Neurobiological Effects

Binge/Intoxication Stage

Opioid drugs are profoundly reinforcing in animal models, independent of pain or discomfort. Opioid drugs, such as heroin, are readily self-administered intravenously by mice, rats, monkeys, and humans. If provided limited access, rats will maintain stable levels of daily drug intake without any major signs of physical dependence, similar to “chipping” in humans. This heroin self-administration pattern typically involves rapid responding at the beginning of a test session, followed by more regular interinjection intervals. This model has been used to study the neurobiological basis of heroin reward, independent of the confounds of dependence or negative reinforcement as elaborated in the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10), or the compulsive-like state now described within the category of Substance Use Disorders of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Decreases in the dose of heroin available to the animal change the pattern of self-administration. The animals will decrease their interinjection interval and increase the number of injections. The animals will also attempt to compensate for opioid antagonism (for example, when they also receive an injection of naloxone) by increasing the amount of drug injected.

Neural elements in the region of the ventral tegmental area and nucleus accumbens are responsible for the activational and reinforcing properties of opioids, with both dopamine-dependent and -independent mechanisms (Figure 5.11). Direct intracerebral administration of opioid antagonists into the nucleus accumbens and ventral tegmental area block the locomotor-activating effects and intravenous self-administration of opioids in rats. Such studies indicate that opioid receptors in both the ventral tegmental area and nucleus accumbens are important for the acute reinforcing actions of opioids. Strong evidence of the role of the ventral tegmental area in the acute reinforcing effects of opioids in nondependent rats has also been found in place conditioning studies

Intracranial self-administration studies, in which opioids are directly self-administered into the brain, showed a significant overlap with the sites identified with opioid receptor antagonists. The lateral hypothalamus, nucleus accumbens, amygdala, periaqueductal gray, and ventral tegmental area all support morphine self-administration. Animals will perform an operant task, such as lever pressing, to have morphine delivered directly into these brain regions.

Further studies of the neurocircuitry involved in opioid reward revealed a dopamine-independent role for the nucleus accumbens and a dopamine-dependent role. Researchers found that dopamine receptor blockade with dopamine antagonists and dopamine denervation in the nucleus accumbens eliminated cocaine and amphetamine self-administration but spared heroin and morphine self-administration. The initiation of heroin self-administration was unaltered by administration of large doses of the dopamine antagonist haloperidol into the midbrain dopamine system, including the nucleus accumbens, prefrontal cortex, caudate putamen, and amygdala. Both observations support the hypothesis that opioid reward is mediated by dopamine-dependent and -independent inputs to the nucleus accumbens (Figure 5.11).

FIGURE 5.9 Schematic representation of μ, δ, and κ1 receptor mRNA expression and binding in the rat central nervous system. The receptor densities, shown as different color hues, are within a receptor type and do not represent absolute receptor capacity. Therefore, dense binding of one receptor type is not equivalent in terms of receptor number to dense binding of another receptor type. This is particularly true for the κ1 receptor binding sites, which represent only 10% of the total opioid receptor binding sites in the rat brain. These rat parasagittal sections are designed, however, to transmit qualitatively the correspondence between receptor mRNA expression and receptor binding distribution. This figure demonstrates that each opioid receptor mRNA has a unique distribution which correlates well with the known μ, δ, and κ1 receptor binding distributions. μ Receptor Distribution. A high correlation between μ receptor mRNA expression and binding is observed in the striatal clusters and patches of the nucleus accumbens and caudate putamen, diagonal band of Broca, globus pallidus and ventral pallidum, bed nucleus of the stria terminalis, most thalamic nuclei, medial and cortical amygdala, mammillary nuclei, presubiculum, interpeduncular nucleus, median raphe, raphe magnus, parabrachial nucleus, locus coeruleus, nucleus ambiguus, and nucleus of the solitary tract. Differences in μ receptor mRNA and binding distributions are observed in regions such as the neocortex, olfactory bulb, superior colliculus, spinal trigeminal nucleus, and spinal cord which might be a consequence of receptor transport to presynaptic terminals. δ Receptor Distribution. A high correlation between δ receptor mRNA expression and binding is observed in such regions as the anterior olfactory nucleus, neocortex, caudate putamen, nucleus accumbens, olfactory tubercle, diagonal band of Broca, globus pallidus and ventral pallidum, septal nuclei, amygdala, and pontine nuclei, suggesting local receptor synthesis. Regions of high δ receptor mRNA expression and comparatively low receptor binding include the internal granular layer of the olfactory bulb and ventromedial nucleus of the hypothalamus. The apparent discrepancy between δ receptor mRNA expression and δ receptor binding in several brainstem nuclei and in the cerebellum is, in part, due to the increased sensitivity of in situ hybridization methods and high levels of nonspecific binding observed with δ-selective ligands. Differences in distributions indicative of receptor transport are observed in the substantia gelatinosa of the spinal cord, external plexiform layer of the olfactory bulb, and the superficial layer of the superior colliculus. κ Receptor Distribution. A high degree of correlation between κ1 receptor mRNA expression and binding is observed in regions such as the nucleus accumbens, caudate putamen, olfactory tubercle, bed nucleus of the stria terminalis, medial preoptic area, paraventricular nucleus, supraoptic nucleus, dorsomedial and ventromedial hypothalamus, amygdala, midline thalamic nuclei, periaqueductal gray, raphe nuclei, parabrachial nucleus, locus coeruleus, spinal trigeminal nucleus, and the nucleus of the solitary tract. Differences in κ1 receptor binding and mRNA distribution in the substantia nigra pars compacta, ventral tegmental area, and neural lobe of the pituitary might be due to receptor transport.

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