Neuroendocrine alterations in a high-dose, extended-access rat self-administration model of escalating cocaine use.

One approach for studying cocaine addiction has been to permit escalating patterns of self-administration (SA) by rats by prolonging daily drug availability. Rats provided long access (LgA) to high cocaine doses, but not rats provided shorter cocaine access (ShA), progressively escalate their cocaine intake and display characteristics of human addiction. The purpose of the present study was to investigate the effects of 14 days of ShA or LgA, high-dose cocaine SA on plasma corticosterone (CORT), prolactin (PRL), and related mRNAs. Acutely, cocaine SA increased plasma CORT and reduced plasma PRL levels. SA training produced circadian increases in CORT that appeared to occur in anticipation of cocaine availability. With repeated LgA, high-dose SA, the daily CORT area under the curve (AUC) progressively decreased, apparently due to tolerance to cocaine's effects on CORT and a reduction in basal CORT levels. In contrast, the daily CORT AUC in ShA rats increased across testing despite constant rates of SA. When measured 12 days after SA testing, pro-opioimelanocortin and glucocorticoid receptor mRNA levels in the anterior pituitary were lower in LgA rats than in ShA rats. The effects of SA on PRL remained constant across SA testing in LgA rats, but increased in duration in ShA rats. Anterior pituitary dopamine D2 receptor mRNA levels were lower in LgA rats than in ShA rats. These findings indicate that the transition to escalating patterns of SA may be associated with altered levels of hormones and gene expression within neuroendocrine systems. Such changes may underlie the onset of human addictive disease.

Nicotine addiction: insights from recent animal studies.

RATIONALE: Recent preclinical behavioral and neurobiological research has characterized important behavioral features and has identified neurobiological substrates that may underlie nicotine reinforcement and addiction. OBJECTIVE: To examine recent advances on nicotine exposure in preclinical models, from three perspectives: (a) the chronopharmacokinetics of nicotine, (b) behavioral studies on nicotine reinforcement, withdrawal, and reinstatement/relapse, and (c) effects of nicotine on neurobiological substrates after repeated exposure. RESULTS: Preclinical studies can be used to operationally model selected aspects of nicotine reinforcement, withdrawal, and reinstatement or relapse. These may be used to investigate the functional in vivo consequences of acute and long-term changes in neuronal acetylcholine receptor populations that follow nicotine exposure. Behavioral studies focusing on distinct stages of nicotine exposure (e.g., active reinforcement vs. cessation or reinstatement) may also be used in parallel with studies on dopaminergic function, a proposed substrate for the reinforcing effects of nicotine, and of opioid receptor function, a possible site of neuroadaptations secondary to nicotine exposure. CONCLUSIONS: While no single current animal model may capture the experience of human smoking or nicotine addiction, increasingly, separate animal models are capturing the full spectrum of behavioral and neurobiological dimensions of this complex condition.

Neurochemical changes and neurotoxic effects of an acute treatment with sydnocarb, a novel psychostimulant: comparison with D-amphetamine.

Sydnocarb [(phenylisopropyl)N-phenylcarbamoylsydnonimine; SYD] was introduced to clinical practice in Russia as a psychostimulant drug used for the treatment of asthenia and apathy, which accompany schizophrenia and manic depression. It has been described as a psychostimulant with addiction liability and toxicity less than amphetamine (AMPH). The precise cellular mechanisms by which sydnocarb elicits its psychostimulant effect are still unclear. At present its neurochemical and neurotoxic effects are compared to those of AMPH in the striatum, the main input structure of the basal ganglia. The expression of c-fos protein in striatal neurons was much more increased after a single injection of D-AMPH (5 mg/kg) than after an equimolar concentration of SYD (23.8 mg/kg) in both the anterior and the posterior part of the striatum. Using in situ hybridization on striatal slices, we observed that AMPH increased the striatal levels of preprodynorphin (PPDYN) mRNAs in both parts of the striatum, while SYD did not affect basal levels of PPDYN mRNAs. Furthermore, AMPH and SYD increased striatal preprotachykinin (PPT-A) and preproenkephalin (PPE) mRNA levels. The effects of AMPH and SYD on PPT-A-mRNA levels were similar. A differential effect of AMPH and SYD was observed only on the PPE-mRNA levels measured in the anterior striatum where SYD increased these levels more than AMPH. The acute neurotoxicity of these two psychostimulants was analyzed by measuring their effects on the parameters of oxidative stress, such as nitric oxide (NO) generation, as well as specific indices of lipid peroxidation (i.e., thiobarbituric acid reactive substances; TBARS), while, on the other hand, the alpha-tocopherol level was taken as an index of antioxidant defense processes. Measuring generation of NO directly by electron paramagnetic resonance, it was observed that AMPH shows a more pronounced increase in comparison to SYD, in the striatum and in cortex. TBARS levels in the striatum and cortex were significantly less enhanced than AMPH after a single injection of SYD. Similarly, the alpha-tocopherol level was decreased only by AMPH in the striatum, and neither AMPH nor SYD had any effect in the cortex. Results show that a single injection of a high dose of AMPH is able to induce several neurotoxic effects. The study also demonstrates that SYD has mild neurochemical effects as well as fewer neurotoxic properties than AMPH.

Regulation of striatal neuropeptide mRNAs: effects of the 5-HT(2) antagonist SR46349B in adult rats with a neonatal 6-hydroxydopamine lesion.

The intrastriatal injection of 6-hydroxydopamine (6-OHDA) in newborn rats produces a marked striatal dopamine (DA) depletion, accompanied by a serotonin (5-HT) hyperinnervation and an up-regulation of 5-HT receptors. The aim of the present study was to investigate whether the increase in 5-HT(2) receptors could compensate for some of the DA lesion-induced effects, such as the increase in striatal preproenkephalin (PPE) and the decrease in preprotachykinin A (PPT-A) mRNA levels. Three months after the DA lesion, the effect of the selective 5-HT(2) antagonist SR46349B was investigated by a subacute treatment (10 mg/kg, IP, twice per day for 3.5 days). In sham-operated rats, the blockade of 5-HT(2) receptors decreased PPE mRNA levels in the striatum and, by contrast, had no effect on PPT-A mRNA levels. In rats with a unilateral neonatal DA lesion, SR46349B had no more effect on PPE mRNA levels in the intact striatum and was unable to modify the lesion induced-increase in PPE mRNA. The decrease in PPT-A mRNA levels induced by the neonatal DA lesion was not changed after SR46349B treatment in the posterior part of the lesioned striatum. Our results suggest that SR46349B indirectly decreases PPE mRNA levels in striatopallidal neurons in intact animals through a desinhibition of DA neuron activity. This is further evidenced by the lack of PPE mRNA changes in the DA lesioned striatum despite the up-regulation of 5-HT(2) receptor transmission induced in this model. Finally, the absence of any effect of 5-HT(2) antagonist on the expression of PPT-A mRNA in intact animals is discussed. The precise role of 5-HT(2) receptor on PPT-A mRNA biosynthesis after a neonatal lesion should be clarified by further experiments using 5-HT(2) agonists.

Mu-, delta- and kappa-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer's disease patients.

The putative role of the opioid system in cognitive and memory functions prompted us to search for possible changes in the cohort of the major opioid receptors, mu, delta and kappa, in Alzheimer's disease. The present study examines alterations in opioid receptor levels by quantitative autoradiography. These experiments were carried out on coronal sections of postmortem brains from Alzheimer's disease patients and from aged-matched, dementia-free individuals. Brain sections were labeled with the tritiated forms of mu-, delta- and kappa-opioid ligands; DAMGO ([D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin), DPDPE ([D-Pen2,5]-enkephalin) and bremazocine (in the presence of mu- and delta-ligands), respectively. Nonspecific binding was determined in the presence of naloxone (10 microM). Brain areas analyzed were caudate, putamen, amygdaloid complex, hippocampal formation and various cerebral and cerebellar cortices. Image analyses of autoradiographs show, that in comparison to the same areas in control brain, statistically significant reductions in mu-opioid receptor binding occur in the subiculum and hippocampus of Alzheimer's disease brains. Binding of delta-opioid receptors is also decreased in the amygdaloid complex and ventral putamen of Alzheimer's disease brains. In contrast, large increases of kappa-opioid receptor binding are found in the dorsal and ventral putamen as well as in the cerebellar cortex of Alzheimer's disease brains. Levels of mu- delta- and kappa-opioid receptor binding are unaltered in the caudate, parahippocampal gyrus and occipito-temporal gyrus. These results may suggest an involvement of the endogenous opioid system in some of the multitude of effects that accompany this dementia.

Inducibility of c-Fos protein in visuo-motor system and limbic structures after acute and repeated administration of nicotine in the rat.

To identify neuroanatomical substrates affected by nicotine, we have studied its effects after acute and repeated administration through the c-Fos protein inducibility in various brain structures. Ninety minutes after acute nicotine (0.35 mg/kg, s.c.) the number of c-Fos-like immunoreactive nuclei was consistently increased in visuo-motor structures such as the superior colliculus, the medial terminal nucleus of accessory optic tract, and the nucleus of the optic tract. The anteroventral and lateroposterior thalamic nuclei, connected with the retina and involved in limbic processing, showed a c-Fos induction. c-Fos was preferentially induced in terminal fields of neurons of the ventral tegmental area such as the nucleus accumbens, the central amygdala, the lateral habenula, the lateral septum, as well as the cingulate, medial prefrontal, orbital and piriform cortices. In chronically treated rats (0.35 mg/kg s.c., 3 x day for 14 days), the last nicotine injection given on the 15th day was still able to induce 90 minutes later c-Fos protein in visuo-motor, retino-limbic, subcortical, and cortical limbic structures. Moreover, this chronic treatment produced an additional recruitment of c-Fos-positive nuclei in the cingulate cortex, the core and the ventral shell of the nucleus accumbens. c-Fos induction after nicotine differs from that reported after other addictive drugs in terms of pattern and chronic inducibility, indicating that different mechanisms are involved for maintaining this transcription factor. In addition to a preferential sensitivity of mesolimbic dopaminergic neurons to nicotine, activation of visuo-limbic and limbic regions could be relevant for understanding some context-dependent and addictive behaviors produced by nicotine.

Repeated administration of cocaine, nicotine and ethanol: effects on preprodynorphin, preprotachykinin A and preproenkephalin mRNA expression in the dorsal and the ventral striatum of the rat.

It is established that dopamine (DA) controls the expression of preprodynorphin (PPDYN), preprotachykinin A (PPT-A) and preproenkephalin (PPE) mRNAs in striatal structures. Since cocaine, nicotine and ethanol enhance extracellular DA concentration, we have examined whether their repeated administration produced common changes in the expression of these mRNAs. Quantitative in situ hybridization histochemistry was performed in rats 2 h after a final challenge subsequent to repeated subcutaneous injections (3 X a day) of cocaine (12.5 mg/kg), nicotine (0.4 mg/kg) for 14 days and ethanol (160 mg/kg) for 7 days. In the dorsal striatum, cocaine produced simultaneous PPDYN and PPT-A mRNA increases without PPE mRNA change whereas nicotine and ethanol produced no modification. After cocaine, PPDYN mRNA was preferentially increased in striatal patch compartment. In the nucleus accumbens, the effects were more complex. In cocaine-treated rats, we measured concomitant increases of PPDYN and PPE mRNA in the rostral pole, an isolated induction of PPT-A mRNA signals in the core without any change in the two shell subregions: the cone and the ventral shell. In contrast, after nicotine and ethanol, the ventral shell was the only accumbal subregion which showed a neuropeptide mRNA alteration, nicotine leading to decreased PPDYN mRNA and ethanol to increased PPT-A mRNA contents. The neuropeptide regulation after chronic treatment with these psychostimulant drugs does not strictly conform to a general DA control scheme in the dorsal and the ventral striatum. The cocaine effects can be clearly distinguished from those of nicotine and ethanol in terms of neuropeptide regulation and striatal subregions affected.