylcholine turnover rates correlated with rat morphine-seeking behaviors

Acetylcholine (ACh) turnover rates were measured in fourteen brain regions of rats intravenously self-administering morphine and in yoked-morphine and yoked-vehicle infused littermates to identify cholinergic neuronal pathways potentially involved in opiate reinforcement processes. Rats receiving chronic passive administration of morphine had increased ACh turnover rates in the frontal cortex and diagonal band and decreased rates in the medial septum. The significant changes in animals self-administering the drug were prominent in limbic regions with increases in the frontal cortex and decreases in the pyriform cortex, nucleus accumbens, amygdala and ventral tegmental area. Some components of opiate reinforcement may be mediated by increases in the activity of cholinergic ventral pallidal and diagonal band fibers innervating the frontal cortex and by decreases in activity of cholinergic fibers innervating the ventral tegmental area. These data and turnover rates for dopamine, norepinephrine, serotonin, aspartate, glutamate and gamma-aminobutyric acid previously determined in similarly treated animals are consistent with two neuronal circuits that may be involved in opiate seeking behaviors and opiate reinforcement processes.

Brain neurotransmitter turnover correlated with morphine-seeking behavior of rats

Neurochemical substrates of intravenous opiate self-administration were investigated in rats using littermate controls for vehicle and passive morphine infusion The rates of turnover of the putative neurotransmitters, dopamine, norepinephrine, serotonin, gamma-aminobutyric acid, aspartate and glutamate were concurrently measured in eleven brain regions of rats intravenously self-administering morphine and in yoked-morphine or yoked-vehicle infused littermates. The passive infusion of morphine resulted in significant changes in the rates of turnover of the biogenic monoamine and amino acid neurotransmitters in six brain regions with the caudate nucleus-putamen-globus pallidus showing the most changes. The contingent infusion of morphine resulted in changes in utilization rates that were generally greater in both magnitude and number than the effects of the drug itself. Twenty-nine significant changes were observed in the self-administering group with most changes occurring in limbic structures. The neurotransmitter turnover rate changes resulting from contingent administration suggest that the drug administration environment is an important factor that should be considered in studies of interactions between drugs and neuronal systems.

Conditional fear, anxiety, and morphine-seeking behavior.

Two Cebus albifrons monkeys were given discriminative operant conditioning with visual stimuli, with Sidman avoidance and punishment as the components. The instrumental response was an unelicited increase in skin conductance. Both animals had surgically implanted catheters for automatic injection of morphine into the heart. After autonomic conditioning, the animals were given the opportunity to self-administer the morphine by touching the primate press panel that displayed the visual stimuli. One contingency-free segment per session was used for morphine injection, while the contingencies remained in force during the other segments. One of the monkeys made significantly more skin conductance responses during avoidance than during punishment, and this monkey received ten times as many shocks in punishment. This monkey also made more responses overall and had a much higher heart rate than the other animal. The other monkey did not differentiate significantly autonomically and received equal numbers of shocks in avoidance and punishment. The monkey that showed autonomic differentiation made significantly (and increasingly) more panel-presses during punishment than during avoidance. The other animal showed hardly any tendency at all to panel-press.

Resistance of morphine-seeking behaviour in rats to pharmacological and behavioural 'treatments'.

OPIATE addicts may be treated by the controlled prescription of an opioid drug such as methadone1,2; such ‘replacement’ therapy aims to meet the addict's need for his drug and so to reduce self-administration. Treatment with antagonists is an alternative; this treatment is designed to diminish the efficacy of any self-administered opiate by ‘blockading’ the receptors with substances such as naloxone or naltrexone3. A third method of treatment involves behavioural aversion procedures, which aim to suppress the actions culminating in drug-taking by associating them with unpleasant stimuli, such as electric shocks or apomorphine-induced nausea. It is extremely difficult to assess the efficacy of these methods in human addicts, and laboratory tests in dependent animals offer one means of comparision. We describe here tests of three conceptually different procedures, each reflecting one of the approaches described above. The dependence behaviour was oral self-administration of morphine solutions (morphine HCl 0.5 mg ml−1) by rats which had previously learned to drink such solutions in preference to water4.

Persistence of relapse of morphine-seeking behavior in rats: the relative role of certain biological variables.

The theory that narcotic-induced protracted biological changes are responsible for relapse of opiate-reinforced behavior was examined in the rat. Groups of rats were conditioned to prefer a distinctive environment by pairing it with morphine doses from 1-200 mg/kg, and were retested for persistence of this preference after a 3-week abstinence period. They were then observed for protracted signs such as sensitivity to naloxone, tolerance to morphine analgesia, hyperaggression, or changes in endocrine activity. Acquisition and relapse of the preference, as well as long-term tolerance, were dose related. None of the purported protracted signs showed any consistent relationship to the tendency to relapse. However, relapse correlated significantly with original acquisition scores in all relapsing groups. The results suggest that original conditioning factors, rather than protracted changes, are responsible for the observed relapse.

Morphine-based secondary reinforcement: Effects of different doses of naloxone

The effects of different doses of naloxone on morphine-based secondary reinforcement were studied in rats. On the first day a neutral stimulus (buzzer) was repeatedly paired with intravenous morphine infusions. Drug treatments consisted of Low, Medium, or High Naloxone doses, or No Naloxone. The next day the ability of the buzzer and saline infusion to support lever pressing was tested. High Naloxone blocked, and Low Naloxone partially blocked this morphine-based secondary reinforcement. Subjects in the Medium Naloxone group demonstrated an apparent avoidance of the lever, suggesting that the morphine infusions were aversive at this dosage level of naloxone. The secondary reinforcement tests reliably predicted behavior on a subsequent test for acquisition of morphine-seeking behavior.

The influence of early lead exposure on morphine reinforcement in the rat

The effect of early lead burdens on morphine-seeking behavior was investigated in the albino rat. Several concentrations of lead acetate were administered to nursing mothers starting at 0, 7 or 14 days after birth, or provided directly to the pups in the drinking water after weaning, so that lead exposure was continuous for 3 successive weeks in each group. The off-spring were later tested for acquisition and maintenance of a goal-box preference based on morphine reinforcement. High lead burdens imposed before the second week of age resulted in a mild but significantly greater incidence of morphine-seeking responses, as well as retarded growth, compared with placebo-treated controls or animals treated at a later age. The data support the proposition that lead, introduced at a critical stage of development via the lactating mother, increases the potency of morphine reinforcement as a result of changes in cerebral dopaminergic activity. This effect may be mediated directly by the high lead burdens in the offspring, or indirectly by interfering with the mother's nursing capacity.

Depression of Morphine-seeking Behaviour by Dopamine Inhibition

MANY of the direct effects of morphine have been attributed to serotonergic mechanisms1 or to the catecholamines2,3. The role of brain monoamines in morphine's capacity as a behavioural reinforcer has only recently been explored4,5, and it has been found that the catecholamine depletor α-methyl-p-tyrosine (AMT) blocks behavioural reinforcement by morphine. Our own wbrk, started before these reports appeared, strongly suggests that dopamine is implicated in this blockade. To study morphine reward we adopted the technique of Beach6 which uses the acquisition and retention of a goal box preference and thereby minimises non-specific effects by experimental drugs on performance.