Subsequent Amphetamine Challenge Research Articles

Increased in vivo [ 11C]raclopride binding to brain dopamine receptors in amphetamine-treated rats

The hypothesis that repeated daily doses of amphetamine increases the number of available dopamine D 2 receptors in vivo in rat striatum, and may enhance the response to subsequent amphetamine challenge doses, was examined. The in vivo binding potentials of [ 11C]raclopride, a D 2 receptor antagonist, were determined in male CD-1 rats under five conditions: (1) drug-naïve with saline challenge, (2) drug naïve with 5 mg/kg amphetamine challenge, (3) amphetamine-dosed (five daily repeated s.c. doses of 5 mg/kg amphetamine) and saline challenge, (4) amphetamine-dosed and amphetamine challenge, and (5) saline treated (five daily repeated s.c. doses) and saline challenged. Radiotracer studies in amphetamine-dosed animals were done after a 10-day drug free interval. In the amphetamine-dosed group the baseline [ 11C]raclopride binding was increased by 63% compared to saline-treated controls. The response to an amphetamine challenge, evidenced by a reduction of [ 11C]raclopride binding, was doubled in amphetamine-dosed animals (40%) compared to drug-naïve controls (20%). These results support increased baseline in vivo dopamine D 2 receptor antagonist radioligand binding after repeated amphetamine administration in rats.

The amphetamine sensitization model of schizophrenia: relevance beyond psychotic symptoms?

A sensitized dopamine system may be linked to the genesis of psychotic symptoms in schizophrenia. Following withdrawal from amphetamine exposures, psychotic-like traits have been robustly demonstrated, but the presence of cognitive/mnemonic deficits remains uncertain. Adult male Lewis and Fischer rats, differing in cognitive performance, were exposed intermittently to escalating doses of amphetamine over 5 weeks. This was effective in producing behavioral sensitization to a subsequent amphetamine challenge. Following 27 days of drug withdrawal, the animals were assessed in Pavlovian conditioning, object recognition, and spatial working memory. In addition, prepulse inhibition (PPI), spontaneous motor activity, and anxiety-like behavior were measured. Amphetamine pretreatment induced behavioral sensitization in both rat strains similarly. Working memory was enhanced in Fischer but not Lewis rats following withdrawal. Spontaneous novel object preference was enhanced in sensitized Fischer rats, but was impaired in sensitized Lewis rats, thus effectively reversing the strain difference in non-sensitized controls. In contrast, Pavlovian fear conditioning remained unaffected and so were anxiety-like behavior, open field activity, and PPI. The face validity of the amphetamine withdrawal model for cognitive deficits was limited to the object recognition memory impairment observed in sensitized Lewis rats. Yet, the possibility that enhancing dopaminergic neurotransmission may facilitate object recognition and spatial working memory performance was demonstrated in sensitized Fischer rats. Identification of the mechanisms underlying such strain-dependent effects would be instrumental in the further specifications of the construct validity, and therefore the limitations and potential of the amphetamine sensitization model of schizophrenia.

Altered extracellular levels of DOPAC and HVA in the rat nucleus accumbens shell in response to sub-chronic nandrolone administration and a subsequent amphetamine challenge

Associated with acts of violence and polydrug use, abuse of anabolic androgenic steroids (AAS) is an increasing problem in society. The aim of the present study was to elucidate whether sub-chronic treatment with the AAS nandrolone decanoate affects dopamine release and dopamine metabolism in the rat nucleus accumbens shell, before and after an amphetamine challenge. Male Sprague–Dawley rats received daily i.m. injections of nandrolone decanoate (15 mg/kg) or vehicle for 14 days. On day 15, the animals were anaesthetized and a microdialysis probe was implanted into the nucleus accumbens shell. Extracellular fluid was collected 1 h before and 3 h after a single amphetamine injection (5 mg/kg). The samples were then analyzed regarding the content of dopamine, and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using HPLC with electrochemical detection. Two weeks of nandrolone decanoate administration caused a significant decrease of the basal DOPAC and HVA levels, which remained low during the first hour following the amphetamine challenge. Dopamine levels did not differ significantly between groups, neither after the nandrolone pre-treatment nor the amphetamine challenge. In conclusion, these novel findings indicate that AAS alter the metabolism of dopamine in a brain region involved in the development of drug dependence.

Retinoid X Receptor and NUR77 modulate amphetamine‐induced locomotor activity

Amphetamine (AMPH) is a drug of abuse that modulates dopamine neurotransmission in the central nervous system. We recently showed that Nur77 expression is modulated by AMPH administration and that Retinoid X Receptor (RXR) ligands can modulate the effect of antipsychotic drugs. In the present study, we analyse the effect of HX531, a RXR antagonist, in wild type and Nur77 knockout mice in order to clarify the role of these transcription factors in AMPH-induced behaviors. We use the classic behavioral sensitization paradigm, which consists in a 5-day AMPH treatment followed by a 5-day washout period. Sensitization is evidenced with a subsequent AMPH challenge on day 11. Ambulatory movements are assessed in a flex field apparatus for a period of 2 h. AMPH induces a progressive increase (sensitization) in the locomotor activity of wild type and Nur77-deficient mice. The RXR antagonist reduces AMPH-induced locomotion, whereas it remains inactive in Nur77-deficient mice. The RXR antagonist also reduces basal locomotor activity of the mice and HX531 pre-treatment partially suppresses acute AMPH effect on ambulatory movements, again only in wild type mice. However, the locomotor sensitization observed following repeated exposure to AMPH is not modified by HX531. These results indicate that both RXR and Nur77 nuclear receptors (possibly as heterodimerization partners) are involved in AMPH-induced locomotor activity, but are not associated with the development of behavioral sensitization. Support contributed by the Canadian Institutes for Health Research (CIHR).

Long-term behavioral and neuronal cross-sensitization to amphetamine induced by repeated brief social defeat stress: Fos in the ventral tegmental area and amygdala

Repeated exposure to stress induces cross-sensitization to psychostimulants. The present study assessed functional neural activation during social defeat stress-induced sensitization to a subsequent amphetamine challenge. Social defeat stress was induced in intruder rats during short confrontations with an aggressive resident rat once every third day during the course of 10 days. Rats received d-amphetamine injections (1 mg/kg, i.p.) 17 or 70 days after the first social defeat stress exposure. Amphetamine administration induced a significantly higher frequency of locomotor activity in stressed animals than in handled control rats, which was still evident 2 months after the last social stress exposure. Immunohistochemistry for Fos-like proteins was used to detect activated neural profiles in the striatum, nucleus accumbens (NAc), prefrontal cortex, amygdala, and ventral tegmental area (VTA). Repeated social defeat stress significantly increased Fos-like immunoreactive (Fos-LI) labeling 17 days after the start of stress exposure in the prelimbic and infralimbic cortical regions, NAc shell and core, medial, central and basolateral amygdala, and VTA, which probably represented the expression of chronic Fos-related antigens. Amphetamine augmented stress-induced Fos-LI labeling 17 days after the first stress episode in the dorsal striatum, NAc core, and medial amygdala, reflecting a cross-sensitization of Fos response. Amphetamine challenge 70 days after social stress exposures revealed sensitized Fos-LI labeling in the VTA and the amygdala. These data suggest that episodes of repeated social stress induce a long-lasting neural change that leads to an augmented functional activation in the VTA and amygdala, which might represent a neurobiological substrate for long-lasting cross-sensitization of repeated social defeat stress with psychostimulant drugs.

Reductions in binding and functions of D 2 dopamine receptors in the rat ventral striatum during amphetamine sensitization

Rats receiving amphetamine (5 mg kg , i.p. once daily) for 14 continuous days develop behavioral sensitization to a subsequent amphetamine challenge (1 mg kg ) at withdrawal days 8 to 10. The present study was aimed at investigating whether there are changes in binding or functions of striatal D 2 dopamine receptors in amphetamine-sensitized rats. The results indicated that the Bmax value of D 2 receptors in the ventral striatum decreased 40% and 52% 7 and 10 days after amphetamine withdrawal, respectively, without changes in their binding affinities ( Kd). During this withdrawal period, the D 2 3 receptor agonist-induced (a) locomotor activation (bromocriptine, 5 mg kg , i.p. or quinpirole, 1 mg kg , i.p.) and (b) inhibition of forskolin-enhanced adenylyl cyclase activity (bromocriptine, 50 or 150 μM) in the ventral striatum were both suppressed as compared with saline controls. The decreases in D 2 receptor function were unrelated to the coupled G-proteins, since none of the Gαi-3, Gαo or Gαq in the ventral striatum exhibited quantitative differences between control and amphetamine sensitized rats. Collectively, these results demonstrate that intermittent amphetamine administration for a period of 14 days leads to diminished D 2 receptor expression and functions in the ventral striatum at late withdrawal periods. The decrease of D 2 receptors might reflect cellular mechanisms underlying the expression of amphetamine sensitization.

Repeated administration of MK-801 produces sensitization to its own locomotor stimulant effects but blocks sensitization to amphetamine

Repeated amphetamine administration produced behavioral sensitization to subsequent amphetamine challenge. The development of sensitization was blocked by coadministration of the N-methyl- d-aspartate (NMDA) antagonist MK-801. Conditioned locomotion, as revealed by saline challenge, was also blocked by MK-801, suggesting that behavioral sensitization and conditioned locomotion may share a requirement for NMDA receptor stimulation. Repeated MK-801 administration produced behavioral sensitization to MK-801 but not amphetamine challenge, suggesting that MK-801 itself produces sensitization through a different mechanism than amphetamine.

Coping and the stress-induced potentiation of stimulant stereotypy in the rat.

It has been shown that stressed rats display increased stereotypy in response to a subsequent amphetamine challenge. Evidence is presented showing that stress potentiates cocaine stereotypy as well. These effects of stress were found to be particular to stress that could not be controlled in that rats receiving an identical amount of stress from footshock, but allowed to control its duration, displayed no more stereotypy than did nonstressed rats. These findings have implications for the role of stress and coping in amphetamine and cocaine psychoses, endogenous psychoses, and some forms of schizophrenia.