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Previous studies suggest that behavioral consequences of heroin treatment depend on the drug history of the animals and that cholinergic neurotransmission is involved in both behavioral and motor sensitization induced by heroin and other drugs of abuse. Immunohistochemistry, using a recently developed antiserum, specific for choline acetyl-transferase of the common type (cChAT), was applied to four different groups of rats, differing in drug regimens. Two groups of rats were submitted to the same schedule of heroin sensitization and then challenged for vehicle or heroin before sacrifice, obtaining two distinct groups, namely heroin-vehicle (HV) and heroin-heroin (HH). The same challenge was applied to another group of rats, previously submitted to a treatment with vehicle, obtaining other two groups, vehicle-vehicle (VV) and vehicle-heroin (VH), respectively. The number of cChAT-positive neurons is significantly increased (p<0.05) in the diagonal band nuclei (with a consequent increase of cChAT positive fibers in the dentate gyrus) and notably, even not significantly (p>0.05), increased in the nucleus accumbens core of heroin-sensitized rats (HV, HH). Instead, acute heroin treatment significantly increase (p<0.05) the number of cChAT-positive cells in the nucleus accumbens shell of both heroin-naïve (VH) and heroin-sensitized (HH) rats. In heroin-sensitized rats (HV, HH), moreover, staining intensity of cChAT-positive fibers is significantly increased in the dorsal striatum, and basolateral amygdala (p<0.05). Unlikely, cChAT positive fibers in the central amygdala are significantly increased (p<0.05) by acute heroin treatments (VH, HH). The increase of cholinergic fibers in the dentate gyrus of the heroin sensitized rats (HV, HH) seems accompanied by a evident reduction in calretinin immunoreactive neurons in the same area. Our results, in a small group of animals, support the view that cholinergic mechanisms are intimately associated with the development of addictive phenotype. Furthermore, they suggest that cholinergic system is differentially engaged, following different heroin treatments., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Immunohistochemical distribution patterns of neuropeptide FF (NPFF) and neuropeptide tyrosine (NPY) were studied in the brain of rats submitted to two different protocols of heroin treatment. In drug-naive rats, acutely injected heroin significantly depleted NPFF-immunoreactive material within the neurons of the nucleus of solitary tract (NTS), significantly decreased the density of NPFF-immunoreactive nerve fibers within the median eminence, pituitary stalk, and neurohypophysis, and markedly increased NPY-immunoreactive neurons and nerve fibers in the thalamic paraventricular nucleus and bed nucleus of stria terminalis. In drug-sensitized rats, heroin significantly increased the number and immunostaining intensity of the NPFF-immunoreactive neurons within the NTS and induced minor changes in the NPFF-immunoreactive nerve fiber network of the median eminence, pituitary stalk, and neurohypophysis and a relatively minor increase in NPY neurons in the thalamic paraventricular nucleus and bed nucleus of stria terminalis. These heroin-induced changes suggest that NPFF is involved in regulating the effects of the heroin injection and in the mechanisms underlying behavioral sensitization. They also add further support to the key role of NPY in any conditions tending to change the animal homeostasis.

Using c-Fos protein immunohistochemistry we previously demonstrated various sites of activation in the rat forebrain according to the animal's drug history. This study originates from a more detailed evaluation ex-post of the same specimens. A discrete number of c-Fos protein immunoreactive nuclei could be observed in some circumventricular organs, including the vascular organ of terminal lamina (OVLT) and subfornical organ (SFO) and in the nucleus of solitary tract near the area postrema, but only in specimens from sensitized rats. We therefore suggest that repeated drug injections activate the normally low drug metabolizing enzyme activity in the circumventricular organs thus implicating these organs in the complex mechanisms underlying behavioral sensitization.

Immunohistochemistry was used to map the induction of c-Fos protein in the forebrain of rats treated with heroin. Acute injection of heroin to drug-naive rats caused significant induction of c-Fos protein in the nucleus accumbens shell, whereas the same dose of heroin given to drug-sensitized rats significantly increased c-Fos immunoreactivity in the dorsomedial caudate-putamen. These results show that the heroin-induced pattern of c-Fos protein in the rat striatum differs according to the rat's drug history. These findings may represent a neural correlate of the motor components of heroin sensitization.

The behavioral consequences of acute heroin challenge (0.5 mg/kg, s.c.) were measured in rats previously submitted to repeated administration of increasing doses of the synthetic cannabinoid receptor agonist, R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate (WIN55212.2) (first day 2 mg/kg, second day 4 mg/kg, third day 8 mg/kg) or vehicle. Heroin administration to rats pretreated with vehicle produced catalepsy. The same dose of heroin in WIN55212.2-pretreated rats was followed by a marked increase of locomotor activity with stereotyped and non-stereotyped behaviors. These effects were blocked by the opioid receptor antagonist, naloxone. These findings indicate that pretreatment with WIN55212.2 produces cross-sensitization to heroin in the rat. These changes might reflect long-lasting changes of receptor population or transcriptional mechanisms in the mesolimbic system.

There is evidence of similarities and interactions between central opioid and cannabinoid system with reference to drug reinforcement and abuse. Here we demonstrate that repeated injection of heroin produces behavioral sensitization towards administration of the synthetic cannabinoid receptor agonist WIN55212.2 in the rat. These effects were blocked by both the cannabinoid antagonist SR141716A and the opioid antagonist naloxone. These findings suggest that repeated exposure to heroin produces neuroadaptative changes in brain circuits that contribute to mediate the behavioral consequences of acute administration of WIN55212.2. The present results expand our knowledge on the interactions between central opioid and cannabinoid systems with respect to drug abuse.

The aim of the study was to measure the changes in cerebral energy metabolism and c-fos mRNA expression following challenge with heroin in drug-naive rats and in animals previously sensitized to the drug. Acute heroin administration to drug naive-rats produced a generalized metabolic depression. In contrast, challenge with heroin in drug-sensitized rats produced selective metabolic increases in structures belonging to the basal ganglia. These changes were accompanied by increased c-fos mRNA expression in the caudate-putamen nucleus. These results demonstrate that the process of sensitization to heroin is coupled to functional changes that are confined to the subcortical motor circuits of the basal ganglia.

The effects of the active ingredient of Cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), and of the highly addictive drug heroin on in vivo dopamine transmission in the nucleus accumbens were compared in Sprague-Dawley rats by brain microdialysis. Delta9-THC and heroin increased extracellular dopamine concentrations selectively in the shell of the nucleus accumbens; these effects were mimicked by the synthetic cannabinoid agonist WIN55212-2. SR141716A, an antagonist of central cannabinoid receptors, prevented the effects of Delta9-THC but not those of heroin. Naloxone, a generic opioid antagonist, administered systemically, or naloxonazine, an antagonist of micro1 opioid receptors, infused into the ventral tegmentum, prevented the action of cannabinoids and heroin on dopamine transmission. Thus, Delta9-THC and heroin exert similar effects on mesolimbic dopamine transmission through a common mu1 opioid receptor mechanism located in the ventral mesencephalic tegmentum.