Rationale and objectives: Repeated exposure to many drugs of abuse results in a progressive and enduring enhancement in the motor stimulant effect elicited by a subsequent drug challenge. This phenomenon, termed behavioral sensitization, is thought to underlie certain aspects of drug addiction. Behavioral sensitization is the consequence of drug-induced neuroadaptive changes in a circuit involving dopaminergic and glutamatergic interconnections between the ventral tegmental area, nucleus accumbens, prefrontal cortex and amygdala. Methods: The literature was critically reviewed in an effort to discern the relative roles of glutamate and dopamine transmission in the induction and expression of sensitization to amphetamine, cocaine and µ-opioids. In addition, the literature was reviewed to evaluate distinctions between these drugs in the involvement of the relevant brain nuclei listed above. Results: The common substrates between sensitizing drugs are glutamate transmission, especially at the NMDA receptor, and an action in the ventral tegmental area. In contrast, a role for dopamine is only clearly seen in amphetamine sensitization and critical involvement of nuclei outside the ventral tegmental area is found for cocaine and morphine. While enhanced dopamine transmission is associated with sensitization by all three drugs, a role for glutamate is clearly identified only with cocaine sensitization. Accordingly, glutamatergic cortical and allocortical brain regions such as the prefrontal cortex appear more critical for cocaine sensitization. Conclusions: The distinctions between drugs in the induction and expression of sensitization indicate that behavioral sensitization can arise from multiple neuroadaptations in multiple brain nuclei. This is not only the result of distinct molecular targets for the drugs, but may also include a differential involvement of learned associations. It is postulated that the relatively more robust pharmacological capacity of amphetamine to release dopamine may induce a form of sensitization that is more dependent on adaptations in mesoaccumbens dopamine transmission compared with cocaine and morphine sensitization.

Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies.

even less so. It was therefore impossible for the functionally minded neuro­ scientist to design and execute experiments taking this heterogeneity into consideration. Even pharmacological studies with these peptides were difficult to interpret in a physiological framework. In 1982, thanks mainly to the recombinant DNA techniques, we learned that all these peptides belong to three genetically distinct peptide families, as we describe below. We now know a great deal more about their anatomy, and we are beginning to clarify their biosynthetic pathways. Suddenly, we can think in terms of circuits rather than in "humors" or in black boxes. In our study offunction, we can no longer ignore the multiple systems, any more than the student of monoamines can ignore differences between dopaminergic and noradrenergic systems. Less clear, but equally critical, is the issue of multiple opioid receptors. Unquestionably, the heterogeneity exists. What remains to be established is whether each of the three families of opioids has its own receptor, or whether a given family can interact with more than one SUbtype, and each receptor subtype with more than one family. More critical to physiology is whether

Endogenous Opioids: Biology and Function

http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Anxiety%20and%20Decision%20Making/Koob%2008%20Neuron%20Brain%20Stress%20Systems%20in%20Addiction.pdf

A Role for Brain Stress Systems in Addiction

Recently, much attention has been given to the problem of drug delivery through the cell-membrane in order to treat and manage several diseases. The discovery of cell penetrating peptides (CPPs) represents a major breakthrough for the transport of large-cargo molecules that may be useful in clinical applications. CPPs are rich in basic amino acids such as arginine and lysine and are able to translocate over membranes and gain access to the cell interior. They can deliver large-cargo molecules, such as oligonucleotides, into cells. Endocytosis and direct penetration have been suggested as the two major uptake mechanisms, a subject still under debate. Unresolved questions include the detailed molecular uptake mechanism(s), reasons for cell toxicity, and the delivery efficiency of CPPs for different cargoes. Here, we give a review focused on uptake mechanisms used by CPPs for membrane translocation and certain experimental factors that affect the mechanism(s).

https://downloads.hindawi.com/archive/2011/414729.pdf

Mechanisms of Cellular Uptake of Cell-Penetrating Peptides

Cocaine regulates the transcription factor CREB (adenosine 3′,5′-monophosphate response element binding protein) in rat nucleus accumbens, a brain region that is important for addiction Overexpression of CREB in this region decreases the rewarding effects of cocaine and makes low doses of the drug aversive Conversely, overexpression of a dominant-negative mutant CREB increases the rewarding effects of cocaine Altered transcription of dynorphin likely contributes to these effects: Its expression is increased by overexpression of CREB and decreased by overexpression of mutant CREB Moreover, blockade of κ opioid receptors (on which dynorphin acts) antagonizes the negative effect of CREB on cocaine reward These results identify an intracellular cascade—culminating in gene expression—through which exposure to cocaine modifies subsequent responsiveness to the drug

https://science.sciencemag.org/content/sci/282/5397/2272.full.pdf

Regulation of Cocaine Reward by CREB

In the guinea pig ileum myenteric plexus--longitudinal muscle preparation, dynorphin-(1--13) and the prototypical kappa agonist ethylketocyclazocine had equally poor sensitivity to naloxone antagonism and showed selective cross protection in receptor inactivation experiments with the alkylating antagonist beta-chlornaltrexamine. In binding assays with membranes from guinea pig brain, ethylketocyclazocine and dynorphin-(1--13) amide were more potent in displacing tritium-labeled ethylketocyclazocine than in displacing typical mu and delta opioid receptor ligands. In the two preparations studied, the dynorphin receptor appears to be the same as the kappa opioid receptor.

http://science.sciencemag.org/content/sci/215/4531/413.full.pdf

Dynorphin is a specific endogenous ligand of the kappa opioid receptor.

Substance P-like immunoreactivity in nerves associated with the vascular system of guinea-pigs. J.B. Furness, R.E. Papka, N.G. Della, M. Costa and R.L. Eskay, Neuroscience, 7 (1982) 447-459. All major blood vessels studied had an extensive network of axons containing substance-P like immunoreactivity. Very dense substance-P networks were found around the large elastic arteries close to the heart and in the arteries of the splanchnic bed. Significantly, arteries of the CNS were supplied with substance-P containing axons! The substance-P in blood vessels was depleted by treatment with capsaicin, indicating its origin from dorsal root ganglion cells.

Dynorphin is a specific endogenous ligand of the κ opioid receptor : Science, 215 (1982) 413–415

We describe nonpeptide opioids found in extracts of beef hypothalamus and adrenal, which are recognized by antisera raised against morphine. Four have been purified to homogeneity. One is morphine. The structures of the other three have not been determined yet. None of them are derived from morphine or normorphine after extraction from the tissues. It is not known whether the opiates described here are of endogenous or exogenous origin.

https://www.pnas.org/content/pnas/82/15/5203.full.pdf

Morphine and other opiates from beef brain and adrenal

Multiple opioid receptors criteria for identification and classification

Opioid receptors on guinea pig brain membranes were alkylated by the naltrexone analogue beta-chlornaltrexamine. Binding of the prototypical mu and kappa ligands, [3H]dihydromorphine and [3H]ethylketocyclazocine, was more readily affected by the reagent than was binding of the delta ligand, 3H-labeled [D-Ala2, D-Leu5]enkephalin. Treatment of membranes with beta-chlornaltrexamine in the presence of dynorphin resulted in significant protection of [3H]ethylketocyclazocine binding sites, without protection of [3H]dihydromorphine or 3H-labeled [D-Ala2, D-Leu5]enkephalin sites. Similarly, [D-Ala2, D-Leu5]enkephalin and sufentanil selectively protected binding sites for 3H-labeled [D-Ala2, D-Leu5]enkephalin and [3H]dihydromorphine, respectively. Scatchard analysis of [3H]ethylketocyclazocine binding to untreated membranes suggested two types of binding site with 40-fold difference in affinities. Membranes treated with beta-chlornaltrexamine in the presence of dynorphin retained about 40% of the high-affinity sites and lost the low-affinity sites. Selective protection of sites with high affinity for dynorphin and ethylketocyclazocine was confirmed in competition binding assays. These results strongly suggest that the three types of opioid receptor are not interconvertible and provide further evidence that the endogenous peptide dynorphin is a highly selective ligand of the kappa opioid receptor.

Iain F. James

Papers

Dynorphin is a specific endogenous ligand of the kappa opioid receptor.

Dynorphin is a specific endogenous ligand of the κ opioid receptor : Science, 215 (1982) 413–415

Morphine and other opiates from beef brain and adrenal

Multiple opioid receptors criteria for identification and classification

Preparation of brain membranes containing a single type of opioid receptor highly selective for dynorphin.