Intra-VTA CART 55-102 reduces the locomotor effect of systemic cocaine in rats: An isobolographic analysis

Abstract

CART (cocaine-and amphetamine-regulated transcript) peptides appear to be mediators or modulators of psychostimulant drugs. An interesting result in the nucleus accumbens has been that injection of CART peptide has no effect by itself on locomotor activity, but it reduces the locomotor activity induced by cocaine or amphetamine. However, in the ventral tegmental area (VTA), injections of CART peptide have been shown to increase locomotor activity, although to a lesser degree (Kimmel et al. 2000). This study was carried out to clarify the interaction of intra-VTA CART 55-102 and systemic cocaine on locomotor activity. The CART-cocaine interaction has been examined using the rigorous isobolographic approach. This type of analysis permits an assessment of additivity, subadditivity, or synergism of two substances. By measuring locomotor activity and using a range of doses of CART peptide and cocaine, both alone and together, with different dosing strategies, clear evidence of subadditivity was found. CART reduced the locomotor activating effects of systemic cocaine, especially at higher doses of CART. These results imply that intra-VTA CART is not simply acting in the same manner as cocaine, and is likely to oppose the action of cocaine. This has implications for the physiological significance of CART-DA (dopamine) interactions and for medications development.

Cocaine- and Amphetamine-Regulated Transcript Peptide Plays a Role in the Manifestation of Depression: Social Isolation and Olfactory Bulbectomy Models Reveal Unifying Principles

“…Scale bar ¼ 200 mm. (Vaarmann and Kask, 2001;Choi et al, 2003;Yang et al, 2004;Hunter et al, 2006;Jaworski et al, 2007;Ma et al, 2007), and it is possible that antidepressant action of CART may be mediated via some of these neurotransmitters.…”

“…CART may modulate affective and anxiety behaviors (Stanek, 2006) and exert an augmenting effect in the treatment of depression because it acts as a putative and potential neurotransmitter/cotransmitter that is also involved in psychostimulant action (Jaworski et al, 2003;Jones and Kuhar, 2006). Preliminary results suggest that, CART directly controls the expression of several important neurotransmitters, which are instrumental in processing neuropsychological behaviors (Vaarmann and Kask, 2001;Yang et al, 2004;Jaworski et al, 2007). Ma et al (2007) have suggested that an increase in 5-hydroxytryptamine (5-HT) may contribute to the antidepressant-like effect of CART.…”

Injection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens reduces cocaine self-administration in rats

“…Weak psychostimulant-related effects are seen after injections of CART peptide into the VTA [ 17,22 ]. Intra-NAcc injections of CART alone have no effect on locomotion, but inhibit locomotion produced by systemic injections of amphetamine [ 21 ] and cocaine [ 18 ].…”

Kinin B1 receptor gene ablation affects hypothalamic CART productionb

“…In the VTA in particular, the CART peptide seems to act as a potent stimulator of locomotor activity and conditioned place preference (Jaworski et al , 2003(Jaworski et al , , 2007, a form of Pavlovian conditioning also elicited by addictive drugs (Tzschentke , 1998 ). It is thought that the behavioral effects of CART activity in the VTA occur by CART directly stimulating dopaminergic neurons or indirectly un-inhibiting gamma-amino-butyric-acid-ergic interneurons .…”