Dissociation of corticotropin-releasing factor receptor subtype involvement in sensitivity to locomotor effects of methamphetamine and cocaine

Abstract

Rationale: Enhanced sensitivity to the euphoric and locomotor-activating effects of psychostimulants may influence an individual's predisposition to drug abuse and addiction. While drug-induced behaviors are mediated by the actions of several neurotransmitter systems, past research revealed that the corticotropin-releasing factor (CRF) system is important in driving the acute locomotor response to psychostimulants.

Objectives: We previously reported that genetic deletion of the CRF type-2 receptor (CRF-R2), but not the CRF type-1 receptor (CRF-R1) dampened the acute locomotor stimulant response to methamphetamine (1 mg/kg). These results contrasted with previous studies implicating CRF-R1 in the locomotor effects of psychostimulants. Since the majority of previous studies focused on cocaine, rather than methamphetamine, we set out to test the hypothesis that these drugs differentially engage CRF-R1 and CRF-R2.

Methods: We expanded our earlier findings by first replicating our previous experiments at a higher dose of methamphetamine (2 mg/kg), and by assessing the effects of the CRF-R1-selective antagonist CP-376,395 (10 mg/kg) on methamphetamine-induced locomotor activity. Next, we used both genetic and pharmacological tools to examine the specific components of the CRF system underlying the acute locomotor response to cocaine (5-10 mg/kg).

Results: While genetic deletion of CRF-R2 dampened the locomotor response to methamphetamine (but not cocaine), genetic deletion and pharmacological blockade of CRF-R1 dampened the locomotor response to cocaine (but not methamphetamine).

Conclusions: These findings highlight the differential involvement of CRF receptors in acute sensitivity to two different stimulant drugs of abuse, providing an intriguing basis for the development of more targeted therapeutics for psychostimulant addiction.

Fig. 1

Genetic deletion or pharmacological blockade of CRF-R1 does not alter acute MA sensitivity. a Locomotor activity counts (mean+ SEM) from male and female CRF-R1 KO and WT mice following administration of saline on days 1–2, and 2 mg/kg MA on day 3 (n=5–10 per sex, per genotype). b Acute MA stimulation scores (day 3 activity minus day 2 activity; mean+SEM) from male and female CRF-R1 KO and WT mice. c Locomotor activity counts (mean+SEM) from male B6 mice following administration of vehicle followed by saline on days 1–2, and either vehicle or 10 mg/kg CP-376,395 (CP) followed by either saline or 2 mg/kg MA on day 3 (n=8 per group). d Acute MA stimulation scores (day 3 activity minus day 2 activity; mean+SEM) from male B6 mice

Fig. 2

Genetic deletion of CRF-R2 dampens acute MA sensitivity. a Locomotor activity counts (mean+SEM) from male and female CRFR2 KO and WT mice following administration of saline on days 1–2, and 2 mg/kg MA on day 3 (n=9–15 per sex, per genotype). b Acute MA stimulation scores (day 3 activity minus day 2 activity; mean+SEM) from male and female CRF-R2 KO and WT mice. Number sign indicates main effect of sex on day 1 (p<0.005); asterisk indicates main effect of genotype (p<0.05)

Fig. 3

Genetic deletion and pharmacological blockade of CRF-R1 dampens acute COC sensitivity. a Locomotor activity counts (mean+SEM) from male and female CRF-R1 KO and WT mice following administration of saline on days 1–2, and 5 mg/kg COC on day 3 (n=7–12 per sex, per genotype). b Acute COC stimulation scores (day 3 activity minus day 2 activity; mean+SEM) from male and female CRF-R1 KO and WT mice. c Locomotor activity counts (mean+SEM) from male B6 mice following administration of vehicle followed by saline on days 1–2, and either vehicle or 10 mg/kg CP- 376,395 (CP) followed by either saline or 5, 7.5, or 10 mg/kg COC on day 3 (n=7–11 per group). d Acute COC stimulation scores (day 3 activity minus day 2 activity; mean+SEM) from male B6 mice. Asterisk indicates main effect of genotype (p<0.05); number sign indicates main effect of sex (p<0.05); single dagger denotes significant difference between vehicle-COC and CP-COC groups (p<0.05); double dagger denotes significant difference between vehicle-COC and CP-COC groups (p<0.01)

Fig. 4

Genetic deletion of CRF-R2 does not alter acute COC sensitivity. a Locomotor activity counts (mean+SEM) from male and female CRF-R2 KO and WT mice following administration of saline on days 1–2, and 5 mg/kg COC on day 3 (n=10–11 per sex, per genotype). b Acute COC stimulation scores (day 3 activity minus day 2 activity; mean+SEM) from male and female CRF-R2 KO and WT mice