Prolonged deficits in presynaptic serotonin function following withdrawal from chronic cocaine exposure as revealed by 5-HTP-induced head-twitch response in mice

Abstract

Recent in vivo microdialysis studies have indicated that presynaptic deficits occur in brain 5-HT neurochemistry during cocaine withdrawal. The purpose of the present study was to utilize the head-twitch response (HTR) produced by 5-hydroxytryptophan (5-HTP) to investigate the dose- and time-response effects of this deficit. The HTR is considered to be a sensitive model for activation of central postsynaptic 5-HT2A receptors in rodents. Thus, different groups of mice were injected with cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg/kg, i.p.) for 7 or 13 days. During HTR testing, at 24 h following last injection, the treated mice received either 1) no cocaine; 2) their corresponding daily dose as challenge injection; or 3) a 10 mg/kg challenge dose. In a second series of experiments, extended abstinence studies were performed under the conditions of experimental protocols 1 and 2 for both 7- and 13-day cocaine (0, 0.5 and 5 mg/kg, twice daily) exposure regimens at 24, 48, 72 and 96 h following last cocaine injection. In protocol 3, the effects of a 10 mg/kg challenge dose of cocaine were studied following prolonged withdrawal from chronic cocaine exposure (0, 0.5, 5 and 10 mg/kg, twice daily for 7 and 13 days) at 24, 96 and 240 h abstinence. In experimental protocol 1 at 24 h abstinence in the 7 day exposure group, only lower doses of cocaine (0.5-2.5 mg/kg) significantly attenuated the 5-HTP-induced HTR. The deficit in 0.5 mg/kg group persisted up to 72 h abstinence. Although in the 13 day cocaine exposure groups (experimental paradigm 1) mean HTRs were generally reduced, they however failed to attain statistical significance throughout the 96 h abstinence. In protocol 2 very low challenge doses of cocaine (0.1-0.5 mg/kg) in their corresponding pretreatment groups significantly reduced the behavior at diverse abstinence intervals in both 7- and 13-day exposure regimens relative to their chronically vehicle-treated controls which had received a vehicle challenge injection during HTR testing. Unlike small doses of cocaine, larger challenge doses (5-10 mg/kg) of the stimulant potentiated the HTR score at various abstinence periods. However, the degree of the potentiations are considerably less than the ability of acute cocaine administration in enhancing the 5-HTP-induced HTR. The 10 mg/kg challenge injection in experimental protocol 3 at 24 h abstinence in the 7-day exposed mice attenuated the 5-HTP-induced HTR in 0.5, 5 and 10 mg/kg cocaine-treated groups relative to their chronic vehicle-treated controls receiving a 10 mg/kg challenge cocaine injection. The deficit in chronic 10 mg/kg cocaine-exposed mice persisted up to 240 h postcocaine abstinence. On the other hand, in the 13-day regimen, the challenge 10 mg/kg dose exhibited significant potentiations at 24 h and at 96 h for 5 and 0.5 mg/kg chronic cocaine doses respectively, but it also produced significant deficits in 0.5 and 10 mg/kg chronic doses of cocaine at 240 h abstinence. Overall, the present results suggest that enduring deficits occur in presyna...

Psychostimulant withdrawal as an inducing condition in animal models of depression

“…Similarly, withdrawal from a high dose of cocaine was associated with decreased D 1 receptor binding in the striatum (Macedo et al, 2004), while dopamine D 2 receptor binding was upregulated. As the dopamine D 1 receptor is positively coupled to cAMP production, whereas the D 2 receptor is negatively coupled, the observed decrease in D 1 receptors (and increase in D 2 ) may represent a functional adaptation to decrease cAMP production in the ventral striatum, consistent with reduced dopamine stimulation of cAMP in the striatum of recently Baumann and Rothman (1996) g Darmani et al (1997) h King et al (1999) i Weiss et al (1992) j Persico et al (1993) k Paulson and Robinson (1996) (2000) w Schmidt et al (2001) x Zhang et al (1996) y Lu et al (1997) z Crespo et al (2002) aa Loftis and Janowsky (2000) ab Lu et al (2003) ac Loftis and Janowsky (2000) ad Crespo et al (2002) ae Loftis and Janowsky (2002) af Dworkin et al (1995) ag Lynch and Leonard (1978b) ah Suzuki et al (2000) ai Mohila and Onn (2005) aj Loftis and Janowsky (2000) ak al Persico et al (1998) am Mutschler et al (2000) abstinent human methamphetamine abusers (Tong et al, 2003). Levels of PKA were higher in the nucleus accumbens after withdrawal from cocaine self-administration .…”

“…The list of serotonergic deficits in MDD is extensive (Graeff et al, 1996;Mann, 1999), and includes both pre-and postsynaptic modifications, as well as regional decreases in neurotransmission. Corresponding changes in pre- (Baumann et al, 1995;Darmani et al, 1997) and post-synaptic (Baumann and Rothman, 1998) serotonergic activity have also been observed during cocaine withdrawal in rodents, as well as decreases in serotonergic neurotransmission in the nucleus accumbens (Parsons et al, 1996;Parsons et al, 1995). To date, relatively few studies have examined the role of norepinephrine function during psychostimulant withdrawal (Herman et al, 1971;Paulson et al, 1991), although it was recently demonstrated that cocaine withdrawal in rats is associated with desensitization of postsynaptic a 2 -adrenoceptors coupled to GH secretion (Baumann et al, 2004).…”

Contribution of Serotonin (5-Hydroxytryptamine; 5-HT) 5-HT2 Receptor Subtypes to the Hyperlocomotor Effects of Cocaine: Acute and Chronic Pharmacological Analyses

“…In addition, cotreatment with neither DOI nor SR 46349B during the repeated cocaine regimen effectively altered the course of sensitization, suggesting that the role for 5-HT 2A R in acquisition of cocaine sensitization is minimal. This may be attributed to the rapid desensitization and down-regulation of 5-HT 2A R that can occur following repeated administration of either 5-HT 2A R agonists or antagonists (for review, see Gray and Roth, 2001) and, potentially, cocaine (e.g., Darmani et al, 1997; but see Baumann and Rothman, 1998). Thus, although the 5-HT 2A R appears to be integral for the enhancement of hyperactivity induced by acute administration of cocaine, the functional role of the 5-HT 2A R appears to be altered with repeated cocaine administration.…”

Augmented Accumbal Serotonin Levels Decrease the Preference for a Morphine Associated Environment During Withdrawal

“…To test the idea that brain 5-HT systems were altered in the chronically morphine treated rats relative to the acute morphine rats, we injected animals with 5-HTP (50 mg/kg) and measured head shake behavior, an indirect measure of brain 5-HT function (Bedard and Pycock 1977;Darmani et al 1997), for 1 hr. Acutely treated morphine rats showed significantly more head shakes than chronically treated morphine rats (19.2 Ϯ 2.7 vs. 5.1 Ϯ 0.36, F (1,10) ϭ 25.7, p Ͻ .01).…”