Ca_v1.2 and Ca_v1.3 L-type Ca²⁺ channels (LTCCs) are believed to underlie Ca²⁺ currents in brain, pancreatic β cells, and the cardiovascular system. In the CNS, neuronal LTCCs control excitation-transcription coupling and neuronal plasticity. However, the pharmacotherapeutic implications of CNS LTCC modulation are difficult to study because LTCC modulators cause card iovascular (activators and blockers) and neurotoxic (activators) effects. We selectively eliminated high dihydropyridine (DHP) sensitivity from Ca_v1.2 α1 subunits (Ca_v1.2DHP–/–) without affecting function and expression. This allowed separation of the DHP effects of Ca_v1.2 from those of Ca_v1.3 and other LTCCs. DHP effects on pancreatic β cell LTCC currents, insulin secretion, cardiac inotropy, and arterial smooth muscle contractility were lost in Ca_v1.2DHP–/– mice, which rules out a direct role of Ca_v1.3 for these physiological processes. Using Ca_v1.2DHP–/– mice, we established DHPs as mood-modifying agents: LTCC activator–induced neurotoxicity was abolished and disclosed a depression-like behavioral effect without affecting spontaneous locomotor activity. LTCC activator BayK 8644 (BayK) activated only a specific set of brain areas. In the ventral striatum, BayK-induced release of glutamate and 5-HT, but not dopamine and noradrenaline, was abolished. This animal model provides a useful tool to elucidate whether Ca_v1.3-selective channel modulation represents a novel pharmacological approach to modify CNS function without major peripheral effects.